Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (33)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Busse, W.
Right arrow Articles by Kraft, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Busse, W.
Right arrow Articles by Kraft, M.
(Chest. 2005;127:1312-1326.)
© 2005 American College of Chest Physicians

Cysteinyl Leukotrienes in Allergic Inflammation*

Strategic Target for Therapy

William Busse, MD and Monica Kraft, MD, FCCP

* From the University of Wisconsin (Dr. Busse), Madison Medical School, Madison, WI; and National Jewish Medical and Research Center (Dr. Kraft), Denver, CO.

Correspondence to: William Busse, MD, University of Wisconsin, Madison Medical School, Department of Medicine, 15/220 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-2454; e-mail: wwb{at}medicine.wisc.edu


   Abstract
TOP
 Abstract
Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
 Conclusion
 References
 
Systemically bioavailable leukotriene receptor antagonists (LTRAs) can reduce the essential components of allergic inflammation in allergic rhinitis (AR) and asthma by blocking cysteinyl leukotriene (CysLT) activity, resulting in a wide range of clinical effects. CysLTs, mediators, and modulators in the pathophysiology of asthma and AR are a key target for therapy because they modulate production of hemopoietic progenitor cells, survival and recruitment of eosinophils to inflamed tissue, activity of cytokines and chemokines, quantity of exhaled NO, smooth-muscle contraction, and proliferation of fibroblasts. The mechanism of action of LTRAs leads to their effects on systemic allergic inflammatory processes.

Key Words: asthma • cytokines • eosinophils • inflammation • leukotrienes • leukotriene receptor antagonists • remodeling • rhinitis


   Introduction
TOP
 Abstract
 Introduction
Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
 Conclusion
 References
 
Asthma and allergic rhinitis (AR) are two of the most common respiratory disorders encountered in clinical practice. They are linked by a unified airway and a common pathophysiology. Asthma is a chronic inflammatory disorder of the lower airway that causes bronchoconstriction, airway edema, mucus secretion, and airway remodeling, leading to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing.123 Similarly, AR is a chronic inflammatory disorder of the upper airway that typically causes rhinorrhea, congestion, sneezing, and pruritus.45

Cysteinyl leukotrienes (CysLTs) are key mediators and modulators of systemic allergic responses, as well as an important component of the inflammatory responses that lead to the typical symptoms of asthma, including bronchoconstriction, wheezing, increased mucus secretion, and decreased mucociliary clearance.678 They are produced by eosinophils, basophils, macrophages, mast cells, and to a lesser extent T cells and endothelial cells.910 CysLTs cause vasodilation and increased microvascular permeability, both of which lead to tissue edema,111213 and can prolong eosinophil survival.14 Increased CysLT levels have been detected in the urine,151617 BAL fluid,18 and sputum1920 of patients with asthma; the increased sputum levels correlate with both eosinophil levels20 and symptom severity.19 Nasal allergen challenge causes a dose-dependent increase in CysLTs that correlates with nasal symptoms.21 Consequently, CysLTs likely represent an important strategic target in both asthma and AR.

The effects of CysLTs in asthma and AR are mediated through the CysLT1 receptor,22 which is a G-protein–coupled receptor expressed in monocytes/macrophages, eosinophils, basophils, mast cells, neutrophils, T cells, B lymphocytes, interstitial cells of the nasal mucosa, and smooth-muscle cells.2223242526 The leukotriene receptor antagonists (LTRAs) montelukast and zafirlukast selectively block the CysLT1 receptor and produce multiple beneficial effects locally in the asthmatic or allergic rhinitic airway and systemically on the allergic inflammatory response. This review examines the wide range of clinical effects produced by LTRAs in asthma and AR as well as the multiple pathophysiologic mechanisms by which LTRAs may alter allergic inflammation.


   Adult Persistent Asthma
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
 Conclusion
 References
 
Pulmonary Function
LTRAs improve pulmonary function, measured as the FEV1, by 8 to 13% in patients with mild,27 mild-to-moderate,282930 and severe31 asthma. Oral montelukast significantly increased baseline FEV1 by 27%, attaining nearly maximal effect within 2 h.32 Similarly, LTRAs significantly increased peak expiratory flow (PEF), measured by patients at home, in patients with mild-to-moderate asthma282930333435 and moderately severe asthma.3136

When montelukast was compared with the inhaled corticosteroid (ICS) beclomethasone, the mean FEV1 increase was significantly (p < 0.05) greater with beclomethasone (13.1% vs 7.4%37 or 0.38 L vs 0.24 L38). Although the mean responses were significantly different, a large portion of those responding with larger improvements (≥ 10% change or > 0.4 L) received montelukast. Figure 1 shows the distribution of incremental improvements of FEV1 for each drug; as shown, there were patients who were better responders and patients who were poorer responders to each drug. Overall, there was an 81% overlap of the responses to each drug.3839 In a 3-year extension study,40 montelukast and beclomethasone produced similar overall improvements in FEV1 during the second and third years.



View larger version (27K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Frequency distributions of percentage change from baseline FEV1 after montelukast (gray bars) and beclomethasone (black bars) treatments. A large portion of individuals responding with larger improvements (> 0.4 L) were patients receiving montelukast. Reproduced with permission from Israel et al.38

 
Airway Hyperresponsiveness
LTRAs have also been found to reduce airway hyperresponsiveness, an indicator of airway inflammation. LTRAs modestly increased the provocative concentration needed to produce a 20% decline in FEV1 (PC20) of methacholine,414243 histamine,4344 and adenosine monophosphate.45 Similarly, adding montelukast or zafirlukast to ICS further increased the PC20 of adenosine monophosphate compared with placebo.4647 Because of its action as a CysLT antagonist, the PC20 for inhaled leukotriene D4 (LTD4) increased 66-fold when zafirlukast was added to ICS therapy.48

