Review |
Therapeutic modulation of allergic airways disease with leukotriene receptor antagonists
From the Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, and 1Department of Respiratory Medicine, Ipswich Hospital, Ipswich, UK
 |
Summary |
|---|
 Top Summary IntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Although asthma is one of the most common chronic respiratory conditions, it often remains unrecognized and undertreated, while patients are often reluctant to comply with regular inhaled anti-inflammatory and bronchodilator therapy. Allergic rhinitis co-exists with asthma in as many as 40% of patients, and can be regarded as a continuum of the same inflammatory disease process. Corticosteroids are the ‘gold standard’ first-line treatment for both conditions, and have a significant impact upon underlying inflammation, symptoms and long-term outcome. Cysteinyl leukotrienes are potent airway inflammatory mediators, suggesting that treatment antagonizing their effects could play a role in disease management. In recent years, leukotriene receptor antagonists have provided a further therapeutic option in the management of allergic airways disease. These drugs are orally active, can be administered once daily, and provide a systemic approach to the management of patients with asthma and allergic rhinitis. We review the pharmacology of leukotriene receptor antagonists, their potential role in clinical practice in patients with allergic airways disease, and likely areas for further research.
|
Introduction |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Asthma is a common chronic heterogeneous condition that displays a complex and varied phenotypic picture. It can present in early childhood as well as adulthood, and varies markedly in severity, clinical course, disability and response to treatment. Despite a greater understanding of the underlying inflammatory and bronchospastic disease process, the worldwide prevalence of asthma is increasing in both developed and developing countries.1,2 Moreover, patients with fatal and near-fatal asthma often have modifiable risk factors such as inadequate or inappropriate therapy, and poor adherence to prescribed medication.3–5
The characteristic features of asthma are bronchial hyper-responsiveness following exposure to inhaled stimuli, inflammation throughout the entire bronchial tree, and variable, mostly reversible airflow obstruction (Figure 1).6 As a consequence of these hallmark physiological features, commonly reported episodic symptoms include non-productive cough, breathlessness, wheeze and chest tightness. Oral and inhaled treatments used in the management of asthma are therefore aimed at attenuating the effects of these integral and often overlapping components. Once symptoms have developed, treatment is usually indicated and can vary from intermittent use of short acting ß2-agonists to combinations of oral and inhaled medications.
|
Many asthmatics are atopic, with up to 40% demonstrating evidence of concomitant allergic rhinitis.7 Apart from the anatomical link between both conditions, asthma and allergic rhinitis share physiological and immunological features. This in turn has led interest into a more co-ordinated approach aimed at the treatment of the unified airway.8 Patients with active upper airway inflammation due to rhinitis often breathe through their mouth (usually normal only during exercise and speech), further exposing the lower airway to the adverse drying and cooling effects of repeated air flow. Furthermore, it is known that treatment of allergic rhinitis results in a commensurate improvement in parameters of asthma control.9–11
This evidence-based review highlights the pharmacological properties of leukotriene receptor antagonists (LTRAs), their role in the management of allergic airways disease, the results of recent randomized clinical trials surrounding their use, and how they compare to other asthma treatments. It also highlights areas where further research into their use is required. We performed a comprehensive literature search using Medline, CINAHL, Clinical Evidence, Cochrane library and Embase. The following key MeSH words were used in the search: asthma, allergic rhinitis, leukotriene, leukotriene receptor antagonist, beta-agonist, corticosteroid, inflammation, lung function. We selected and extracted recent articles (almost exclusively placebo-controlled randomized trials and meta-analyses) that we felt to be of relevance or interest to practising clinicians, and chose topics that we thought were of potential importance.
|
Cysteinyl leukotrienes |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Orally and nasally inhaled corticosteroids are the gold standard treatments of asthma and allergic rhinitis, respectively.12,13 Many patients, especially with both conditions, have concerns regarding the burden of corticosteroid to which they are exposed. Moreover, despite treatment with corticosteroids, suppression of inflammation is often incomplete and their effect upon cysteinyl leukotriene biosynthesis and release is limited.14–16
Cysteinyl leukotrienes are lipid mediators produced from an arachidonic acid precursor and fall into two main classes. Leukotriene B4 is a neutrophil chemoattractant, while the cysteinyl leukotrienes (C4, D4 and E4) are eosinophil chemoattractants. The cysteinyl leukotrienes are produced from the phospholipid bilayer by a series of enzymic steps involving the rate-limiting enzyme leukotriene C4 synthase (Figure 2). They exert their effects following activation of specific receptors located on cell membranes of pulmonary smooth muscle and macrophages. Cysteinyl leukotrienes produce an array of effects implicated in the pathogenesis of the asthmatic inflammatory process (Figure 2). Antagonizing their actions could thus play an important role in attenuating integral features of asthma pathophysiology. Pharmacologically, this can be achieved by drugs preventing their synthesis using a 5-lipoxygenase inhibitor (zileuton), or blocking specific cysteinyl leukotriene receptors using a leukotriene receptor antagonist (LTRA).
|
|
Leukotriene receptor antagonists: pharmacology and prescribing |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Two LTRAs are licensed for clinical use: montelukast and zafirlukast (Figure 3). Both are orally active, with the former used at a daily dose of 10 mg and the latter given as 20 mg twice daily (in adults); pranlukast, another LTRA, has not been licensed for use in the UK. Montelukast and zafirlukast share some pharmacokinetic properties including rapid oral absorption (3 h to peak plasma concentrations), near maximal plasma protein binding and after extensive hepatic biotransformation, excretion principally in bile. Their terminal half-lifes are 5 h and 10 h, respectively. Montelukast can be used in children from the age of 2 years and has been formulated as a chewable, pink, cherry flavoured tablet. Oral efficacy has the obvious advantages of avoiding the technical difficulties associated with, and dislike of, inhaled medication, especially in children, adolescents and the elderly.
