PEDIATRICS Vol. 107 No. 2 February 2001, pp. 381-390

REVIEW ARTICLE:
Leukotriene Modifiers in Pediatric Asthma Management

Hans Bisgaard, MD, DMSc

From the Department of Paediatrics, Copenhagen University Hospital, Copenhagen, Denmark.

	ABSTRACT

Top Abstract Conclusion References

Cysteinyl leukotrienes (Cys-LTs) are mediators released in asthma and virus-induced wheezing. Corticosteroids appear to have little or no effect on this release in vivo. Cys-LTs are both direct bronchoconstrictors and proinflammatory substances that mediate several steps in the pathophysiology of chronic asthma, including inflammatory cell recruitment, vascular leakage, and possibly airway remodeling. Blocking studies show that Cys-LTs are pivotal mediators in the pathophysiology of asthma. Cys-LTs are key components in the early and late allergic airway response and also contribute to bronchial obstruction after exercise and hyperventilation of cold, dry air in asthmatics. LT modifiers reduce airway eosinophil numbers and exhaled nitric oxide levels. Together these findings support an important role for the Cys-LTs in the asthma airway inflammation. Cys-LT receptor antagonists (Cys-LTRA) are generally well-tolerated. Phase III randomized, controlled clinical trials (RCT) show that LT modifiers are moderately effective, apparently with a particular between-patient variability in their clinical response. The clinical effects of LT modifiers are additive to those of -agonists and corticosteroids. The onset of action of LT modifiers is within 1 to several days, and not rapid enough to make them useful as rescue treatment. Although LT modifiers possess some antiinflammatory activity, they cannot substitute for corticosteroids for inflammation control. LT modifiers are alternatives to long-acting -agonists as complementary treatment to inhaled corticosteroids in pediatric asthma management because they provide bronchodilation and bronchoprotection without development of tolerance, and complement the antiinflammatory activity unchecked by steroids. In addition, the Cys-LTRA montelukast has been shown to ameliorate asthmatic symptoms and provide bronchoprotection in asthmatic preschool children from 2 years of age, which is of particular importance in this difficult-to-manage group of asthmatics. Given their efficacy, antiinflammatory activity, oral administration, and safety, LT modifiers will play an important role in the treatment of asthmatic children.

Leukotriene (LT) modifiers represent the first new therapeutic class in asthma since the introduction of inhaled steroids in 1972, and they are the first mediator-specific therapy for asthma. This treatment is tailored to the known pathophysiology of asthma and represents the first example of drug development design based on our increased understanding of the molecular biology of asthma. The long history is fascinating from its discovery in 1938 as a biologic substance characterized by its particular slow contracting ability of smooth muscles, through the unraveling of its chemical nature 4 decades later followed by the awarding of the Nobel prize in 1982, up to the engineering in the recent decade of specific receptor antagonists and identification of the LT receptor in human bronchioles. LT modifiers (both receptor antagonists and biosynthesis inhibitors) have proven efficacious in randomized, controlled clinical trials (RCTs) of asthma in adults, children and even preschool children. They have been rapidly introduced into clinical practice worldwide, although their position in treatment guidelines is still evolving. Therefore, it seems timely to review the role of LTs in asthma airway inflammation and the evidence for the effect of LT modifiers from RCTs with a view to their potential role in pediatric asthma management.

	BIOCHEMISTRY OF LTS (FIG 1)

LTs are 20-carbon unsaturated fatty acids released from membrane phospholipids via the arachidonic acid (AA) cascade. Activation of phospholipase A2 results in the release of membrane-bound AA. Free AA can be converted by cyclooxygenase (CO) to form prostanoids (prostaglandins, prostacyclin, and thromboxane) or converted via the 5-lipoxygenase (5-LO) pathway to form LTs. The AA is presented to the 5-LO enzyme by the 5-LO-activating protein (FLAP) resident in the nuclear membrane. The 5-LO pathway results in the formation of 2 classes of LTs, the nonpeptide LTs LTA₄ and LTB₄ and the cysteinyl leukotrienes (Cys-LTs) LTC₄, LTD₄, and LTE₄. LTC₄ is actively transported extracellularly, where subsequent cleavage of amino acids yields LTD₄ and LTE₄. Cys-LTs are degraded rapidly in the extracellular space with a very short half-life. LTE₄ undergoes biliary and urinary excretion partly as an end-product and is partly oxidized to inactive metabolites.

View larger version (18K): [in this window] [in a new window]   Fig. 1.   AA cascade. CO indicates cyclooxygenase; 5-LO, 5-lipoxygenase; FLAP, 5-LO activating protein.

The Cys-LT1 receptor was recently cloned. In the normal human lung, expression of Cys-LT1 receptor mRNA was observed in bronchial smooth muscle cells and tissue macrophages, among other cell types,¹ which corroborate the bronchoconstrictive and proinflammatory nature of Cys-LT. The cloning of the human Cys-LT1 receptor allows fascinating future studies into receptor distribution, species differences, and possible receptor heterogeneity.

	SOURCES OF CYS-LT

LTs are synthesized de novo from cell membrane phospholipids in response to a variety of biologic signals including antigen challenge of sensitized tissues. Cys-LTs are produced both by constitutive cells in the lungs (mast cells and alveolar macrophages) and by infiltrating cells (eosinophils). LTB₄ is predominantly produced by neutrophils.

Cys-LT production is upregulated in asthma. Blood eosinophils from children with asthma release more Cys-LT than do those of controls.^2,3 Cys-LT levels were increased at baseline in asthma patients,⁴ correlating with disease severity⁵ and with additional increases observed during spontaneous attacks,⁶ allergen challenge,^7,8 and exercise-induced bronchoconstriction (EIB).^9,10

LTs also seem upregulated in wheezy disorders in young children. Alveolar macrophages from wheezy infants were shown to release more LTB₄ than those from nonwheezy infants.¹¹ Children with wheezing released significantly more LTC₄ in nasopharyngeal secretions than did healthy controls, and this increase was further augmented in wheezy children who shed respiratory virus as compared with wheezy children without evidence of viral infection.^12,13 In infants, increased quantities of eicosanoids, correlating with disease severity, were found in nasopharyngeal secretions during episodes of acute viral bronchiolitis.¹⁴

Cys-LT levels are also increased in airway samples from infants with severe bronchopulmonary dysplasia and in children with cystic fibrosis.^16,17

	BIOLOGIC EFFECTS OF CYS-LT

Cys-LTs cause profound bronchoconstriction in peripheral and central airways and are the most potent bronchoconstricting agent yet discovered, about 100 to 1000 times more potent than histamine and with a more sustained bronchoconstriction.^17-20

Asthmatics are hyperreactive to Cys-LTs,^17,20 and Cys-LTs further increase this hyperreactivity^18,21,22 as well as the maximum bronchoconstrictor response²³ probably through an inflammatory mechanism.²⁴

LTD₄ specifically increases blood flow in human skin and airway mucosa and increases the vascular permeability and interstitial transport of macromolecules in human skin, processes that contribute to edema.^25-27 The escape of plasma proteins into the tissue provides the source of potent plasma protein-derived inflammatory mediators, including the kinins and complement and clotting systems, which may form mucus plugs, inhibit mucociliary clearance, and fuel the inflammatory process.