Symptoms and Quality of Life
Montelukast significantly decreased both daytime asthma symptoms and nocturnal awakenings in patients with mild asthma27 and with mild-to-moderate asthma.29 Zafirlukast reduced daytime asthma symptom scores by 26.5%28 and increased symptom-free days by 89%.49 Montelukast significantly improved the asthma quality of life (Fig 2 ) in all four domains (activity, symptoms, emotional function, and exposure to environmental stimuli).2950 In more severe forms of asthma (FEV1 45 to 80% of predicted), zafirlukast improved daytime symptom scores by 23 to 26%.3150



View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Improvement in asthma-specific quality-of-life scores in 681 patients with asthma randomized to 12 weeks of therapy with montelukast or placebo. Bars depict the mean value, and error bars depict the SE. *p < 0.001. Reproduced with permission from Reiss et al.29

 
ß-Agonist Use
In patients with mild asthma, the LTRA montelukast significantly reduced the need for rescue ß-agonist use by 32% and increased the number of rescue-free days by 25%.27 In mild-to-moderate asthma, montelukast or zafirlukast reduced ß-agonist use by 20 to 24%.282950 It was also effective when added to high-dose ICS therapy.51

Eosinophilia
LTRAs significantly decrease eosinophil levels in blood, BAL fluid, and sputum.295253

LTRA as Add-on Therapy
The LTRA montelukast can be added to ICS therapy to obtain better control, as measured by significant improvement of FEV1, daytime asthma symptom scores, and nocturnal awakenings.54 It was as effective as doubling the dose of budesonide.55 In patients requiring moderate-to-high doses of ICS, adding montelukast permitted significant tapering of the ICS dose without loss of asthma control.56 In chronic asthma inadequately controlled with a high dose of ICS (1,000 to 4,000 µg/d), zafirlukast not only significantly improved pulmonary function and asthma symptom scores5157 but also significantly reduced the risk of an asthma exacerbation by 39%.51


   Persistent Asthma in Pediatric Patients
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
 Conclusion
 References
 
Pulmonary Function
Montelukast (approved for children ≥ 2 years old) and zafirlukast (approved for children ≥ 5 years old) significantly improved pulmonary function and reduced symptoms, irrespective of concomitant ICS use.585960 In children 6 to 14 years of age who were inadequately controlled by budesonide, the addition of montelukast significantly increased FEV1 (6.0% vs 4.1% with placebo; p = 0.01) and PEF (difference from placebo: morning PEF, 9.7 L/min, p = 0.023; evening PEF, 10.7 L/min, p = 0.012).61

In an open-label extension trial40 in children 6 to 14 years of age, both montelukast and beclomethasone maintained a 17% improvement of FEV1 at the end of 68 weeks. Both children and their parents reported significantly more satisfaction with montelukast than with beclomethasone therapy, as they found it more convenient and less difficult to use.62

Symptoms and Quality of Life
Montelukast significantly reduced the percentage of days with daytime asthma symptoms and increased the percentage of asthma-free days in children 2 to 5 years of age with persistent asthma.59 Zafirlukast significantly reduced nighttime awakenings in 5- to 11-year-old children.60 In a small study63 with very young children (5 to 20 months) with severe virus-induced bronchiolitis poorly responsive to ICS and bronchodilators, montelukast provided clinical improvement within 1 week. In children with respiratory syncytial virus bronchiolitis, 3 months to 3 years of age, montelukast produced symptom-free days and nights 22% of the time (4% with placebo); cough and the rate of exacerbations were reduced as well.64

ß-Agonist Use
The LTRAs reduce the need for rescue ß-agonists in children by up to 25%.5960 In children 6 to 14 years of age inadequately controlled by budesonide, the addition of montelukast significantly decreased the need for ß-agonist.61 Similarly, montelukast increased the number of rescue-free days per week by 4.5 days.65

Eosinophilia
LTRAs significantly decrease eosinophil levels in blood of children with asthma.585966


   Other Asthma Phenotypes
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
AR
 Inflammation in Allergic...
 Conclusion
 References
 
Acute Asthma
In adult patients presenting with moderate-to-severe asthma symptoms acutely, IV montelukast (7 or 14 mg) was administered in the emergency department with standard therapy. The FEV1 significantly improved during the first 20 min (14.8% vs 3.6% with placebo; p = 0.007) and lasted > 2 h after infusion (Fig 3 ). Significantly fewer patients administered montelukast received ß-agonist nebulizations or corticosteroids than did patients who received placebo.67



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. Improvement in FEV1 after IV montelukast in patients with moderate-to-severe acute asthma. Patients received either IV montelukast, 7 mg (diamonds; n = 66); IV montelukast, 14 mg (squares; n = 64); or IV placebo (triangles; n = 64). Data are presented as least square means ± SE of the percentage change from baseline for each treatment. *p < 0.05 vs placebo; {dagger}p < 0.01 vs placebo. Reproduced with permission from Camargo et al.67

 
Exercise-Induced Bronchoconstriction
After exercise, montelukast produced a 32% reduction of the maximum decrease in FEV1 after exercise, a 27% reduction of the time to recovery from the maximal decrease in FEV1, and a 47% inhibition of the area under the FEV1-vs-time curve (AUC) after exercise. The protection against exercise-induced bronchoconstriction was measured 20 to 24 h after an evening dose.68 Zafirlukast significantly attenuated the maximum decrease in FEV1 after exercise by 57%.69

Just as with adults, children experience protective effects of LTRAs after exercise for up to 24 h after the previous nighttime dose.70 Zafirlukast, administered 4 h before exercise, significantly reduced the maximum decrease of FEV1 and the AUC in children 6 to 14 years of age (Fig 4 ). The time for recovery from exercise was reduced by almost half.71 In children 7 to 13 years of age with allergic asthma, montelukast significantly reduced the maximum fall in FEV1 and the AUC when exercise was performed 12 h after dosing.72