|
These drugs are unique in that they demonstrate both bronchodilator and anti-inflammatory properties (albeit less than long-acting ß2-agonists and corticosteroids, respectively), suggesting that they may have an important dual action in the treatment of allergic airways disease (Figure 4). A further therapeutic benefit is that LTRAs are clinically active following single doses.17 Moreover, unlike long acting ß2-agonists, tolerance to their bronchoprotective effects has not been demonstrated.
|
As a class of drug, they are generally well tolerated, although adverse effects such as abdominal pain, rashes, headaches, angioedema, pulmonary eosinophilia and arthralgia have been reported. Due to lack of data, their use in pregnancy is not advised. Concerns have been raised regarding the development of Churg-Strauss syndrome (CSS) and administration of LTRAs. Many, although not all, of the documented cases of CSS have been in patients in whom concomitant LTRA treatment has permitted a reduction in dose of inhaled corticosteroid. This in turn suggests that latent CSS may have been unmasked by a reduction in anti-inflammatory therapy delivered to the lungs.18 However, LTRAs do in general demonstrate a favourable adverse effect profile in comparison to inhaled corticosteroids, as the latter demonstrates such effects in a dose-dependent fashion. For example, it is generally accepted that at orally inhaled beclomethasone doses (or equivalent) >800 µg/day, the dose-response curve for beneficial effects becomes flat, while that for systemic adverse effects becomes steep.19,20 Typical dose-dependant adverse sequelae include adrenal and growth suppression, and skin thinning and bruising, especially at high doses.19 The systemic bioactivity of intranasal corticosteroids at standard doses in terms of effects upon the hypothalamic-pituitary-adrenal axis is negligible.21 Troublesome local effects of orally inhaled corticosteroids include candidiasis and dysphonia, while nasally administered drug can cause dryness, irritation and occasionally septal perforation.
The exact positioning of LTRAs in the management of asthma has been the source of considerable debate over the past few years, often as a result of paucity of data. The following sections of this review article present an evidence-based update of different areas where LTRAs have had an expanding role in the management of allergic airways disease, and identify potential areas of future research.
|
Leukotriene receptor antagonists as monotherapy |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Accumulating evidence suggests that LTRAs are clinically inferior when used as monotherapy compared to a low dose of inhaled corticosteroid, and as a consequence, are not generally advocated for use in this manner. This comparison has been rigorously reviewed and evaluated elsewhere.22,23 For example, Ducharme performed a systematic review of randomized controlled trials examining the effects of LTRAs as monotherapy vs. daily doses of <450 µg beclomethasone or equivalent.23 Thirteen trials were examined that incorporated mild-to-moderate asthmatics. Patients treated with a LTRA alone were 60% more likely to have an exacerbation than those using an inhaled corticosteroid. The latter treatment also conferred significantly greater improvements upon measure of lung calibre. However, a role does exist for LTRAs as monotherapy in mild asthmatics with exercise-induced symptoms alone.24
|
Inhaled corticosteroids plus leukotriene receptor antagonists as second-line therapy |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Inhaled corticosteroids exert their effects by binding to cytoplasmic receptors, concentrated in airway epithelial and endothelial cells. Once bound, they act by increasing and decreasing transcription of a variety of anti-inflammatory and pro-inflammatory mediators, respectively. Although corticosteroids are potent anti-inflammatory agents, they have little or no impact on cysteinyl leukotriene synthesis or release,14–16 suggesting that add-on therapy with a LTRA may provide a more complete and complimentary role in asthma control. Many studies have evaluated the effects of concomitant treatment with LTRA plus inhaled corticosteroids.22,25 Indeed, beneficial effects have been observed with add-on LTRA on a multitude of outcome measures, including reduced rescue treatment requirement, symptoms, improved pulmonary function, fewer exacerbations and effects on surrogate inflammatory markers.22,25 For example, in a randomized double-blind, double-dummy study, Laviolette evaluated 642 symptomatic asthmatics with impaired lung function26 where montelukast 10 mg /day was added to 400 µg /day beclomethasone. Active treatment compared to placebo provided significant (p < 0.05) clinical benefit in terms of improving FEV1, asthma symptom scores and nocturnal awakenings.
Additive effects have also been demonstrated in patients receiving high-dose inhaled corticosteroids. Tamaoko evaluated 79 asthmatics who required at least 1500 µg /day of beclomethasone.27 Addition of zafirlukast 20 mg twice daily permitted a reduction in beclomethasone dose while maintaining asthma control. This in turn highlights the fact that LTRAs can exert a steroid-sparing effect, which is of particular importance when patients have concerns regarding potential effects of high inhaled corticosteroid doses. Another study28 examined the effects of montelukast 10 mg /day when added to a constant dose of budesonide (400–1600 µg /day) over a 16-week period. This multi-centre, double-blind, parallel group trial randomized 326 patients to receive montelukast and 313 to receive identical placebo; subjects were symptomatic despite inhaled corticosteroid treatment, and the mean FEV1 was 81% predicted in both groups. Individuals receiving active treatment experienced 35% fewer asthma exacerbation days with a 56% increase in asthma-free days compared to placebo. Thus, concomitant treatment with a LTRA plus inhaled corticosteroid confers benefit in patient orientated end-points such as fewer nocturnal awakenings and short-acting ß2-agonist use, in addition to a reduction in asthma exacerbations.