Cys-LTs may have an effect on airway remodeling in chronic asthma. Cys-LTs have been shown to significantly enhance the mitogenesis of cultured human airway epithelial cells and human bronchial smooth muscle cells.^28-30 In an animal model, the increase in bronchial smooth muscle mass after allergen challenge was effectively blocked by Cys-LT receptor antagonists (Cys-LTRAs).³¹

Cys-LTs also act on the upper respiratory tract where they caused a dose-related nasal obstruction, but not the reflex-mediated symptoms of allergic rhinitis, such as nasal itching, sneezing, or secretion.²⁶ The significant nasal blockage still present in allergic rhinitis after antihistamine treatment³² may be attributable to Cys-LTs-induced nasal mucosal engorgement; as such nasal obstruction was reduced by 5-LO inhibition.^33,34

The presence of thick, tenacious mucus plugs in airway lumina is a frequent finding in asthmatic patients. Mucus may accumulate because of its increased production or resulting from inefficient elimination caused by ciliary dysfunction. LTC₄ and LTD₄ are potent airway mucus secretagogues in vitro.^35,36 However, Cys-LTs did not increase nasal secretion in humans²⁶ nor was a noticeable increase in mucus production reported by healthy or asthmatic patients after inhaling Cys-LTs.^17-20 This therefore casts doubt on the role for Cys-LTs as secretagogues in humans. Cys-LTs have been shown to cause a slight but progressive slowing of ciliary beat frequency in human airway cells.^37,38 This effect may contribute to the reduced mucociliary clearance typical of the asthmatic patient and increase the retention of inhaled allergens and other possibly noxious substances. The number of eosinophils in lamina propria increased by a factor of 10 in asthmatic patients 4 hours after inhalation of LTE₄, although no such change was observed after inhalation of methacholine with a dose eliciting a comparable degree of bronchospasm.³⁹ Similarly, LTD₄ inhalation increased airway eosinophils in asthmatic patients as measured in cellular differentials of induced sputum taken 4 hours after challenge.⁴⁰ The mechanism seems to be a direct chemotactic activity of Cys-LTs for eosinophils.⁴¹

The role of LTB₄ remains obscure. We previously showed LTB₄ to be a potent chemoattractant for eosinophils and neutrophils in human skin.⁴² However, inhaled LTB₄ had no effect on airway resistance and responsiveness in both controls and asthmatic patients.⁴³ Whereas a LTB₄ receptor antagonist decreased the number of neutrophils in bronchoalveolar (BAL) fluids as expected, it failed to affect the number of lymphocytes, macrophages, and eosinophils in the fluid and failed to reduce bronchoconstriction.⁴⁴ LTB₄ may thus not be involved in chronic asthma, although it may be associated with the neutrophilia observed in the late response to allergen challenge and during acute severe asthma.⁴⁵

	EFFECTS OF CYS-LTS BLOCKADE IN MODELS OF ASTHMA

The development of Cys-LT inhibitors has added new and compelling evidence to support a central role of Cys-LTs in asthma pathophysiology. The early and late responses to allergen challenge are classic models of asthmatic inflammation that capture several important aspects of the disease. The early response is significantly attenuated by Cys-LT inhibition by approximately 60% to 80% compared with placebo.^46-48 The combination of a Cys-LT modifier and an antihistamine further improved lung function during the early and the late allergic reactions.⁴⁸ Attenuation of the late response has been observed in most studies on Cys-LT modifiers^46,48 although not in all.⁴⁷ Cys-LT release seems to increase during the late-phase reaction according to some reports.^48,49 In summary, it appears that Cys-LTs contribute to both the early and late allergic reactions.

Bronchial hyperreactivity is integral to asthma pathophysiology and correlates in some studies with the degree of airway inflammation. Bronchial hyperreactivity is reflected in an abnormal response to inhaled irritants (eg, histamine and methacholine), exercise, or hyperventilation of cold, dry air. Bronchial hyperresponsiveness to methacholine was significantly reduced with the use of Cys-LT antagonists in certain studies,^50,51 even in patients on concurrent treatment with inhaled corticosteroids.⁵² In contrast, montelukast exerted no significant effect on methacholine reactivity in a 12-week treatment of 110 adult asthmatic patients.⁵³ EIB was significantly attenuated by Cys-LT modifiers.^53-56 The protection was on the order of 40% to 60% in most studies, irrespective of different potencies of the Cys-LT modifiers under study. These results suggest the relative importance of Cys-LTs in EIB. Cold-air induced bronchoconstriction was also attenuated by Cys-LTRAs as well as by 5-LO inhibitors.^57-59

Eosinophils are considered pivotal cells in the airway inflammation of asthma. LT modifiers reduce airway eosinophilia. The LT synthesis inhibitor zileuton blunted eosinophilic influx 24 hours after bronchial segmental allergen challenge, as reflected by BAL cell counts^4,60 and decrease in peripheral blood eosinophils.⁶¹ The Cys-LTRA zafirlukast in supraclinical doses decreased the number of eosinophils in BAL fluid 48 hours after segmental allergen challenge.⁶² Montelukast at the clinical dose reduced sputum eosinophilia in adult asthmatics.⁶³ The number of T cells (CD3 and CD4), mast cells, and activated eosinophils in bronchial biopsies was reduced by treatment with pranlukast.⁶⁴ Peripheral blood eosinophils were consistently reduced by a median 15% by treatment with montelukast in a number of RCTs comprising a total of 1920 adults,^63,65-68 336 school-aged children,⁶⁹ and 689 preschool children with asthma.⁷⁰ This effect on peripheral eosinophils was comparable to that of 0.4 mg of inhaled beclomethasone dipropionate (BDP).⁶⁶

Exhaled nitric oxide (FeNO) is also reduced by treatment with a Cys-LTRA (montelukast). The reduction was apparent in children irrespective of concurrent treatment with inhaled corticosteroids and was noticeable 2 days after start of treatment.⁷¹ FeNO probably reflects the eosinophilic inflammation of the conducting airways.⁷² A reduction in FeNO by Cys-LTRAs corroborates the role of Cys-LTs in the airway inflammation of asthmatics.