View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. Percentage change in FEV1 after exercise challenge in children with exercise-induced bronchoconstriction. Data are presented as least-square (LS) means ± SE. The reduction of fall in FEV1 after zafirlukast, 10 mg, was significantly less than after placebo (p = 0.01). The time to recovery within 5% of the preexercise value was also significantly shorter with zafirlukast compared with placebo (p ≤ 0.05); it was about half the time of the placebo group. Adapted from Pearlman et al.71

 
Aspirin-Induced Asthma
Nonsteroidal antiinflammatory drugs can dramatically increase the production of CysLTs. In nonsteroidal antiinflammatory drug-intolerant patients, 90% of whom were already receiving moderate-to-high doses of corticosteroids, montelukast significantly improved pulmonary function, asthma-specific quality of life, the need for bronchodilator use, and frequency of exacerbations.73

Allergen-Induced Asthma
Montelukast and zafirlukast significantly inhibited inhaled allergen-induced early and late asthmatic responses.747576 Similarly, in subjects with asthma and cat allergy, montelukast and zafirlukast significantly attenuated the fall in FEV1 on exposure to high levels of cat antigen.777879 During the grass pollen season, zafirlukast (20 mg bid) significantly reduced asthma and AR symptoms. The LTRAs inhibited antigen-induced inflammatory cell infiltration and activation, including a reduction in lymphocytes, basophils, and macrophages in the BAL fluid obtained after segmental allergen challenge in allergic subjects with asthma.5280 The number of eosinophils in nasal lavage fluid decreased in patients with both asthma and AR, while neutrophils levels remained unchanged.80


   AR
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
Inflammation in Allergic...
 Conclusion
 References
 
Montelukast significantly reduced daytime nasal symptoms (congestion, rhinorrhea, pruritus, and sneezing), daytime eye symptoms, nighttime symptoms (difficulty sleeping, nighttime awakenings, and congestion on awakening), and peripheral eosinophilia.818283 Montelukast also significantly improved the rhinoconjunctivitis-specific quality-of-life score,818283 which included significant improvement in domains such as activity, ocular symptoms, practical problems, and emotional symptoms (Fig 5 ).838485 Zafirlukast significantly improved nasal airway resistance by 68% in patients with AR80 and reduced nasal congestion in patients allergic to cats.78 Likewise, the number of eosinophils in nasal lavage fluid were decreased.80



View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5. Change in overall rhinoconjunctivitis quality-of-life (QOL) score (0 = best, 6 = worst) in patients with fall or spring AR randomized to treatment with montelukast or placebo during their allergy season. Symbols represent the mean change (decrease in score represents improvement in symptoms). and error bars represent the 95% confidence intervals. Adapted from Nayak et al,84 Philip et al,85 and van Adelsberg et al.83

 

   Inflammation in Allergic Respiratory Disease
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
Conclusion
 References
 
Evidence of a Systemic Response
Allergic respiratory disorders are the result of a pathophysiologic process that extends well beyond the local, antigen-exposed airway. Inflammation in one part of the airway often manifests itself in another. For example, 21 to 58% of patients with AR have concomitant asthma,8687 and 85 to 95% of patients with asthma have concomitant AR.8688 Moreover, isolated allergen challenge in either the upper or lower airway produces demonstrable inflammatory changes in the nonchallenged site.

In a randomized, double-blind, crossover evaluation89 of 10 subjects previously sensitized to grass pollen but free of nasal and respiratory symptoms, isolated nasal provocation with grass extract induced not only a marked nasal allergic reaction but also a significant increase in bronchial hyperresponsiveness to methacholine, at both 30 min (p = 0.011) and 4.5 h (p < 0.001), compared with placebo. Separately, in nine subjects with seasonal AR but not asthma, isolated nasal allergen challenge, outside of their allergy season, resulted in significant (p ≤ 0.05) eosinophil influx into bronchial epithelium and lamina propria in addition to the nasal epithelium and lamina propria.90 Furthermore, this influx of cells correlated with detectable increases of intercellular adhesion molecule (ICAM)-1, vascular-cell adhesion molecule (VCAM)-1, and E-selectin expression in vessels in nasal and bronchial tissues.

Similarly, segmental bronchial challenge significantly increased eosinophil and basophil levels in nasal lamina propria as well as interleukin (IL)-5 expression in blood and nasal epithelium (p < 0.05),91 in addition to increases in eosinophil and basophil concentrations in bronchial mucosa (p < 0.05).92 Moreover, even in the absence of rhinitis, patients with asthma have increased eosinophil levels in their nasal mucosa (p < 0.01), and these levels correlate with bronchial eosinophil values (r = 0.851; p < 0.001).93 Finally, clinical signs and symptoms of sinusitis are often detected during acute exacerbations of asthma; conversely, aggressive treatment of sinus disease has been shown to decrease medication requirements needed to control concomitant asthma.1

Systemic Immune Response
The basis of these comorbidities that involve a remote airway response needs to be viewed in the context of the immune response. In atopic individuals, initial antigen exposure leads to the synthesis of antigen-specific IgE, which binds to high-affinity receptors on the surface of tissue mast cells and circulating basophils as well as to low-affinity receptors on the surface of circulating lymphocytes, eosinophils, platelets, and macrophages.94 Reexposure to antigen produces molecular bridging of these IgE-receptor complexes, activating the cell to release preformed and newly synthesized mediators.94

Located in the mucosa and submucosa of the airway, mast cells are the first cells to be activated on antigen reexposure,994 causing the release of mediators, including histamine, CysLTs, prostaglandins, platelet-activating factor (PAF), and cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, granulocyte-macrophage colony–stimulating factor [GM-CSF], and tumor necrosis factor [TNF]-{alpha}).599495 These mediators produce the early phase reaction and are responsible for the initial acute symptoms (bronchoconstriction in asthma and sneezing, pruritus, rhinorrhea, and to some extent congestion in AR) of antigen exposure.2996 Furthermore, these mediators initiate the processes leading to the infiltration into local tissues by circulating inflammatory cells, including eosinophils, basophils, T cells, and macrophages. It is proposed that these inflammatory cells then become activated and release their mediators, which act to sustain and enhance the inflammatory response, thus producing the chronic or late-phase response.