|
Leukotriene receptor antagonists versus long-acting ß2-agonists |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
In symptomatic patients using low-to-moderate doses of inhaled corticosteroids (step 3), British Thoracic Society (BTS) guidelines suggest adding a long-acting ß2-agonist, after checking compliance, inhaler technique and addressing trigger factors.12 However, several large studies29,30 have been published since the guidelines were disseminated, which have shown that in inhaled-corticosteroid-treated patients, concomitant therapy with a LTRA can provide similar efficacy in terms of exacerbation reduction to that for an add-on long-acting ß2-agonist. For example, 1490 chronic asthmatics uncontrolled on inhaled fluticasone 200 µg/day were randomized to receive add-on montelukast 10 mg/day or salmeterol 50 µg twice daily.29 After a year of treatment, 20.1% of patients in the montelukast group, compared with 19.1% in the salmeterol group, experienced an exacerbation of asthma, with a non-significant confidence interval between groups. However, salmeterol-treated patients had a significantly greater FEV1 and morning PEF (p
0.001), while the combination of fluticasone plus montelukast conferred greater reduction (p = 0.011) upon blood eosinophils than add-on salmeterol. Previous in vitro data have demonstrated that long-acting ß2-agonists can potentiate the anti-inflammatory effects of inhaled corticosteroids,31,32 although in the present study, no additional effect upon blood eosinophils was observed with salmeterol. This is in keeping with other studies in which no further beneficial effects upon surrogate inflammatory markers (i.e. in vivo) occurred with add-on long-acting ß2-agonist.33,34 In contrast, in a multicentre trial by Fish et al.,35 the addition of salmeterol 50 µg twice daily was superior to that of add-on montelukast 10 mg/day in uncontrolled asthmatics using inhaled corticosteroids. This was in terms of measures of lung calibre (the primary endpoint) and symptom scores. Similarly, in the multi-centre trial of Nelson et al.,36 adding salmeterol to fluticasone was superior to concomitant treatment with zafirlukast 20 mg /day. Indeed, the former treatment provided significantly greater improvement in pulmonary function, significantly greater relief of both daytime and night-time asthma symptoms and a significantly greater improvement in the Asthma Quality of Life Questionnaire, compared with oral zafirlukast. When evaluating the results of clinical trials, it is important to consider whether the primary end-point includes a ‘bronchodilator-sensitive’ parameter such as PEF or FEV1. This is especially important when head-to-head comparisons are made between LTRAs and long-acting ß2-agonists. Long-acting ß2-agonists are potent bronchodilators and exert an ‘airway-stabilizing’ effect on acute exposure to a bronchoconstrictor stimulus.37 As a consequence, it is of little surprise that when the primary outcome in a study is based on effects on relaxing bronchial smooth muscle, long-acting ß2-agonists fare significantly better than LTRAs (which are only weak bronchodilators). As demonstrated by studies by Bjermer29 and Ilowite,30 in patients using inhaled corticosteroids, add-on montelukast provides similar asthma control to that of add-on salmeterol when outcome measures such as exacerbations are evaluated, with montelukast conferring superiority in terms of effects upon surrogate inflammatory markers. Whether future updated guidelines will suggest that LTRAs should be given a more equal place with long-acting ß2-agonists at step 3 remains to be seen.
|
‘Triple therapy’ with leukotriene receptor antagonists, inhaled corticosteroids plus long-acting ß2-agonists |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Despite treatment with an inhaled corticosteroid plus long-acting ß2-agonist, many asthmatic patients remain symptomatic. Since inhaled corticosteroids have limited effects upon biosynthesis of cysteinyl leukotrienes,14–16 add-on therapy with a LTRA could therefore confer additional benefit in terms of attenuating endobronchial inflammation. However, very few trials have evaluated the effects of LTRAs along with combinations of inhaled and oral pharmacotherapy.
Robinson et al.38 evaluated whether LTRAs confer additional benefit in symptomatic asthmatics, despite inhaled corticosteroids plus additional second-line controller therapy. In a study evaluating 72 moderate-to-severe asthmatics maintained on inhaled corticosteroids and mostly taking long-acting ß2-agonists, the addition of montelukast 10 mg daily for 2 weeks conferred no significant improvement in terms of peak expiratory flow (PEF) and symptom scores. However, several limitations of this study were observed,39 in turn raising questions with regard to their negative findings. For example, no assessment was made of effects upon bronchial hyper-responsiveness or surrogate inflammatory biomarkers such as airway eosinophils. Moreover, no meaningful data upon exacerbations could be obtained, due to the relatively short duration of treatment. Since patients in the study were maximally bronchodilated (due to the effects of the long-acting ß2-agonist) no room for improvement in PEF (the primary endpoint in the study) could reasonably be expected from adding in montelukast.
In an attempt to address some of these concerns, another randomized placebo controlled crossover study evaluated the effects of add-on montelukast 10 mg /day in patients taking inhaled fluticasone 500 µg /day in combination with salmeterol. The addition of montelukast conferred additional beneficial effects upon several surrogate inflammatory biomarkers, in addition to attenuating bronchial hyper-responsiveness. Similar to the study by Robinson et al.,38 montelukast conferred no additional bronchodilator benefit in terms of PEF or FEV1. In other words, the long-acting ß2-agonist moiety would have sufficiently relaxed the airway smooth muscle, allowing no further improvement in airway calibre.
Thus, serial monitoring of PEF or FEV1 often allows no evaluation of the potential benefits of non-steroidal anti-inflammatory therapy such as LTRAs when patients are using regular long-acting ß2-agonists. This problem of determining clinical efficacy not only exists in clinical trials, but also in everyday life. Further prospective studies are therefore required to evaluate the effects of LTRAs in patients using combination inhalers in terms of more long-term outcome parameters such as exacerbations, markers of airway remodelling and quality of life, as well as inflammatory biomarkers, lung function and bronchial hyper-responsiveness.
|
Aspirin-sensitive asthma |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Aspirin-sensitive asthma has an uncertain prevalence, although it may exist in as many as 20% of all asthmatics.40 It is characterized by profound bronchoconstriction following aspirin ingestion, and is associated with rhinosinusitis, nasal polyposis and sometimes abdominal cramps. It is caused by aspirin and non-steroidal anti-inflammatory drugs that selectively inhibit cyclo-oxygenase-1. This in turn shunts arachidonic acid down the 5-lipoxygenase-activating protein pathway, causing the overproduction of cysteinyl leukotrienes. As a consequence, elevated levels of cysteinyl leukotrienes can be found in bronchial and nasal aspirates, and in urine following aspirin challenge.41,42 Moreover, the rate-limiting enzyme, leukotriene C4 synthase, is found to a greater extent in eosinophils and mast cells in patients with aspirin-sensitive asthma.43
Thus, LTRAs might play an important role in ameliorating the clinical symptoms of aspirin sensitive asthma. Montelukast was effective in aspirin-sensitive patients who were receiving inhaled corticosteroids.44 This study evaluated 80 patients with aspirin-sensitive asthma, who were randomized to receive placebo or montelukast 10 mg /day for 4 weeks. Pulmonary function and symptoms were improved in the latter group, in turn suggesting that LTRAs such as montelukast improve asthma control in aspirin-sensitive patients over and above that achieved by inhaled corticosteroids. Other studies using both LTRAs and zileuton have blocked the response following ingestion of aspirin.45–47 These results demonstrate that LTRAs play a complimentary role in attenuating the effects of aspirin in predisposed individuals.