Aspirin-sensitive asthma is caused by a specific mechanism present in a minority of asthmatic patients. This mechanism is poorly understood but may be a shunting of the AA substrate from the CO pathway to the 5-LO pathway, upregulating the Cys-LT pathway. LT inhibition seems particularly effective in patients with aspirin-sensitive asthma. LT modifiers resulted in almost complete inhibition of aspirin-induced bronchoconstriction as well as symptoms of the skin and gastrointestinal tract.^34,73

The aforementioned studies of Cys-LT modifiers in several asthma models show that Cys-LTs are pivotal mediators in the pathophysiology of bronchial asthma. Clearly, Cys-LTs are not simply bronchoconstrictors but may also contribute to chronic inflammatory changes.

	EFFECTS OF STEROIDS ON CYS-LT SYNTHESIS

Corticosteroids generally reduce the in vitro production of Cys-LTs, presumably through blockade of the phospholipase enzyme responsible for liberating AA from the cell membrane phospholipid.⁷⁴ While one ex vivo study found that dexamethasone exposure was unable to inhibit stimulated LTC₄ release from alveolar macrophages from wheezy infants,¹¹ many studies do show in vitro inhibition. Indeed, inhibition of LT formation has been thought to contribute to the efficacy of corticosteroids in the treatment of asthma.⁷⁵ However, several studies have highlighted differences between the effects of corticosteroids on LT synthesis in vivo and in vitro. In vivo, baseline excretion of Cys-LTs is not suppressed by corticosteroids.^75,76 Oral prednisone for 1 week had no effect on LTE₄ concentrations in BAL and urine samples nor was an effect observed on the rise after local bronchial allergen challenge. The in vitro synthesis of LTB₄ and thromboxane from macrophage-rich BAL cells, however, was reduced in the same patients.⁷⁷ The inhaled corticosteroid fluticasone propionate effectively prevented the asthma attack from allergen challenge. It had no effect, however, on increased urinary LTE₄ excretion after allergen challenge.⁷⁸ The reasons for such differences between in vitro and in vivo data are unknown. It has been suggested that other mediators present in vivo, such as interleukin 3, may modulate susceptibility to corticosteroids.⁷⁹ Collectively, these studies suggest that Cys-LT production is unchecked by corticosteroids in vivo.

	CLINICAL EFFICACY OF CYS-LT MODIFIERS

Zileuton is the only marketed drug with a specific effect on Cys-LT synthesis via inhibition of the 5-LO enzyme. Three Cys-LTRAspranlukast, zafirlukast, and montelukasthave been approved in various markets.

Zileuton

Zileuton is administered orally 4 times daily (QID). It is metabolized by the cytochrome P450 isoenzymes and may therefore interact with other drugs metabolized by these enzymes, such as theophylline and warfarin.^80,81 The use of zileuton is hampered by the QID dosing regimen and the requirement for monitoring of liver enzymes.^81,82 It is approved for the treatment of asthma in patients 12 years and older.⁸¹ Three RCTs have reported the effects of 6 to 13 weeks treatment with zileuton^61,83,84 while one RCT showed no difference from theophylline treatment.⁸⁵ Zileuton 1.6 g/day and 2.4 g/day proved modestly effective against placebo in parallel groups of adult patients with moderate to severe asthma (mean forced expiratory volume in 1 second [FEV₁] 67%-78% predicted; 4-6 daily doses of inhaled 2-agonist and 3-5 nocturnal awakenings per week attributable to asthma) yet without concurrent steroid treatment. The top of the dose-response curve was not ascertained.

There have been no RCTs on the effect of zileuton in pediatric asthma.

Zafirlukast

Zafirlukast (AstraZeneca, Wilmington, DE) is a Cys-LTRA approved for treatment of asthma in children 7 years and older.⁸⁶ It is administered orally twice daily (BID). There is up to a 40% reduction in bioavailability when zafirlukast is taken with food.⁸⁷ Zafirlukast is metabolized by the liver, and hepatic cytochrome P450 is inhibited by therapeutic concentrations of zafirlukast. Therefore, there is a risk of drug interactions, and transient elevations of liver enzymes have been reported. These reports in patients receiving high doses of zafirlukast (80 mg BID) preclude the use of dosages exceeding current labeling.⁸⁷ There is also concern that the recommended dosage may not achieve optimal inhibition of Cys-LTs.

Zafirlukast has proved modestly effective for asthmatics 12 years and older. Three RCTs have reported the effect of 3 to 12 weeks treatment with Zafirlukast over placebo. The patients included were adult asthmatics with moderate to severe asthma (mean FEV₁ 60-68% predicted; 5-6 daily doses of inhaled 2-agonist and 4-6 nocturnal awakenings per week attributable to asthma), yet without concurrent treatment with steroid.^88-90 Dose-related clinical effect on daily asthma symptoms, use of as-needed medication, and baseline lung function were demonstrated. FEV₁ improved by 11% over placebo and use of 2-agonist decreased by up to 1 puff per day and nocturnal awakenings by 2.6 per week as compared with placebo.⁸⁸ The number of symptomatic days was reduced from 27 to 24 per month, and the number of days without use of -agonists increased from 6.0 to 11.3 per month. The number of health care contacts decreased from 0.40 to 0.19 per month.⁹¹ These effects seem modest, although statistically significant. The study failed to define a plateau at the highest dose used, which may indicate that higher doses might be more efficacious.

Pediatric Study With Zafirlukast The therapeutic effects of zafirlukast have been reported in 1 RCT in children. In a randomized, double-blind, 3-way, crossover study of 39 asthmatic children from 6 to 14 years old, zafirlukast 5, 10, 20, and 40 mg and placebo were tested for their effects on EIB.⁹² At exercise challenge at 4 hours after dosing, treatment with zafirlukast attenuated the maximal percentage decrease in FEV₁ compared with placebo (mean value range for maximal FEV₁ decrease: 11.9% to 9% after zafirlukast, 17.9% to 16.9% after placebo) with no apparent dose-response relation in the range of 5 to 40 mg.

Montelukast

Montelukast (Merck & Co, Inc, Whitehouse Station, NJ) is an orally bioavailable Cys-LTRA administered once daily.⁹³ The drug has been approved for the treatment of asthma in children 2 years and older.⁹⁴ There is no difference in bioavailability in young and elderly patients, and food does not have a clinically important influence with chronic administration.⁹⁴ Therapeutic concentrations of montelukast do not inhibit the cytochrome P450 isoenzymes.