Eosinophils characterize and reflect the systemic nature of this late phase (Fig 6 ). Their development is under the regulatory control of cytokines IL-3, IL-5, and GM-CSF.594 IL-5, released from cells as part of the allergic response, is proposed to circulate to the bone marrow, where it induces the terminal differentiation of immature eosinophils.94 These eosinophils then enter the circulation and bind to selectins and adhesion molecules VCAM-1 and ICAM-1 located on vascular endothelial surfaces near inflammatory sites.9495 Migrating through the endothelial surface into the inflammatory tissue, eosinophils become activated to synthesize and release additional inflammatory mediators, including CysLTs, prostaglandin E1, PAF, IL-3, IL-5, IL-8, and GM-CSF, and to reactive oxygen intermediates, major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase.159495 Furthermore, GM-CSF, IL-5, and CysLTs reduce apoptosis, prolonging eosinophil survival in inflammatory tissue, likely sustaining their mediator release, and resulting in ongoing tissue damage and inflammation.594



View larger version (104K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6. Eosinophils in allergic respiratory disorders. In response to antigen activation, mast cells and Th2 cells located in the airway release inflammatory mediators, such as histamine and leukotrienes, and cytokines, such as IL-4, IL-5, and GM-CSF. IL-5 travels to the bone marrow, where it stimulates the terminal differentiation of eosinophils. These eosinophils enter the circulatory system and, through interactions with selectins and adhesion proteins (VCAM-1 and ICAM-1), ultimately migrate to and infiltrate regions of inflammation. Once activated in the local tissue, these eosinophils release inflammatory mediators such as leukotrienes and granule proteins, leading to airway injury. In addition, they generate GM-CSF, which, along with IL-5, reduces apoptosis, prolonging their survival and contributing to persistent airway inflammation. MCP = monocyte chemotactic protein, MIP = macrophage inflammatory protein. RANTES = regulated upon activation, normal T-cell expressed and secreted. Reproduced with permission from Busse and Lemanske.94

 
Similar to eosinophils, basophils, T cells, especially type 2 T helper (Th2) cells, and macrophages migrate to the inflammatory site, become activated, and release their mediators.158895 Basophils release CysLTs, IL-4, and IL-13 and appear to be the primary source of histamine in the late phase of allergic reactions.59 Th2 cells are one of the principal cells that regulate and coordinate IgE-mediated allergic inflammation5; they release IL-3, IL-4, IL-5, IL-9, IL-10, IL-13, and GM-CSF on activation.59 Finally, macrophages release similar cytokines plus lysosomal enzymes and histamine-releasing factors, which appear to act on mast cells and basophils to perpetuate the allergic response independent of repeated allergen exposures.9

This allergen-induced up-regulation of inflammatory cell function leads to migration and infiltration of these cells into all susceptible tissues. Consequently, tissue sites far removed from the inciting focus may manifest clinical or subclinical inflammatory activity, further illustrating the systemic nature of this response.188

Role of CysLTs in the Systemic Inflammatory Response
Progenitor Cells:
In the bone marrow, CysLTs act synergistically with either GM-CSF or IL-5 to facilitate the growth and subsequent differentiation of progenitor cells. The CysLT1 receptor has been detected on CD34+ progenitor cells, eosinophils, monocytes, macrophages, and some lymphocytes, and a model has been proposed in which CysLTs could prime progenitor cells to differentiate into mature blood cells (Fig 7 ).24 This model was subsequently confirmed when it was demonstrated that adding LTD4 (0.1 µmol/L) to GM-CSF caused a small but significant (p < 0.001) increase in the proliferation of eosinophil hemopoietic progenitor cells in peripheral blood and that adding LTD4 to IL-5 significantly (p = 0.01) increased the proliferation of eosinophil hemopoietic progenitor cells in bone marrow.97 Moreover, adding montelukast (1 µmol/L) suppressed both of these (peripheral blood suppression, p = 0.01; bone marrow suppression, p = 0.001).97



View larger version (31K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 7. Proposed model of how CysLT1 receptor expression in CD34+ progenitor cells and peripheral blood cells promotes the maturation of these cells. LTE4 = leukotriene E4; M-CSF = macrophage-colony stimulating factor. Reproduced with permission from Figueroa et al.24

 
Recruitment:
CysLTs facilitate eosinophil recruitment. Leukocyte rolling is a prerequisite for vascular adhesion and subsequent migration into inflammatory tissues.98 The CysLT LTD4 induces P-selectin–dependent increases of leukocyte rolling flux and a reduction in leukocyte rolling velocity.98 CysLTs also increase eosinophil adhesion by up-regulating ß2-integrin expression in eosinophils (Fig 8 )99100 and stimulate vascular endothelial cells to produce PAF, a phospholipid known to increase leukocyte adhesion by activating ß2-integrin.98 Finally, CysLTs are chemoattractants that induce eosinophil migration (Fig 8).99101 Conversely, LTRAs significantly inhibit both the up-regulation of adhesion molecule expression and eosinophil chemotaxis.99100



View larger version (21K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 8. Effects of LTD4 on eosinophil adhesion molecule expression and eosinophil chemotaxis ex vivo. Blood eosinophils from 32 atopic patients were stimulated with LTD4 (10 nmol/L). Significant up-regulation of adhesion molecule expression (*p < 0.01 compared with constitutive expression) was measured as constitutive expression of macrophage activated protein-1 (Mac-1), expressed as mean fluorescence channel. Significant chemotaxis ({dagger}p < 0.001 compared with random migration) was measured as cellular migration, expressed as cells counted in 10 high-power fields. Adapted from Fregonese et al.99