|
Exercise-induced asthma |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Many patients with asthma develop symptoms in relation to exercise. This is thought to be due to drying and cooling effects occurring in the airway, with the subsequent release of pro-inflammatory mediators such as cysteinyl leukotrienes and histamine.48 LTRAs and inhibitors of the cysteinyl leukotriene pathway have protected against exercise-induced bronchoconstriction in a number of studies in both adults and children.49–52 For example, in 100 corticosteroid-naive asthmatics with a mean FEV1 of 83% predicted, the effects of montelukast 10 mg /day were evaluated over a 12-week period.24 Compared to placebo, montelukast was significantly superior in protecting against exercise-induced bronchoconstriction, with patients experiencing better asthma control during active treatment. Moreover, tolerance to its effects was not observed, which is often the case with long-acting ß2-agonists.53 This suggests that treatment with a LTRA is an effective option in patients with troublesome exercise-induced symptoms, either alone, or in combination with inhaled corticosteroids.
|
Allergic rhinitis |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
Allergic rhinitis is a complex inflammatory disease of the upper airway characterized by sneezing, nasal pruritus, rhinorrhoea and nasal obstruction.54 In addition to sharing the same epithelial lining, exaggerated airway responsiveness and underlying inflammation can be demonstrated in both conditions with the subsequent appearance of symptoms.7 Uncontrolled allergic rhinitis is known to precipitate and exacerbate asthma, suggesting that clinicians should positively search for typical nasal and ocular symptoms, especially in those with difficult-to-control asthma.55 Cysteinyl leukotrienes are inflammatory mediators common to both the upper and lower airways,56,57 which has prompted investigators to evaluate their therapeutic potential in allergic rhinitis.58,59
The pioneering work on LTRAs in the upper airway began a decade ago,60 with the exciting possibility of oral therapy with few adverse effects, avoiding the discomfort of nasal sprays.61 In in vitro studies, montelukast and pranlukast reduced levels of nasal pro-inflammatory mediators and inhibited antigen-induced microvascular leakage.62–65
The effects of cysteinyl leukotrienes and LTRAs on nasal symptoms of allergic rhinitis have been evaluated by examining the response following antigen provocation. Sneezing and rhinorrhoea are thought to represent the early-phase response, whereas oedema and eosinophilic infiltration predominate the late-phase response.66,67 Cysteinyl leukotrienes mediate both early- and late-phase responses.67 Pranlukast suppressed the increase in nasal airway resistance, but was ineffective in suppressing sneezing and rhinorrhoea.67 Cysteinyl leukotrienes are therefore important mediators in allergic rhinitis,68 especially with regard to nasal obstruction.69,70 Moreover, cysteinyl leukotrienes have a greater role in the development of mucosal swelling in nasal allergy than that of histamine.71 The mechanism by which nasal blockage develops in allergic rhinitis is thought to be due to activation of the CysLT1-receptor66 and overproduction of nitric oxide, leading to dilatation of nasal blood vessels and congestion of the nasal mucosa.72
Montelukast as monotherapy is effective in the treatment of allergic rhinitis. For example, in a study of 1302 patients with allergic rhinitis, montelukast 10 mg /day improved day- and night-time nasal symptoms, as well as quality of life parameters.73 Similar results were obtained in two other large studies,74,75 where the treatment effects of montelukast were found to be more persistent than those of loratadine.75 A study of 1862 symptomatic patients with allergic rhinitis, which showed superiority of montelukast over placebo in improving nasal symptoms, also evaluated the interaction between treatment effects and timing. A greater response to montelukast was seen in patients who were exposed to a higher pollen count. Similarly, zafirlukast has also been shown to improve nasal symptoms in allergic rhinitis with reduction in nasal resistance and lavage eosinophil count.76
Data relating to the combined effects of LTRAs and histamine H1-receptor antagonists on nasal symptoms in allergic rhinitis offer conflicting results. In one study of 460 patients with allergic rhinitis, the combination of montelukast and loratadine improved day-time nasal symptoms, while less benefit was observed with either drug alone.77 In contrast, in another larger study of 907 patients with allergic rhinitis, both drugs alone improved day-time nasal symptoms with no further additional benefit from the combination.78 In a study of 62 patients, the combination of montelukast and loratadine was no more effective than montelukast alone on day-or night-time nasal symptoms,79 while the combination of montelukast and cetirizine was more effective than cetirizine as monotherapy in another study.80 The lack of superiority with combination therapy compared to monotherapy with either LTRA or histamine H1-receptor antagonist has been replicated in one study using nasal adenosine monophosphate provocation,81 while non-inferiority of LTRA compared to histamine H1-receptor antagonist has been demonstrated in another study using nasal mannitol provocation.82 In comparison to intranasal corticosteroids, the use of oral combined LTRA and histamine H1-receptor antagonist was similar in two studies83,84 and less effective in three other studies,79,85,86 in terms of nasal symptoms.