Dose-ranging studies evaluating multiple doses and dosage schedules of montelukast have been reported in adults with chronic asthma. These studies have evaluated measures of asthma control, including lung function, use of rescue treatment, and symptom scores. Doses of 10 to 200 mg had similar efficacy, while 2 mg produced suboptimal response.^65,67 BID dosing provided no additional benefit over once-daily dosing.⁶⁷ The bronchoprotective effect against EIB was also dose-related up to 10 mg in adult asthmatics, and there was no additional improvement with higher doses.⁵⁶

Dose-ranging studies have not been performed in children. Instead, the pediatric dosage was chosen as the dosage yielding a pharmacokinetic profile (single-dose area under the plasma concentration-time curve) in children comparable to that achieved with the 10-mg tablet in adults.⁹⁵

The effects of 3 to 12 weeks of treatment of montelukast over placebo on chronic asthma in adults were reported in 5 RCTs.^65-67,68,96 The patients included were adult asthmatics with moderate to severe asthma (mean FEV₁ 60-68% predicted; 5-6 daily puffs of inhaled 2-agonist and 4-6 nocturnal awakenings per week attributable to asthma), yet without concurrent treatment with steroid. Montelukast showed an effect over placebo on daily asthma symptoms, use of as-needed medication, asthma exacerbations, nocturnal awakenings, and baseline lung function. Mean improvement in lung function during montelukast treatment was 6% to 13% over placebo. Use of rescue was reduced by approximately 1 puff per day and nocturnal awakenings by approximately 1 night per week.

The effect of montelukast was compared with that of 200 µg BDP BID in a RCT of adult patients with moderate to severe asthma (mean FEV₁ of 66% of predicted value, 5-6 daily doses of -agonist and 5-6 nocturnal awakenings per week attributable to asthma). Inhaled corticosteroid was more efficacious than montelukast.⁶⁶

The complementary effect of montelukast to that of established treatment with BDP was reported in 2 RCT.^96,97 The addition of montelukast provided significantly improved lung function, symptom control, and reduced exacerbation rates compared with beclomethasone monotherapy, and allowed tapering of the steroid dose.

Montelukast provided some bronchoprotection against EIB in mild asthmatic adults.⁵³ The patients had mild symptoms and were treated only with inhaled -agonists as needed. During treatment, montelukast provided a 47% reduction in maximum percentage decrease in FEV₁ as compared with placebo. Considerable variation was observed among patients; 23% had complete protection, whereas another 25% had little or no response.

Tolerance to the effect of montelukast was studied in adult asthmatics and compared with that of salmeterol. An exercise challenge was performed at the end of the dosing interval (21 hours for montelukast and 9 for salmeterol) after 3 days, 4 weeks, and 8 weeks of treatment.⁹⁸ Montelukast exhibited a higher level of protection, which was maintained when first- and last-dose effects were compared (58% vs 57% protection), whereas salmeterol showed reduced protection (44% vs 30%) over this period attributable to development of tolerance.

Pediatric Studies With Montelukast

Four RCTs with montelukast in pediatrics have been published.^59,69,70,99 Exercise-induced bronchoprotection was studied in asthmatic children. Montelukast provided an ~30% reduction in maximum percentage decrease in FEV₁ with 5 mg montelukast at ~20 hours after dosing.⁹⁹

Montelukast was compared with placebo in 336 children 6 to 15 years old with moderate to severe asthma (mean FEV₁ 72% predicted; 2-3 daily doses of -agonist; 1-2 nocturnal awakenings per week attributable to asthma).⁶⁹ Approximately one third of the children were maintained on inhaled steroids during the study at a constant dose. The primary outcome variable, FEV₁, increased by a mean of 8% from baseline, compared with 4% in the placebo group (P < .001). The use of inhaled -agonists was significantly reduced by 0.6 dose per day compared with a 0.2 dose per day in the placebo group. Asthma exacerbations were significantly reduced with montelukast (85% of patients) compared with placebo group (96% of patients). Quality of life was slightly but significantly higher within all domains for the montelukast-treated children. Nocturnal awakenings did not decline significantly with active treatment. The onset of action of montelukast occurred within 1 day after the first dose. There was no evidence of development of tolerance during the 8-week treatment period.

Subsequent subanalyses focused on 122 patients receiving concurrent treatment with inhaled corticosteroids. In this subgroup, FEV₁ improved 9.4% with montelukast compared with 4.7% with placebo. In the 206 children with no concurrent corticosteroid treatment, FEV₁ improved 9.2% with montelukast versus 5.2% with placebo.¹⁰⁰ These results show that the treatment effect of montelukast was additive to that of concurrent corticosteroid treatment.

We recently documented the bronchoprotective effect of montelukast in asthmatic preschool children <6 years old. Cold-air hyperventilation caused a 17% increase in airway resistance after pretreatment with montelukast compared with 47% after placebo pretreatment (P < .01).⁵⁹ The bronchoprotective effect seemed independent of concurrent steroid treatment. This indicates clinically significant bronchoprotection with montelukast for the difficult-to-treat population of asthmatic toddlers.

Montelukast caused significant improvement in the overall asthma control in patients 2 to 5 years old. The effect of montelukast was recently reported in a RCT of 689 children 2 to 5 years old with physician-diagnosed asthma (defined as at least 3 episodes within 1 year before start of study).⁷⁰ Treatment entailed 4-mg chewable montelukast tablets once daily for 12 weeks after a run-in period. Twenty-seven percent of the patients received concomitant inhaled corticosteroids, and 13% inhaled cromolyn at a constant daily dose. There were no notable differences between treatment groups in the incidence of clinical and laboratory adverse experiences except that a significantly smaller percentage of patients on montelukast than on placebo reported adverse respiratory experiences. Montelukast caused a significant reduction in days with symptoms, daytime asthma symptom scores, days of -agonist use, use of corticosteroid rescue, and peripheral blood eosinophils.⁷⁰ Montelukast caused significant improvement in asthma control in patients 2 to 5 years old.

In summary, Cys-LTRAs have proved moderately effective in asthmatic children from 2 years of age and older, an effect which appears to be complementary to current corticosteroid treatment.