 
Apoptosis:
Once eosinophils migrate into the inflammatory site, CysLTs prolong their survival, contributing to maintenance of the inflammatory reaction. LTD4 (1 µmol/L) was as effective as GM-CSF (5 ng/mL) or fibronectin (400 ng/mL) in promoting the survival of peripheral blood eosinophils obtained from asthmatic subjects.14 Moreover, inhibition of CysLTs with either leukotriene synthesis inhibitors or LTRAs reduced eosinophil survival both under basal conditions and following stimulation with GM-CSF or fibronectin, demonstrating that CysLTs play a central role in this survival.14

Cytokine Production:
In addition to their modulating effects on cytokine activity, CysLTs also modulate cytokine production and the production of other inflammatory mediators and markers. Leukotriene C4 (LTC4) and LTD4 have been shown to induce messenger RNA expression, stimulating the production of IL-5 (Fig 9 ), TNF-{alpha}, and macrophage inflammatory protein-1ß in mast cells derived from human cord blood and primed with IL-4.102 Moreover, an LTRA inhibited not only this exogenous CysLT-induced cytokine production but also the production of IL-5 (Fig 9) and TNF-{alpha} in response to IgE receptor cross-linking, implying a positive feedback loop involving endogenous CysLTs.102 Similarly, in sensitized mice, high-dose IV montelukast for 3 days prior to antigen inhalation significantly blunted antigen-induced increases in IL-5 and total IgE levels in serum; IL-4, IL-5, and eotaxin levels in BAL fluid; and IL-4, IL-5, and IL-13 protein expression in the total lung.103 Likewise, in allergic asthmatic patients, pranlukast suppressed antigen-induced increases in IL-3, IL-4, IL-5, and GM-CSF in peripheral blood mononuclear cells,104 and zafirlukast suppressed an antigen-induced increase in TNF-{alpha} in BAL fluid.52



View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 9. LTC4 and LTD4 caused an increase of IL-5 in human mast cells (hMCs) primed with IL-4 in vitro. The increase of IL-5 was blocked with 1 µmol/L MK-571, an LTRA, demonstrating that this increase was specific to CysLTs and not the result of IL-4. Adapted from Mellor et al.102

 
Nitric Oxide:
Exhaled nitric oxide (NO), a surrogate marker of airway inflammation, is elevated in asthmatic patients, and LTC4 causes an increase of NO in human polymorphonuclear leukocytes in vitro105 (Fig 10 ). In two separate evaluations of school-age children with mild-to-moderate asthma, exhaled NO was elevated at baseline compared with age-matched nonasthmatic control subjects (p < 0.001) and significantly reduced by 20% (p = 0.02)106 and 30% (p < 0.01)107 following 2 to 4 weeks of montelukast therapy.



View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 10. LTC4 caused an increase of NO in human polymorphonuclear leukocytes (PMN) in vitro. Reproduced from Lärfars et al.105

 
Smooth Muscle:
Epithelial and smooth-muscle cells also generate CysLTs in the lower airway, where they produce both acute and chronic adverse structural changes.108 Acutely, CysLTs are potent bronchoconstrictors.6108 This effect is enhanced in small, clinically significant bronchi (inner diameter, 0.5 to 2 mm), where they are 30-fold more potent than in larger bronchi (inner diameter, 4 to 6 mm).109 LTRAs decrease this bronchoconstriction.109110 In small bronchi isolated from macroscopically normal sections of human lung removed during carcinoma surgery, montelukast and its two main metabolites produced parallel rightward (antagonist) shifts in the concentration-response curves for LTC4-, LTD4-, and leukotriene E4-induced bronchoconstriction.109

Remodeling:
The chronic effects of CysLTs on airway remodeling may be even more important than acute bronchoconstriction. CysLTs enhanced the proliferation of lung fibroblasts to known mitogens.108111 In cultures of murine peritoneal macrophages, LTC4 stimulated a dose-dependent increase in macrophage-derived fibroblast growth factor; conversely, this reaction was inhibited by an LTRA.112 The stimulation response depended on the local balance between CysLTs and prostaglandins.111 In cultures of normal human skin fibroblasts, LTC4 and LTD4 caused dose-dependent cell proliferation when 50 µmol/L indomethacin was added to the medium.111 Moreover, this proliferation could be reproduced by the addition of other cyclooxygenase inhibitors, such as ibuprofen and aspirin, and was abolished by the addition of prostaglandin E2.111 Of note, a reduction in prostaglandin E2 synthesis by respiratory epithelium has been reported in both an equine model of asthma and in patients with aspirin-sensitive asthma.108 In addition, CysLTs promoted pulmonary fibrosis by stimulating fibroblasts to increase collagen synthesis.108 In cultured rat lung fibroblasts, LTC4 produced a dose-dependent increase in collagen synthesis (85% at 1 nmol/L; p < 0.02) that was independent of fibroblast proliferation; this increase was suppressed by an LTRA (FPL-55712).113 Additionally, CysLT levels were increased fivefold in wild-type mice, but were undetectable in 5-lipoxygenase gene knockout mice, following intratracheal instillation of 0.5 U of bleomycin; this difference was associated with decreased histologic evidence of collagen deposition and a 60% reduction (p < 0.05) in lung hydroxyproline, 14 days following the intratracheal instillation, in knockout compared with wild-type mice.114 Similarly, in ovalbumin-sensitized/challenged mice, montelukast markedly reduced collagen deposition in lung interstitium, decreasing the airway fibrosis score by 98.8% (p < 0.001) compared with ovalbumin control (Fig 11 ).115 Through use of electron microscopy, montelukast appeared to reduce the thickness and number of collagen bundles in the lung interstitium.