In summary, LTRAs can provide an effective treatment option for patients with allergic rhinitis. Moreover, in patients with concomitant asthma, the combination of a LTRA plus histamine H1-receptor antagonist may provide similar asthma control to that of orally and nasally inhaled corticosteroids, although further large scale studies are required to confirm this finding.87 Montelukast has recently gained approval from the Food and Drug Administration in the US for use in allergic rhinitis alone, although this is not the case currently in the UK.
|
Polymorphisms of leukotriene C4 synthase |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
An interesting ‘real life’ property of LTRAs is their propensity for greater therapeutic effects in subgroups of asthmatics. Polymorphisms of leukotriene C4 synthase, the terminal enzyme in leukotriene synthesis, have been discovered, and are postulated to be important in determining this differential response to treatment. They are characterized by adenine (A) to cytosine (C) translocation at the –444 nucleotide. Moreover, in aspirin-sensitive asthmatics, overactive transcription of variant C polymorphism is associated with enhanced expression of leukotriene C4 synthase in peripheral blood eosinophils.88
In a study by Sampson et al.89 of 23 asthmatics, zafirlukast 20 mg twice daily for 2 weeks resulted in a numerically greater (although statistically non-significant) response in FEV1, comparing genotypes AA vs. AC or CC. Furthermore, Asano et al.90 evaluated the effects of pranlukast for 4 weeks in 48 patients with moderate-to-severe persistent asthma. Patients with AC/CC had a significantly greater bronchodilator response with LTRA in FEV1, compared to patients with AA. In a retrospective analysis,91 polymorphisms of leukotriene C4 synthase were not associated with clinical response to LTRAs in terms of surrogate inflammatory markers and measures of airway calibre. However, it may not be surprising to discover that a single allelic variation does not determine the response to LTRAs, since cysteinyl leukotrienes are synthesized via a cascade of enzymes. Indeed, whether a combination of polymorphisms is implicated in the interindividual variability in response to LTRAs requires further evaluation.
|
Conclusions |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
As a consequence of greater insight into the underlying inflammatory process synonymous with asthma, LTRAs have emerged as a distinct class of drug over the past decade. It is evident that there is a role for LTRAs across a broad spectrum of asthma severities and manifestations, ranging from beneficial effects as add-on second-line therapy in patients using low through to high doses of inhaled corticosteroids, and those with mild through to marked impairment in lung calibre. LTRAs also have an impact in patients with activity-related and aspirin-sensitive asthma. With the emergence of new data, and greater emphasis placed on more holistic outcome measures such as quality of life, patient satisfaction and exacerbation frequency, it is likely that over the next few years LTRAs will more comfortably fit into updated asthma guidelines. Indeed, when compared to add on long-acting ß2-agonists in patients using inhaled corticosteroids, it is important for the prescribing physician to be aware that adding in a LTRA (instead of a long-acting ß2-agonist) confers similar effects upon reductions in exacerbation frequency, despite less dramatic improvements in lung function.
Current British Thoracic Society guidelines suggest that a LTRA should be considered at step 4, when the combination of inhaled corticosteroid dose plus long-acting ß2-agonist fails to adequately control symptoms. Alternatively, they may be given to patients maintained on inhaled corticosteroids after a failed therapeutic trial of long-acting ß2-agonist. In patients with persistent symptoms despite a low-to-moderate dose of inhaled corticosteroid, compliance and inhaler technique should obviously be assessed, along with trigger factors such as aeroallergens, concomitant allergic rhinosinusitis and gastro-oesophageal reflux disease. Many patients using inhaled corticosteroids have preserved lung function, with underlying inflammation and bronchial hyper-responsiveness being the driving forces behind episodic airflow obstruction and persistent symptoms. In these patients, add-on therapy with a LTRA would appear to be the most logical therapeutic option, in view of its dual actions of attenuating bronchial hyper-responsiveness and suppressing inflammation, in turn reducing exacerbation frequency. Indeed, the use of a long-acting ß2-agonist, with no intrinsic anti-inflammatory properties,92,93 would do little to deal with these underlying problems. In patients with persistent symptoms and impaired lung function (FEV1 <80% predicted), adding in a long-acting ß2-agonist as a combination inhaler (such as fluticasone propionate/salmeterol), while keeping the inhaled corticosteroid dose the same would appear to be the most reasonable step. Further increases in anti-inflammatory therapy (either with a LTRA or increased inhaled corticosteroid dose) would be unlikely to improve lung function to any great extent,94 and a combined inhaled corticosteroid/long acting ß2-agonist inhaler would ensure maximal bronchodilation.
While not licensed for use in patients with allergic rhinitis per se, LTRAs have consistently demonstrated efficacy in asthmatics with concomitant upper airway inflammation, especially when combined with an anti-histamine. Thus, therapy directed towards the nose would offer the added advantage of attenuating lower airway inflammation and perhaps reducing corticosteroid requirement in patients with concomitant asthma. Moreover, their favourable adverse effect profile, for example compared to patients using both inhaled and nasal corticosteroids, is certainly advantageous. Patient compliance tends also to be greater with oral treatment than compared to inhaled,95 and patient acceptance, adherence and ease of administration plays a part in the effectiveness of any therapeutic regime.
In conclusion, LTRAs are one of the first asthma drugs to be developed as an attempt to antagonize the effects of a specific inflammatory pathway. They not only provide a further therapeutic tool in which to control inflammation, bronchial hyper-responsiveness and symptoms, but facilitate an orally active means by which to reduce the burden of asthma in both primary and secondary care settings.
|
Acknowledgments |
|---|
Conflicts of interest: GPC and OJD have received funding from MSD and GSK for attending postgraduate educational meetings. PS has received funding from GSK for attending postgraduate educational meetings.
|
Footnotes |
|---|
Address correspondence to Dr G.P. Currie, Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN. e-mail: graeme_currie{at}yahoo.com
|
References |
|---|
|
TopSummaryIntroductionCysteinyl leukotrienesLeukotriene receptor...Leukotriene receptor antagonists...Inhaled corticosteroids plus...Leukotriene receptor antagonists...‘Triple therapy’...Aspirin-sensitive asthmaExercise-induced asthmaAllergic rhinitisPolymorphisms of leukotriene C4...ConclusionsReferences |
|---|
1. Beasley R, Pearce N, Crane J. International trends in asthma mortality. Ciba Found Symp 1997; 206:140–50; discussion 50–6, 57–9.[Medline]
2. Beasley R, Crane J, Lai CK, Pearce N. Prevalence and etiology of asthma. J Allergy Clin Immunol 2000; 105:S466–72.[CrossRef][Web of Science][Medline]
3. Bucknall CE, Slack R, Godley CC, Mackay TW, Wright SC. Scottish Confidential Inquiry into Asthma Deaths (SCIAD), 1994–6. Thorax 1999; 54:978–84.