	MODE OF ACTION OF LT MODIFIERS

LT modifiers do not fit into the traditional grouping of bronchodilators and antiinflammatory drugs. They have bronchodilatory properties, which in asthmatics are additive to the activity of -agonists.^83,101,102 This makes them useful as adjunctive therapy, but they should never substitute for -agonists in rescue therapy because of their slow onset of action although studies in acute asthma with intravenous formulations are in progress. In contrast to -agonists, LT modifiers do not induce bronchodilation in healthy volunteers.¹⁰³ This suggests that persistent activation of Cys-LT receptors, resulting in increased airway tone, is an integral and specific component of asthma inflammation that is not present in people without asthma.

LT modifiers provide some antiinflammatory effects, as reflected in reduced airway eosinophilia, reduced FeNO levels, and modified microvascular permeability. However, the inflammation is not checked to the same extent as with corticosteroids. Therefore, LT modifiers could not substitute steroids for antiinflammatory control.

Most of the improvement in airway function occurs within the first treatment day, although delayed effects have been reported in some trials.^58,83,104

Cys-LTRAs have been found to have complementary effects to those of corticosteroids in chronic asthma in agreement with the apparent lack of effect by steroids of the Cys-LT release. Dose tapering from the required high-dose corticosteroid monotherapy was facilitated by addition of Cys-LTRAs.^{96,97,104,105}

Patients do not appear to develop tolerance to LT modifiers, even in 24-month extensions of clinical trials, and no rebound effect is observed after treatment is ended.

	ADVERSE EFFECTS OF LT INHIBITORS

Cys-LTRAs are generally well-tolerated. The majority of reported adverse events were mild or transient. The Cys-LTs do not seem necessary for normal homeostasis. Speculatively, these mediators, like others such as histamine, may be remnants of phylogenesis that are essential at earlier stages of development. Knock-out mice in which the gene for 5-LO is inactivated showed no abnormalities except that their responses to various inflammatory insults were occasionally abnormal.¹⁰⁶

A clinical syndrome characterized by pulmonary infiltrates, cardiomyopathy, and eosinophilia was described in a small subset of 8 patients who had been treated with zafirlukast.¹⁰⁷ In this report, all patients who developed the syndrome had been dependent on corticosteroids. Other reports have described individual cases of similar eosinophil syndromes unrelated to steroid withdrawal. This has been noted with zafirlukast and with montelukast, though not with zileuton^108-110 suggesting a class effect, albeit quite rare.

	HETEROGENEITY OF LT MODULATION

Many reports have indicated heterogeneity in the effects of LT modifiers in asthmatic patients, as is observed with other asthma therapies as well. Often, only 2 of 3 patients experienced protection with LT modifiers in asthma models.^46,53,54,57 This may indicate that the relative contribution of Cys-LT-dependent bronchoconstriction to asthma differs from patient to patient.¹¹¹ Genetic polymorphism in the 5-LO pathway enzymes may underlie the variable response to Cys-LT modifiers.¹¹² The number of cells with lipoxygenase activity in bronchial mucosal biopsies from patients with asthma has been found to be significantly higher than in healthy patients¹¹³ and thus some variability within asthmatic patients might be expected. Also, a genetic polymorphism in LTC₄ synthase has been reported with a particularly high frequency in patients intolerant to aspirin¹¹⁴ and the number of cells expressing LTC₄ synthase has been shown to be significantly increased in bronchial biopsies taken from patients with aspirin-sensitive asthma compared with aspirin-tolerant asthmatics and normal controls.¹¹⁵

It is still unclear whether the asthma population of responders and nonresponders fall into a bimodal distribution or a simple, continuous unimodal distribution. It is probable that there is a unimodal response to all asthma medications, including corticosteroids,⁶⁶ long-acting -agonists¹¹⁶ and Cys-LTRAs⁶⁶ with some having little or no effect and others yielding good response. If an outcome is small in comparison with the scatter of the outcome measure, a certain percentage of patients will seemingly experience no effect from the treatment. Whether such apparent nonresponse is attributable to heterogeneity in asthma pathophysiology or a simple stochastic phenomenon can only be determined via design of RCTs exploring whether the group of suspected nonresponders consistently comprises the same patients in repeat tests and whether such nonresponders respond to other treatments, ie, N-of-one studies.

	POSITIONING LT MODIFIERS IN PEDIATRIC ASTHMA MANAGEMENT

Most available studies on LT modifiers have sought to prove the concept of the treatment; few studies have addressed treatment in patient groups relevant to our current treatment algorithms. With few exceptions, the available studies have been conducted in adult asthmatics, and pediatric evidence has been limited to 5 RCTs.^{59,69,70,92,99}

Asthmatic Toddlers and Infants

Most children with chronic asthma first show symptoms as toddlers or infants. There is reason to believe that moderate to severe asthmatic symptoms in young children are early signs of underlying airway inflammatory disease. No evidence exists, however, of how the pathophysiology of mild, intermittent asthmatic symptoms in young children relates to asthma pathophysiology. A separate entity may exist related not to chronic asthma but rather to viral-induced airway inflammation. Inhaled corticosteroids are effective in treating moderate to severe asthmatic symptoms in infants and toddlers.^117,118 However, safety is of particular concern in infants and toddlers, and inhalation therapy is cumbersome for some of these children. Therefore, inhaled corticosteroids are only used in children with persistent symptoms.

Patients with mild symptoms for whom steroid treatment is not appropriate are often treated with regular oral bronchodilators (with little documented efficacy) or with inhaled -agonists. Intermittent treatment of young children with short-term relievers is often insufficient, as treatment decisions and drug delivery depend on a trained caretaker, who frequently has to leave observation and care of the child to others for large parts of the day. Therefore, a long-term treatment effect is of special importance for young children. LT modifiers present an interesting option for young wheezy children because of their oral administration, good safety profile, prolonged effect, and partial antiinflammatory effects.

Two of the 4 reported pediatric studies addressed the effect of montelukast on 2- to 5-year-old asthmatic children.^59,70 This study showed bronchoprotection and reductions in symptoms, need for rescue treatment, asthma exacerbations, and peripheral eosinophils. It is important to compare the efficacy of Cys-LTRAs with those of inhaled steroids and inhaled -agonists. Viral-induced wheezers should be specifically addressed in future studies of LTRA. Based on evidence thus far, LT modifiers may play an important role as first-line treatment of young wheezy children with mild recurrent symptoms.

Mild Asthma

There are no pediatric studies addressing asthma control in children with mild persistent symptoms.