View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 11. Ovalbumin-treated mice (14 days of intraperitoneal ovalbumin followed by intranasal ovalbumin on days 14 to 75) were used as a model of human asthma. Using morphometric analysis, on a scale of 0 to 4+, the mean airway fibrosis score was 2.2 in ovalbumin-treated mice compared with 0.55 in saline solution-treated mice (*p < 0.0001). The airway fibrosis score was reduced by 98.8% by treatment with the LTRA montelukast. Reproduced from Henderson et al.115

 
Proliferation of Smooth Muscle:
Finally, CysLTs augment growth factor-induced proliferation of airway smooth-muscle cells.108 In human tracheal smooth-muscle cells obtained from lung transplant donors, LTD4 potentiated the effects of either epidermal growth factor or thrombin on DNA synthesis leading to cell proliferation.116 This potentiation was abolished by pranlukast but unaffected by zafirlukast.116 Consistent with this finding, in sensitized mice, ovalbumin challenge produced a 2.1-fold increase in the thickness of the smooth-muscle layer surrounding the airway (p < 0.001); montelukast therapy reduced this proliferative response by 80.1% (p < 0.001).115 The relevance and relationship of these in vitro observations to airway remodeling in asthma awaits further study.


   Conclusion
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
 Conclusion
References
 
In summary, allergic respiratory disorders are the result of a systemic inflammatory process that involves the complex interaction of numerous cell types and mediators. In many of these interactions, CysLTs are key mediators and modulators. Locally, CysLTs increase mucus secretion, promote tissue edema, enhance inflammatory cell survival, and modulate cytokine production and activity. In the bone marrow and peripheral blood, CysLTs facilitate the production and maturation of inflammatory cells. In the vascular system, these products increase adhesion molecule expression, enhance recruitment of these inflammatory cells and, in the airway, promote tissue fibrosis, hypertrophy, hyperplasia, and constriction of smooth-muscle cells.

LTRAs have high systemic bioavailability and, consequently, are able to target various sites of allergic reactions to produce disease control. Data from both animal and human studies747576777879 demonstrate that these agents inhibit the early phase allergic reaction, suppress progenitor cell proliferation, reduce eosinophil survival, decrease cytokine production, and inhibit airway remodeling. Consequently, LTRAs are designed to modify airway tissue responses to CysLTs and thus provide effective treatment of asthma or AR.


   Footnotes
 
Abbreviations: AR = allergic rhinitis; AUC = area under the FEV1-vs-time curve; CysLT = cysteinyl leukotriene; GM-CSF = granulocyte-macrophage colony–stimulating factor; ICAM = intercellular adhesion molecule; ICS = inhaled corticosteroid; IL = interleukin; LTC4 = leukotriene C4; LTD4 = leukotriene D4; LTRA = leukotriene receptor antagonist; NO = nitric oxide; PAF = platelet-activating factor; PC20 = provocative concentration needed to produce a 20% decline in FEV1; PEF = peak expiratory flow; Th2 = type 2 T helper; TNF = tumor necrosis factor; VCAM = vascular cell adhesion molecule

Dr. Busse discloses the following financial interests (2001–2003): consultancies: Bristol-Myers Squibb, Dynavax, Hoffman LaRoche, Fujisawa; advisory boards: GlaxoSmithKline, Aventis, Schering, Pfizer, AstraZeneca; lectures: Merck, GlaxoSmithKline, Aventis; industry-sponsored grants: GlaxoSmithKline, Fujisawa, Aventis, Hoffman LaRoche, Pfizer.

Dr. Kraft discloses the following financial interests: research funding: Merck; consultancies: Aventis, Merck, Genentech, Novartis, Forest; speaker’s bureau: Aventis, Merck, Genentech, Novartis, GlaxoSmithKline.

Received for publication January 29, 2004. Accepted for publication October 8, 2004.


   References
TOP
 Abstract
 Introduction
 Adult Persistent Asthma
 Persistent Asthma in Pediatric...
 Other Asthma Phenotypes
 AR
 Inflammation in Allergic...
 Conclusion
 References
 