4. Burr ML, Davies BH, Hoare A, Jones A, Williamson IJ, Holgate SK, Arthurs R, Hodges IG. A confidential inquiry into asthma deaths in Wales. Thorax 1999; 54:985–9.
5. Mitchell I, Tough SC, Semple LK, Green FH, Hessel PA. Near-fatal asthma: a population-based study of risk factors. Chest 2002; 121:1407–13.[Medline]
6. Currie GP, Jackson CM, Lipworth BJ. Does bronchial hyperresponsiveness in asthma matter? J Asthma 2004; 41:247–58.[Medline]
7. Corren J. Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol 1997; 99:S781–6.[CrossRef][Web of Science][Medline]
8. Lundblad L. Allergic rhinitis and allergic asthma: a uniform airway disease? Allergy 2002; 57:969–71.[Medline]
9. Reed CE, Marcoux JP, Welsh PW. Effects of topical nasal treatment on asthma symptoms. J Allergy Clin Immunol 1988; 81:1042–7.[CrossRef][Medline]
10. Henriksen JM, Wenzel A. Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing, and asthma. Am Rev Respir Dis 1984; 130:1014–18.[Web of Science][Medline]
11. Foresi A, Pelucchi A, Gherson G, Mastropasqua B, Chiapparino A, Testi R. Once daily intranasal fluticasone propionate (200 micrograms) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis. J Allergy Clin Immunol 1996; 98:274–82.[CrossRef][Web of Science][Medline]
12. British guideline on the management of asthma. Thorax 2003; 58 Suppl 1:i1–94.[Medline]
13. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108:S147–334.[CrossRef][Web of Science][Medline]
14. Pavord ID, Ward R, Woltmann G, Wardlaw AJ, Sheller JR, Dworski R. Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med 1999; 160:1905–9.
15. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997; 156:737–43.
16. Booth H, Richmond I, Ward C, Gardiner PV, Harkawat R, Walters EH. Effect of high dose inhaled fluticasone propionate on airway inflammation in asthma. Am J Respir Crit Care Med 1995; 152:45–52.[Abstract]
17. Currie GP, Haggart K, Lee DK, Fowler SJ, Wilson AM, Brannan JD, Anderson SD, Lipworth BJ. Effects of mediator antagonism on mannitol and adenosine monophosphate challenges. Clin Exp Allergy 2003; 33:783–8.[CrossRef][Medline]
18. Lipworth BJ, Wilson AM. Montelukast and Churg-Strauss syndrome. Thorax 2001; 56:244.
19. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999; 159:941–55.
20. Lipworth BJ, Wilson AM. Dose-response to inhaled corticosteroids: benefits and risks. Sem Respir Crit Care Med 1998; 19:625–46.
21. Lee DK, Robb FM, Sims EJ, Currie GP, McFarlane LC, Lipworth BJ. Systemic bioactivity of intranasal triamcinolone and mometasone in perennial allergic rhinitis. Br J Clin Pharmacol 2003; 55:310–13.[Medline]
22. Dempsey OJ. Leukotriene receptor antagonist therapy. Postgrad Med J 2000; 76:767–73.
23. Ducharme FM. Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: systematic review of current evidence. Br Med J 2003; 326:621.
24. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, Dockhorn R, Kundu S, Zhang J, Seidenberg BC, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998; 339:147–52.
25. Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999; 353:57–62.[CrossRef][Web of Science][Medline]
26. Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet JC, Peszek I, Zhang J, Reiss TF. Montelukast added to inhaled beclomethasone in treatment of asthma. Montelukast/Beclomethasone Additivity Group. Am J Respir Crit Care Med 1999; 160:1862–8.
27. Tamaoki J, Kondo M, Sakai N, Nakata J, Takemura H, Nagai A, Takizawa T, Konno K. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am J Respir Crit Care Med 1997; 155:1235–40.[Abstract]
28. Vaquerizo MJ, Casan P, Castillo J, Perpina M, Sanchis J, Sobradillo V, Valencia A, Verea H, Viejo JL, Villasante C, et al. Effect of montelukast added to inhaled budesonide on control of mild to moderate asthma. Thorax 2003; 58:204–10.
29. Bjermer L, Bisgaard H, Bousquet J, Fabbri LM, Greening AP, Haahtela T, Holgate ST, Picado C, Menten J, Dass SB, et al. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. Br Med J 2003; 327:891.
30. Ilowite J, Webb R, Friedman B, Kerwin E, Bird SR, Hustad CM, Edelman JM. Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study. Ann Allergy Asthma Immunol 2004; 92:641–8.[Web of Science][Medline]
31. Eickelberg O, Roth M, Lorx R, Bruce V, Rudiger J, Johnson M, Block LH. Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J Biol Chem 1999; 274:1005–10.
32. Roth M, Johnson PR, Rudiger JJ, King GG, Ge Q, Burgess JK, Anderson G, Tamm M, Black JL. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002; 360:1293–9.[CrossRef][Web of Science][Medline]
33. Currie GP, Bates CE, Lee DK, Jackson CM, Lipworth BJ. Effects of fluticasone plus salmeterol versus twice the dose of fluticasone in asthmatic patients. Eur J Clin Pharmacol 2003; 59:11–15.[Medline]
34. Currie GP, Lee DK, Haggart K, Bates CE, Lipworth BJ. Effects of montelukast on surrogate inflammatory markers in corticosteroid-treated patients with asthma. Am J Respir Crit Care Med 2003; 167:1232–8.
35. Fish JE, Israel E, Murray JJ, Emmett A, Boone R, Yancey SW, Rickard KA. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001; 120:423–30.[CrossRef][Web of Science][Medline]
36. Nelson HS, Nathan RA, Kalberg C, Yancey SW, Rickard KA. Comparison of inhaled salmeterol and oral zafirlukast in asthmatic patients using concomitant inhaled corticosteroids. MedGenMed 2001; 3:3.[Medline]
37. Currie GP, Jackson CM, Ogston SA, Lipworth BJ. Airway-stabilizing effect of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids. Qjm 2003; 96:435–40.
38. Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001; 357:2007–11.[CrossRef][Web of Science][Medline]
39. Green RH, Pavord ID. Leukotriene antagonists and symptom control in chronic persistent asthma. Lancet 2001; 357:1991–2.[CrossRef][Web of Science][Medline]
40. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. Br Med J 2004; 328:434.
41. Christie PE, Tagari P, Ford-Hutchinson AW, Charlesson S, Chee P, Arm JP, Lee TH. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991; 143:1025–9.[Web of Science][Medline]
42. Knapp HR, Sladek K, Fitzgerald GA. Increased excretion of leukotriene E4 during aspirin-induced asthma. J Lab Clin Med 1992; 119:48–51.[Medline]
43. Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998; 101:834–46.[Web of Science][Medline]
44. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, Lumry WR, Picado C, Stevenson DD, Bousquet J, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165:9–14.
45. Israel E, Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Shapiro J, Cohn J, Rubin P, Drazen JM. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 1993; 148:1447–51.[Web of Science][Medline]
46. Dahlen B, Kumlin M, Margolskee DJ, Larsson C, Blomqvist H, Williams VC, Zetterstrom O, Dahlen SE. The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics. Eur Respir J 1993; 6:1018–26.[Abstract]
47. 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; 144:957–8.[Web of Science][Medline]
48. Anderson SD, Brannan JD. Exercise-induced asthma: is there still a case for histamine? J Allergy Clin Immunol 2002; 109:771–3.[Medline]
49. Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, Bronsky E, Guerreiro D, Hendeles L. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997; 52:1030–5.[Abstract]
50. Meltzer SS, Hasday JD, Cohn J, Bleecker ER. Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor. Am J Respir Crit Care Med 1996; 153:931–5.[Abstract]
51. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, Reiss TF. 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; 62:556–61.[CrossRef][Web of Science][Medline]
52. Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, Knorr B. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 1998; 133:424–8.[CrossRef][Web of Science][Medline]
53. Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994; 88:363–8.[CrossRef][Web of Science][Medline]
54. Haberal I, Corey JP. The role of leukotrienes in nasal allergy. Otolaryngol Head Neck Surg 2003; 129:274–9.[Medline]
55. Rachelefsky GS. National guidelines needed to manage rhinitis and prevent complications. Ann Allergy Asthma Immunol 1999; 82:296–305.[Medline]
56. Busse WW. The role of leukotrienes in asthma and allergic rhinitis. Clin Exp Allergy 1996; 26:868–79.[CrossRef][Web of Science][Medline]
57. Meltzer EO. Role for cysteinyl leukotriene receptor antagonist therapy in asthma and their potential role in allergic rhinitis based on the concept of ‘one linked airway disease’. Ann Allergy Asthma Immunol 2000; 84:176–85; quiz 185–7.[Medline]
58. Quraishi SA, Davies MJ, Craig TJ. Inflammatory responses in allergic rhinitis: traditional approaches and novel treatment strategies. J Am Osteopath Assoc 2004; 104:S7–15.
59. Lipworth BJ. Emerging role of antileukotriene therapy in allergic rhinitis. Clin Exp Allergy 2001; 31:1813–21.[CrossRef][Web of Science][Medline]
60. Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med 1995; 151:1734–9.[Abstract]
61. Tkachyk SJ. New treatments for allergic rhinitis. Can Fam Physician 1999; 45:1255–60.[Medline]
62. Shirasaki H, Asakura K, Narita S, Kataura A. The effect of a cysteinyl leukotriene antagonist, ONO-1078 (pranlukast) on agonist- and antigen-induced nasal microvascular leakage in guinea pigs. Rhinology 1998; 36:62–5.[Medline]
63. Yamasaki ML, Sasaki K, Mizutani N, Nabe T, Sakura Y, Matsumoto T, Ashida Y, Kohno S. Pharmacological characterization of the leukocyte kinetics after intranasal antigen challenge in a guinea pig model of allergic rhinitis. Inflamm Res 2001; 50:474–82.[Medline]
64. Ueda T, Takeno S, Furukido K, Hirakawa K, Yajin K. Leukotriene receptor antagonist pranlukast suppresses eosinophil infiltration and cytokine production in human nasal mucosa of perennial allergic rhinitis. Ann Otol Rhinol Laryngol 2003; 112:955–61.[Medline]
65. Ciprandi G, Frati F, Marcucci F, Sensi L, Tosca MA, Milanese M, Ricca V. Nasal cytokine modulation by montelukast in allergic children: a pilot study. Allerg Immunol (Paris) 2003; 35:295–9.[Medline]
66. Fujita M, Nakagawa N, Yonetomi Y, Takeda H, Kawabata K, Ohno H. Cysteinyl leukotrienes induce nasal symptoms of allergic rhinitis via a receptor-mediated mechanism in guinea pigs. Jpn J Pharmacol 1997; 75:355–62.[Medline]
67. Fujita M, Yonetomi Y, Shimouchi K, Takeda H, Aze Y, Kawabata K, Ohno H. Involvement of cysteinyl leukotrienes in biphasic increase of nasal airway resistance of antigen-induced rhinitis in guinea pigs. Eur J Pharmacol 1999; 369:349–56.[CrossRef][Medline]
68. Fujita M, Yonetomi Y, Takeda H, Nakagawa N, Kawabata K, Ohno H. Effects of a specific cysteinyl leukotriene antagonist, pranlukast, on antigen-induced cysteinyl leukotriene-mediated rhinitis in guinea pigs. Jpn J Pharmacol 1997; 75:347–53.[Medline]
69. Yamasaki M, Mizutani N, Sasaki K, Nabe T, Matsumoto T, Ashida Y, Kohno S. Involvement of thromboxane A2 and peptide leukotrienes in early and late phase nasal blockage in a guinea pig model of allergic rhinitis. Inflamm Res 2001; 50:466–73.[Medline]