Moderate to Severe Asthma

The patients in most of the published Phase III trials in adults and children had moderate to severe asthma and are candidates for corticosteroid treatment according to the consensus guideline but only subgroups actually received steroids. In these studies, the Cys-LTRA proved modestly effective. The patients' asthma was insufficiently controlled despite active treatment. Nocturnal awakening, a factor that may help predict asthma mortality, still occurred 2 to 4 times per week on average with active treatment.^65,69,88 Rescue medication use was still required 2 to 5 times per day during active treatment.⁸⁸ Such symptom severity would necessitate corticosteroid treatment according to consensus guidelines. Thus, LT modifiers would not be considered sufficient monotherapy for moderate to severe asthma based on the available evidence.

Children with moderate to severe asthma symptoms may require high doses of inhaled corticosteroids, but their symptoms may not be sufficiently controlled by such steroids. Inhaled steroids do not always normalize asthmatic airways, and bronchial hyperreactivity rarely normalizes. Also, some evidence shows that adult patients on high-dose inhaled steroids still have signs of ongoing eosinophilic inflammation.^119,120 This may indicate that corticosteroids cannot control all aspects of asthma inflammation, including the unchecked release of Cys-LTs. An increase in the dose of inhaled steroids is not accompanied by a proportional increase in asthma control, whereas systemic bioavailability and risk of systemic adverse events are proportional to the dose.¹²¹ Therefore, add-on therapy such as long-acting -agonist therapy or LTRA should be considered before additional increases are made in the doses of corticosteroids for children who remain symptomatic despite moderate use of inhaled corticosteroids. Long-acting -agonists, however, are purely bronchodilators and have no antiinflammatory effect. They are marginally effective on lung function, and some tolerance develops to the bronchoprotective effect after repeated dosing.¹¹⁶ Accordingly, there is a need for a corticosteroid-sparing complementary treatment with antiinflammatory properties to check all aspects of airway inflammation in asthma. When added to established corticosteroid treatment in adults with moderate to severe asthma, LT modifiers showed a complementary effect.^{96,97,100,104,105} Subanalyses in a pediatric study also found a complementary effect from LTRA in children treated with inhaled corticosteroids.¹⁰⁰ Such a complementary effect is consistent with the unchecked release of Cys-LTs during asthma despite corticosteroid treatment. Accordingly, there is a good rationale for positioning LT modifiers as complementary to corticosteroid treatment in children whose symptoms are not optimally controlled with a moderate dosage of steroids such as 400 µg/day. To support such positioning, RCTs should assess the potential of LT modifiers as corticosteroid-sparing drugs for children. Long-term trials are necessary, and it may be worthwhile to investigate the potential additive effects of LT modifiers on very low doses of inhaled corticosteroids. Additional insight is required into how this new treatment modality compares with long-acting -agonists.

EIB

EIB is a cardinal symptom in pediatric asthma. Ability to interact in a play environment is essential to the social and physical development of the child, making this the most important symptom to treat from the child's perspective.

The current guidelines emphasize the use of short-acting -agonists for EIB. This is, however, an insufficient solution for most children. Typically, children do not have a scheduled life in which exercise is planned ahead of time. Rather, exercise is spontaneous. Therefore, the recommendation to use short-acting -agonists 15 minutes before exercise is seldom realistic for children, as it is for adults. Therefore, long-term coverage is preferable in children for protection against EIB.

EIB is not a separate form of asthma but a reflection of general disease control and bronchial hyperreactivity. Because it improves with better asthma control, inhaled corticosteroids can be used to treat EIB and provide full-time coverage. Long-acting -agonists generally provide 12-hour coverage against EIB, but some tolerance develops after repeated dosing and bronchoprotection is heterogeneous. Also, -agonists offer no antiinflammatory control.¹¹⁶ There is a need for an asthma medication that provides long-lasting bronchoprotection with an antiinflammatory component. LT modifiers may provide both of these. The bronchoprotective effect of LT modifiers should be compared with long-acting -agonists as complementary treatment for children with poorly controlled asthma despite established steroid treatment.

	CONCLUSION

Top Abstract Conclusion References

Given their efficacy, partial antiinflammatory activity, safety, and oral availability LT modifiers may be used as first-line treatment of young wheezy preschool children with mild recurrent symptoms.

In asthmatic school children monotherapy with LT modifiers cannot sufficiently control moderate to severe asthma, and their efficacy in mild asthma has not been studied. Therefore, based on the presently available data, these drugs should be used as complementary treatment to be added to inhaled corticosteroids in asthmatic school children. Additional research issues that must be addressed include the effects of LT modifiers on inflammation and long-term disease control, long-term safety, effects on development and progression of disease in later life, and potential disease-modifying effects. Until these issues are addressed and studied, the positioning of LT modifiers in pediatric asthma management must be approached with a pragmatic perspective.

	FOOTNOTES

Received for publication Jan 31, 2000; accepted May 30, 2000.

Address correspondence to Hans Bisgaard, MD, Dr Med Sci, Department of Paediatrics, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. E-mail: bisgaard{at}copsac.dk

	ABBREVIATIONS

LT, leukotriene; RCT, randomized, controlled clinical trial; AA, arachidonic acid; CO, cyclooxygenase; 5-LO, 5-lipoxygenase; FLAP, 5-LO-activating protein; Cys-LT, cysteinyl leukotriene; EIB, exercise-induced bronchoconstriction; Cys-LTRA, Cys-LT receptor antagonist; BAL, bronchoalveolar lavage; FeNO, exhaled nitric oxide; QID, 4 times daily; FEV₁, forced expiratory volume in 1 second; BID, 2 times daily.