  1. Lemanske, RF, Jr, Busse, WW (1997) Asthma. JAMA 278,1855-1873[Abstract]
  2. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics–2002. J Allergy Clin Immunol 2002;110,S141-S219[Medline]
  3. National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma: expert panel report 2. 1997 National Institutes of Health/National Heart, Lung, and Blood Institute. Bethesda, MD:
  4. Lierl, MB Allergy of the upper respiratory tract. Lawlor, GJ Fischer, TJ Adelman, DC eds. Manual of allergy and immunology 1995,95-111 Little, Brown and Company. Boston, MA:
  5. Bousquet, J, van Cauwenberge, P, Khaltaev, N Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108,S147-S334[CrossRef][ISI][Medline]
  6. Barnes, NC, Piper, PJ, Costello, JF Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax 1984;39,500-504[Abstract]
  7. Busse, WW Leukotrienes and inflammation. Am J Respir Crit Care Med 1998;157,S210-S213discussion S247–S218[ISI][Medline]
  8. Johnson, HG, McNee, ML Secretogogue responses of leukotriene C4, D4: comparison of potency in canine trachea in vivo. Prostaglandins 1983;25,237-243[CrossRef][ISI][Medline]
  9. Hamid, Q, Tulic, MK, Liu, MC, et al Inflammatory cells in asthma: mechanisms and implications for therapy. J Allergy Clin Immunol 2003;111,S5-S12discussion S12–S17[CrossRef][Medline]
  10. Salvi, SS, Krishna, MT, Sampson, AP, et al The anti-inflammatory effects of leukotriene-modifying drugs and their use in asthma. Chest 2001;119,1533-1546[Abstract/Free Full Text]
  11. Bisgaard, H, Olsson, P, Bende, M Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans. Clin Allergy 1986;16,289-297[CrossRef][ISI][Medline]
  12. Hay, DW, Torphy, TJ, Undem, BJ Cysteinyl leukotrienes in asthma: old mediators up to new tricks. Trends Pharmacol Sci 1995;16,304-309[CrossRef][Medline]
  13. Samuelsson, B Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983;220,568-575[Abstract/Free Full Text]
  14. Lee, E, Robertson, T, Smith, J, et al Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am J Respir Crit Care Med 2000;161,1881-1886[Abstract/Free Full Text]
  15. Taylor, GW, Taylor, I, Black, P, et al Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet 1989;1,584-588[CrossRef][ISI][Medline]
  16. Drazen, JM, O’Brien, J, Sparrow, D, et al Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis 1992;146,104-108[ISI][Medline]
  17. Reiss, TF, Hill, JB, Harman, E, et al Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997;52,1030-1035[Abstract]
  18. Wenzel, SE, Larsen, GL, Johnston, K, et al Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis 1990;142,112-119[ISI][Medline]
  19. Pavord, ID, Ward, R, Woltmann, G, et al Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med 1999;160,1905-1909[Abstract/Free Full Text]
  20. Macfarlane, AJ, Dworski, R, Sheller, JR, et al Sputum cysteinyl leukotrienes increase 24 hours after allergen inhalation in atopic asthmatics. Am J Respir Crit Care Med 2000;161,1553-1558[Abstract/Free Full Text]
  21. Miadonna, A, Tedeschi, A, Leggieri, E, et al Behavior and clinical relevance of histamine and leukotrienes C4 and B4 in grass pollen-induced rhinitis. Am Rev Respir Dis 1987;136,357-362[ISI][Medline]
  22. Lynch, KR, O’Neill, GP, Liu, Q, et al Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999;399,789-793[CrossRef][Medline]
  23. Evans, J, Figueroa, DJ Cloning and expression of leukotriene receptors. Clin Exp Allergy Rev 2001;1,142-144[CrossRef]
  24. Figueroa, DJ, Breyer, RM, Defoe, SK, et al Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med 2001;163,226-233[Abstract/Free Full Text]
  25. Mellor, EA, Maekawa, A, Austen, KF, et al Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc Natl Acad Sci U S A 2001;98,7964-7969[Abstract/Free Full Text]
  26. Shirasaki, H, Kanaizumi, E, Watanabe, K, et al Expression and localization of the cysteinyl leukotriene 1 receptor in human nasal mucosa. Clin Exp Allergy 2002;32,1007-1012[CrossRef][ISI][Medline]
  27. Barnes, N, Wei, LX, Reiss, TF, et al Analysis of montelukast in mild persistent asthmatic patients with near-normal lung function. Respir Med 2001;95,379-386[CrossRef][ISI][Medline]
  28. Fish, JE, Kemp, JP, Lockey, RF, et al Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group. Clin Ther 1997;19,675-690[CrossRef][ISI][Medline]
  29. Reiss, TF, Chervinsky, P, Dockhorn, RJ, et al Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998;158,1213-1220[Abstract/Free Full Text]
  30. Barnes, NC, Pujet, JC Pranlukast, a novel leukotriene receptor antagonist: results of the first European, placebo controlled, multicentre clinical study in asthma. Thorax 1997;52,523-527[Abstract]
  31. Kemp, JP, Minkwitz, MC, Bonuccelli, CM, et al Therapeutic effect of zafirlukast as monotherapy in steroid-naive patients with severe persistent asthma. Chest 1999;115,336-342[Abstract/Free Full Text]
  32. Dockhorn, RJ, Baumgartner, RA, Leff, JA, et al Comparison of the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax 2000;55,260-265[Abstract/Free Full Text]
  33. Zhang, J, Yu, C, Noonan, G, et al Effect of montelukast, a once-daily leukotriene receptor antagonist, on peak expiratory flow variability. Clin Ther 2002;24,574-582[CrossRef][ISI][Medline]
  34. Ishioka, S, Hozawa, S, Haruta, Y, et al Effects of pranlukast, a cysteinyl leukotriene antagonist, on bronchial responsiveness to methacholine in aspirin-intolerant asthmatics treated with corticosteroids. Hiroshima J Med Sci 2000;49,105-108[Medline]
  35. Obase, Y, Shimoda, T, Tomari, S, et al Efficacy and safety of long-term treatment of asthmatic patients with pranlukast, a cysteinyl-leukotriene-receptor antagonist: four-year follow-up study. Ann Allergy Asthma Immunol 2001;87,43-47[ISI][Medline]
  36. Ferreira, MB, Santos, AS, Pregal, AL, et al Leukotriene receptor antagonists (montelukast) in the treatment of asthma crisis: preliminary results of a double-blind placebo controlled randomized study. Allerg Immunol (Paris) 2001;33,315-318[Medline]
  37. Malmstrom, K, Rodriguez-Gomez, G, Guerra, J, et al Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med 1999;130,487-495[Abstract/Free Full Text]