70. Narita S, Asakura K, Shirasaki H, Kataura A. Effects of a cysteinyl leukotriene antagonist, ONO-1078 (pranlukast), on total airway resistance after antigen challenge in sensitized guinea pigs. Inflamm Res 1997; 46:143–6.[Medline]
71. Numata T, Konno A, Yamakoshi T, Hanazawa T, Terada N, Nagata H. Comparative role of peptide leukotrienes and histamine in the development of nasal mucosal swelling in nasal allergy. Ann Otol Rhinol Laryngol 1999; 108:467–73.[Medline]
72. Mizutani N, Nabe T, Imai A, Sakurai H, Takenaka H, Kohno S. Markedly increased nasal blockage by intranasal leukotriene D4 in an experimental allergic rhinitis model: contribution of dilated mucosal blood vessels. Jpn J Pharmacol 2001; 86:170–82.[Medline]
73. Philip G, Malmstrom K, Hampel FC, Weinstein SF, LaForce CF, Ratner PH, Malice MP, Reiss TF. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy 2002; 32:1020–8.[CrossRef][Web of Science][Medline]
74. van Adelsberg J, Philip G, LaForce CF, Weinstein SF, Menten J, Malice MP, Reiss TF. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2003; 90:214–22.[Web of Science][Medline]
75. van Adelsberg J, Philip G, Pedinoff AJ, Meltzer EO, Ratner PH, Menten J, Reiss TF. Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy 2003; 58:1268–76.[Medline]
76. Piatti G, Ceriotti L, Cavallaro G, Ambrosetti U, Mantovani M, Pistone A, Centanni S. Effects of zafirlukast on bronchial asthma and allergic rhinitis. Pharmacol Res 2003; 47:541–7.[CrossRef][Web of Science][Medline]
77. Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF, Wolfe JD, Reiss TF. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 2000; 105:917–22.[CrossRef][Medline]
78. Nayak AS, Philip G, Lu S, Malice MP, Reiss TF. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol 2002; 88:592–600.[Web of Science][Medline]
79. Pullerits T, Praks L, Ristioja V, Lotvall J. Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 2002; 109:949–55.[CrossRef][Medline]
80. Kurowski M, Kuna P, Gorski P. Montelukast plus cetirizine in the prophylactic treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal allergic inflammation. Allergy 2004; 59:280–8.[Medline]
81. Lee DK, Jackson CM, Soutar PC, Fardon TC, Lipworth BJ. Effects of single or combined histamine H1-receptor and leukotriene CysLT1-receptor antagonism on nasal adenosine mono phosphate challenge in persistent allergic rhinitis. Br J Clin Pharmacol 2004; 57:714–19.[Medline]
82. Lee DK, Haggart K, Currie GP, Anderson SD, Lipworth BJ. The effects of histamine and leukotriene receptor antagonism on nasal mannitol challenge in allergic rhinitis. Br J Clin Pharmacol 2003; 55:639–42.[Medline]
83. Wilson AM, Orr LC, Sims EJ, Lipworth BJ. Effects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotriene receptor antagonists in seasonal allergic rhinitis. Clin Exp Allergy 2001; 31:61–8.[Medline]
84. Wilson AM, Sims EJ, Orr LC, Coutie WJ, White PS, Gardiner Q, Lipworth BJ. Effects of topical corticosteroid and combined mediator blockade on domiciliary and laboratory measurements of nasal function in seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2001; 87:344–9.[Medline]
85. Di Lorenzo G, Pacor ML, Pellitteri ME, Morici G, Di Gregoli A, Lo Bianco C, Ditta V, Martinelli N, Candore G, Mansueto P, et al. Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis. Clin Exp Allergy 2004; 34:259–67.[Medline]
86. Saengpanich S, deTineo M, Naclerio RM, Baroody FM. Fluticasone nasal spray and the combination of loratadine and montelukast in seasonal allergic rhinitis. Arch Otolaryngol Head Neck Surg 2003; 129:557–62.
87. Wilson AM, Orr LC, Sims EJ, Dempsey OJ, Lipworth BJ. Antiasthmatic effects of mediator blockade versus topical corticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med 2000; 162:1297–301.
88. Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol 2000; 23:290–6.
89. Sampson AP, Siddiqui S, Buchanan D, Howarth PH, Holgate ST, Holloway JW, Sayers I. Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000; 55 (Suppl. 2):S28–31.[Medline]
90. Asano K, Shiomi T, Hasegawa N, Nakamura H, Kudo H, Matsuzaki T, Hakuno H, Fukunaga K, Suzuki Y, Kanazawa M, et al. Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 2002; 12:565–70.[CrossRef][Web of Science][Medline]
91. Currie GP, Lima JJ, Sylvester JE, Lee DK, Cockburn WJ, Lipworth BJ. Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma. Br J Clin Pharmacol 2003; 56:422–6.[CrossRef][Web of Science][Medline]
92. Roberts JA, Bradding P, Britten KM, Walls AF, Wilson S, Gratziou C, Holgate ST, Howarth PH. The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma. Eur Respir J 1999; 14:275–82.[Abstract]
93. Gardiner PV, Ward C, Booth H, Allison A, Hendrick DJ, Walters EH. Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Am J Respir Crit Care Med 1994; 150:1006–11.[Abstract]
94. Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. Bmj 2001; 323:253–6.
95. Kamada AK, Szefler SJ, Martin RJ, Boushey HA, Chinchilli VM, Drazen JM, Fish JE, Israel E, Lazarus SC, Lemanske RF. Issues in the use of inhaled glucocorticoids. The Asthma Clinical Research Network. Am J Respir Crit Care Med 1996; 153:1739–48.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. P. Currie, D. K. C. Lee, and P. Srivastava Long-Acting Bronchodilator or Leukotriene Modifier as Add-on Therapy to Inhaled Corticosteroids in Persistent Asthma? Chest, October 1, 2005; 128(4): 2954 - 2962. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||