  38. Israel, E, Chervinsky, PS, Friedman, B, et al Effects of montelukast and beclomethasone on airway function and asthma control. J Allergy Clin Immunol 2002;110,847-854[CrossRef][ISI][Medline]
  39. Baumgartner, RA, Martinez, G, Edelman, JM, et al Distribution of therapeutic response in asthma control between oral montelukast and inhaled beclomethasone. Eur Respir J 2003;21,123-128[Abstract/Free Full Text]
  40. Williams, B, Noonan, G, Reiss, TF, et al Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older. Clin Exp Allergy 2001;31,845-854[CrossRef][ISI][Medline]
  41. Riccioni, G, Vecchia, RD, D’Orazio, N, et al Comparison of montelukast and budesonide on bronchial reactivity in subjects with mild-moderate persistent asthma. Pulm Pharmacol Ther 2003;16,111-114[CrossRef][ISI][Medline]
  42. Carratu, P, Morelli, N, Freire, AX, et al Effect of zafirlukast on methacholine and ultrasonically nebulized distilled water challenge in patients with mild asthma. Respiration 2003;70,249-253[CrossRef][ISI][Medline]
  43. Yoshida, S, Ishizaki, Y, Shoji, T, et al Effect of pranlukast on bronchial inflammation in patients with asthma. Clin Exp Allergy 2000;30,1008-1014[CrossRef][ISI][Medline]
  44. Westbroek, J, Pasma, HR Effects of 2 weeks of treatment with fluticasone propionate 100 mcg b.d. by comparison with zafirlukast 20 mg b.d. on bronchial hyper-responsiveness in patients with mild to moderate asthma. Respir Med 2000;94,112-118[CrossRef][ISI][Medline]
  45. Rorke, S, Jennison, S, Jeffs, JA, et al Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma. Thorax 2002;57,323-327[Abstract/Free Full Text]
  46. Dempsey, OJ, Wilson, AM, Sims, EJ, et al Additive bronchoprotective and bronchodilator effects with single doses of salmeterol and montelukast in asthmatic patients receiving inhaled corticosteroids. Chest 2000;117,950-953[Abstract/Free Full Text]
  47. Dempsey, OJ, Fowler, SJ, Wilson, A, et al Effects of adding either a leukotriene receptor antagonist or low-dose theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. Chest 2002;122,151-159[Abstract/Free Full Text]
  48. Smith, LJ, Hanby, LA, Lavins, BJ, et al A single dose of zafirlukast reduces LTD4-induced bronchoconstriction in patients on maintenance inhaled corticosteroid therapy. Ann Allergy Asthma Immunol 1998;81,43-49[ISI][Medline]
  49. Suissa, S, Dennis, R, Ernst, P, et al Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997;126,177-183[Abstract/Free Full Text]
  50. Nathan, RA, Bernstein, JA, Bielory, L, et al Zafirlukast improves asthma symptoms and quality of life in patients with moderate reversible airflow obstruction. J Allergy Clin Immunol 1998;102,935-942[CrossRef][ISI][Medline]
  51. Virchow, JC, Prasse, A, Naya, I, et al Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162,578-585[Abstract/Free Full Text]
  52. Calhoun, WJ, Lavins, BJ, Minkwitz, MC, et al Effect of zafirlukast (Accolate) on cellular mediators of inflammation: bronchoalveolar lavage fluid findings after segmental antigen challenge. Am J Respir Crit Care Med 1998;157,1381-1389
  53. Pizzichini, E, Leff, JA, Reiss, TF, et al Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999;14,12-18[Abstract]
  54. Laviolette, M, Malmstrom, K, Lu, S, et al Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999;160,1862-1868[Abstract/Free Full Text]
  55. Price, DB, Hernandez, D, Magyar, P, et al Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003;58,211-216[Abstract/Free Full Text]
  56. Lofdahl, C-G, Reiss, TF, Leff, JA, et al Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999;319,87-90[Abstract/Free Full Text]
  57. Centanni, S, Santus, P, Casanova, F, et al Evaluation of the effects of zafirlukast 40 mg b.i.d. in addition to preexisting therapy of high-dose inhaled steroids on symptomatic patients with reversible respiratory obstruction: preliminary data. Drugs Exp Clin Res 2000;26,133-138[ISI][Medline]
  58. Knorr, B, Matz, J, Bernstein, JA, et al Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 1998;279,1181-1186[Abstract/Free Full Text]
  59. Knorr, B, Franchi, LM, Bisgaard, H, et al Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108,E48
  60. Pearlman, DS, Lampl, KL, Dowling, PJ, Jr, et al Effectiveness and tolerability of zafirlukast for the treatment of asthma in children. Clin Ther 2000;22,732-747[CrossRef][ISI][Medline]
  61. Simons, FE, Villa, JR, Lee, BW, et al Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study. J Pediatr 2001;138,694-698[CrossRef][ISI][Medline]
  62. Maspero, JF, Duenas-Meza, E, Volovitz, B, et al Oral montelukast versus inhaled beclomethasone in 6- to 11-year-old children with asthma: results of an open-label extension study evaluating long-term safety, satisfaction, and adherence with therapy. Curr Med Res Opin 2001;17,96-104[CrossRef][ISI][Medline]
  63. Ng, DK, Law, AK, Chau, KW, et al Use of montelukast in the treatment of early childhood wheezing from clinical experience with three cases. Respirology 2000;5,389-392[CrossRef][Medline]
  64. Bisgaard, H A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167,379-383[Abstract/Free Full Text]
  65. Phipatanakul, W, Greene, C, Downes, SJ, et al Montelukast improves asthma control in asthmatic children maintained on inhaled corticosteroids. Ann Allergy Asthma Immunol 2003;91,49-54[ISI][Medline]
  66. Stelmach, I, Jerzynska, J, Kuna, P A randomized, double-blind trial of the effect of treatment with montelukast on bronchial hyperresponsiveness and serum eosinophilic cationic protein (ECP), soluble interleukin 2 receptor (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1 (sICAM-1) in children with asthma. J Allergy Clin Immunol 2002;109,257-263[CrossRef][ISI][Medline]
  67. Camargo, CA, Jr, Smithline, HA, Malice, MP, et al A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003;167,528-533[Abstract/Free Full Text]
  68. Leff, JA, Busse, WW, Pearlman, D, et al Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339,147-152[Abstract/Free Full Text]
  69. Dahlen, B, Roquet, A, Inman, MD, et al Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction. J Allergy Clin Immunol 2002;109,789-793[CrossRef][ISI][Medline]
  70. Kemp, JP, Dockhorn, RJ, Shapiro, GG, et al Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 1998;133,424-428[CrossRef]