	REFERENCES

Top Abstract Conclusion References

1. Lynch KR, O'Neill GP, Liu Q, Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999; 399:789-793 [CrossRef][Medline]
2. Schauer U, Eckhart A, Muller R, Gemsa D, Rieger CH Enhanced leukotriene C4 production by peripheral eosinophilic granulocytes from children with asthma. Int Arch Allergy Appl Immunol. 1989; 90:201-206 [Medline]
3. Sampson AP, Thomas RU, Costello JF, Piper PJ Enhanced leukotriene synthesis in leukocytes of atopic and asthmatic subjects. Br J Clin Pharmacol. 1992; 33:423-430 [Medline]
4. Wenzel SE, Trudeau JB, Kaminsky DA, Cohn J, Martin RJ, Westcott JY Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med. 1995; 152:897-905 [Abstract]
5. Chavis C, van Vyve T, Chanez P, Leukotriene E4 plasma levels in adult asthmatic patients with variable disease severity. Allergy. 1997; 52:589-592 [Medline]
6. Sampson AP, Castling DP, Green CP, Price JF Persistent increase in plasma and urinary leukotrienes after acute asthma. Arch Dis Child. 1995; 73:221-225 [Abstract/Free Full Text]
7. Manning PJ, Rokach J, Malo JL, Urinary leukotriene E4 levels during early and late asthmatic responses. J Allergy Clin Immunol. 1990; 86:211-220 [CrossRef][Medline]
8. Kumlin M, Dahlén B, Björck T, Zetterström O, Granström E, Dahlén SE Urinary excretion of leukotriene E 4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4, and histamine in asthmatics. Am Rev Respir Dis. 1992; 146:96-103 [Medline]
9. Kikawa Y, Miyanomae T, Inoue Y, Urinary leukotriene E4 after exercise challenge in children with asthma. J Allergy Clin Immunol. 1992; 89:1111-1119 [CrossRef][Medline]
10. Reiss TF, Hill JB, Harman E, 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]
11. Azevedo I, de Blic J, Scheinmann P, Vargaftig BB, Bachelet M Enhanced arachidonic acid metabolism in alveolar macrophages from wheezy infants. Modulation by dexamethasone. Am J Respir Crit Care Med. 1995; 152:1208-1214 [Abstract]
12. Volovitz B, Welliver RC, De Castro G, Krystofik DA, Ogra PL The release of leukotrienes in the respiratory tract during infection with respiratory syncytial virus: role in obstructive airway disease. Pediatr Res. 1988; 24:504-507 [Medline]
13. Volovitz B, Faden H, Ogra PL Release of leukotriene C4 in respiratory tract during acute viral infection. J Pediatr. 1988; 112:218-222 [CrossRef][Medline]
14. Garofalo R, Kimpen JLL, Welliver RC, Ogra PL Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection. J Pediatr. 1992; 120:28-32 [CrossRef][Medline]
15. Mirro R, Armstead W, Leffler C Increased airway leukotriene levels in infants with severe bronchopulmonary dysplasia. Am J Dis Child. 1990; 144:160-161 [Abstract/Free Full Text]
16. Spencer DA, Sampson AP, Green CP, Costello JF, Piper PJ, Price JF Sputum cysteinyl-leukotriene levels correlate with the severity of pulmonary disease in children with cystic fibrosis. Pediatr Pulmonol. 1992; 12:90-94 [Medline]
17. Bisgaard H, Groth S, Madsen F Bronchial hyperreactivity to leucotriene D4 and histamine in exogenous asthma. Br Med J (Clin Res Ed). 1985; 290:1468-1471
18. Bisgaard H, Groth S Bronchial effects of leukotriene D4 inhalation in normal human lung. Clin Sci. 1987; 72:585-592 [Medline]
19. Smith LJ, Greenberger PA, Patterson R, Krell RD, Bernstein PR The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis. 1985; 131:368-372 [Medline]
20. Adelroth E, Morris MM, Hargreave FE, O'Byrne PM Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med. 1986; 315:480-484 [Abstract]
21. O'Hickey SP, Hawksworth RJ, Fong CY, Arm JP, Spur BW, Lee TH Leukotrienes C4, D4, and E4 enhance histamine responsiveness in asthmatic airways. Am Rev Respir Dis. 1991; 144:1053-1057 [Medline]
22. Arm JP, Spur BW, Lee TH The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects. J Allergy Clin Immunol. 1988; 82:654-660 [CrossRef][Medline]
23. Bel EH, van der Veen H, Kramps JA, Dijkman JH, Sterk PJ Maximal airway narrowing to inhaled leukotriene D4 in normal subjects. Comparison and interaction with methacholine. Am Rev Respir Dis. 1987; 136:979-984 [Medline]
24. Bel EH, van der Veen H, Dijkman JH, Sterk PJ The effect of inhaled budesonide on the maximal degree of airway narrowing to leukotriene D4 and methacholine in normal subjects in vivo. Am Rev Respir Dis. 1989; 139:427-431 [Medline]
25. Bisgaard H, Lerche A, Kristensen JK Leukotriene- and histamine-induced increases in vascular permeability and interstitial transport in the skin. J Invest Dermatol. 1985; 84:427-429 [CrossRef][Medline]
26. 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][Medline]
27. Bisgaard H Vascular effects of leukotriene D4 in human skin. J Invest Dermatol. 1987; 88:109-114 [CrossRef][Medline]
28. Leikauf GD, Claesson HE, Doupnik CA, Hybbinette S, Grafstrom RC Cysteinyl leukotrienes enhance growth of human airway epithelial cells. Am J Physiol. 1990; 259:L255-L261 [Abstract/Free Full Text]
29. Cohen P, Noveral JP, Bhala A, Nunn SE, Herrick DJ, Grunstein MM Leukotriene D4 facilitates airway smooth muscle cell proliferation via modulation of the IGF axis. Am J Physiol. 1995; 269:L151-L157 [Abstract/Free Full Text]
30. Panettieri RA Jr, Tan EML, Ciocca V, Luttmann MA, Leonard TB, Hay DWP Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol. 1998; 19:453-461 [Abstract/Free Full Text]
31. Wang CG, Du T, Xu LJ, Martin JG Role of leukotriene D4 in allergen-induced increases in airway smooth muscle in the rat. Am Rev Respir Dis. 1993; 148:413-417 [Medline]
32. Mygind N, Dahl R, Bisgaard H Leukotrienes, leukotriene receptor antagonists and rhinitis. Allergy. 2000; 55:421-424 [CrossRef][Medline]
33. Knapp HR Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med. 1990; 323:1745-1748 [Abstract]
34. Israel E, Fischer AR, Rosenberg MA, The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis. 1993; 148:1447-1451 [Medline]
35. Coles SJ, Neill KH, Reid LM, Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins. 1983; 25:155-170 [CrossRef][Medline]
36. Marom ZVI, Shelhamer JH, Bach MK, Morton DR, Kaliner M Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis. 1982; 126:449-451 [Medline]
37. Bisgaard H, Pedersen M SRS-A leukotrienes decrease the activity of human respiratory cilia. Clin Allergy. 1987; 17:95-103 [CrossRef][Medline]
38. Ganbo T, Hisamatsu K, Inoue H, Mizukoshi A, Goto R, Murakami Y The effects of leukotrienes C4 and D4 on ciliary activity of human paranasal sinus mucosa in vitro. Rhinology. 1995; 33:199-202 [Medline]
39. Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet. 1993; 341:989-990 [CrossRef][Medline]
40. Diamant Z, Hiltermann JT, van Rensen EL, The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma. Am J Respir Crit Care Med. 1997; 155:1247-1253 [Abstract]
41. Spada CS, Nieves AL, Krauss AH-P, Woodward DF Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol. 1994; 55:183-191 [Abstract]
42. Bisgaard H, Helqvist S, Boudet L, Venge P, Dahl R, Sondergaard J Chemotactic activity of LTB4 in man. Allergy. 1986; 41:365-372 [Medline]
43. Sampson SE, Costello JF, Sampson AP The effect of inhaled leukotriene B4 in normal and in asthmatic subjects. Am J Respir Crit Care Med. 1997; 155:1789-1792 [Abstract]
44. Evans DJ, Barnes PJ, Spaethe SM, van Alstyne EL, Mitchell MI, O'Connor BJ Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax. 1996; 51:1178-1184 [Abstract/Free Full Text]
45. Christie PE, Barnes NC Leukotriene B4 and asthma. Thorax. 1996; 51:1171-1173 [Free Full Text]
46. Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet. 1991;204;337:690-694
47. O'Shaughnessy KM, Taylor IK, O'Connor B, O'Connell F, Thomson H, Dollery CT. Potent leukotriene D4 receptor antagonist ICI.219 given by the inhaled route inhibits the early but not the late phase of allergen-induced bronchoconstriction. Am Rev Respir Dis. 1993;204;147:1431-1435
48. Roquet A, Dahlen B, Kumlin M, Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med. 1997; 155:1856-1863 [Abstract]
49. O'Sullivan S, Roquet A, Dahlén B, Dahlén S-E, Kumlin M Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions. Clin Exp Allergy. 1998; 28:1332-1339 [CrossRef][Medline]
50. Fujimura M, Sakamoto S, Kamio Y, Matsuda T Effect of a leukotriene antagonist, ONO-1078, on bronchial hyperresponsiveness in patients with asthma. Respir Med. 1993; 87:133-138 [CrossRef][Medline]
51. Hamilton A, Faiferman I, Stober P, Watson RM, O'Byrne PM Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects. J Allergy Clin Immunol. 1998; 102:177-183 [CrossRef][Medline]
52. Dekhuijzen PN, Bootsma GP, Wielders PL, van den Berg LR, Festen J, van Herwaarden CL Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids. Eur Respir J. 1997; 10:2749-2753 [Abstract]
53. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L 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]
54. Makker HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The protective effect of inhaled leukotriene D4 receptor antagonist ICI,219 against exercise-induced asthma. Am Rev Respir Dis. 1993;204;147:1413-1418
55. Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med. 1990; 323:1736-1739 [Abstract]
56. 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; 62:556-561 [CrossRef][Medline]
57. Israel E, Dermarkarian R, Rosenberg M, The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med. 1990; 323:1740-1744 [Abstract]
58. Fischer AR, McFadden CA, Frantz R, Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med. 1995; 152:1203-1207 [Abstract]
59. Bisgaard H, Nielsen KG Bronchoprotection from leukotriene receptor antagonist in asthmatic pre-school children. Am J Respir Crit Care Med. 2000; 162:187-190 [Abstract/Free Full Text]
60. Kane GC, Pollice M, Kim CJ, A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings. J Allergy Clin Immunol. 1996; 97:646-654 [CrossRef][Medline]
61. Liu MC, Dube LM, Lancaster J Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol. 1996; 98:859-871 [CrossRef][Medline]
62. Calhoun WJ, Williams KL, Simonson SG, Lavins BJ Effect of zafirlukast (Accolate) on airway inflammation after segmental allergen challenge in patients with mild asthma. Allergy. 1997; S37:90
63. Pizzichini E, Leff JA, Reiss TF, Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J. 1999; 14:12-18 [Abstract]
64. Nakamura Y, Hoshino M, Sim JJ, Ishii K, Hosaka K, Sakamoto T Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax. 1998; 53:835-841 [Abstract/Free Full Text]
65. Noonan MJ, Chervinsky P, Brandont M, Montelukast, a potent leukotriene receptor antagonist, causes dose related improvements in chronic asthma. Eur Respir J. 1998; 11:1232-1239 [Abstract]
66. Malmstrom K, Rodriguez-Gomez G, Guerra J, Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med. 1999; 130:487-495 [Abstract/Free Full Text]
67. Altman LC, Munk Z, Seltzer J, A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. J Allergy Clin Immunol. 1998; 102:50-56 [CrossRef][Medline]
68. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med. 1998; 158:1213-1220 [Abstract/Free Full Text]
69. Knorr B, Matz J, Bernstein JA, Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. JAMA. 1998; 279:1181-1186 [Abstract/Free Full Text]
70. Knorr B, Franchi LM, Maspero JF, et al. Montelukast (MK-0476) improves asthma over a 3 month treatment period in 2- to 5-year-olds. Am J Respir Crit Care Med. 2000. Abstract
71. Bisgaard H, Loland L, Anhøj J NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med. 1999; 160:1227-1231 [Abstract/Free Full Text]
72. Mattes J, Storm vG, Reining U, et al NO in exhaled air is correlated with markers of eosinophilic airway inflammation in corticosteroid-dependent childhood asthma. Eur Respir J. 1999; 13:1391-1395 [Abstract]
73. Yamamoto H, Nagata M, Kuramitsu K, Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078. Am J Respir Crit Care Med. 1994; 150:254-257 [Abstract]
74. Peers SH, Flower RJ The role of lipocortin in corticosteroid actions. Am Rev Respir Dis. 1990; 141:S18-S21 [Medline]
75. Sebaldt RJ, Sheller JR, Oates JA, Roberts LJII, FitzGerald GA Inhibition of eicosanoid biosynthesis by glucocorticoids in humans. Proc Natl Acad Sci U S A. 1990; 87:6974-6978 [Abstract/Free Full Text]
76. Taylor GW, Taylor I, Black P, Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet. 1989; 1:584-588 [CrossRef][Medline]
77. Dworski R, Fitzgerald GA, Oates JA, Sheller JR Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med. 1994; 149:953-959 [Abstract]
78. O'Shaughnessy KM, Wellings R, Gillies B, Fuller RW Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis. 1993; 147:1472-1476 [Medline]
79. Crocker IC, Zhou CY, Bewtra AK, Kreutner W, Townley RG Glucocorticosteroids inhibit leukotriene production. Ann Allergy Asthma Immunol. 1997; 78:497-505 [Medline]
80. McGill KA, Busse WW Zileuton. Lancet. 1996; 348:519-524 [CrossRef][Medline]
81. Zileuton for asthma. Med Lett. 1997;39:18
82. Lazarus SC, Lee T, Kemp JP, Safety and clinical efficacy of zileuton in patients with chronic asthma. Am J Manag Care. 1998; 4:841-848 [Medline]
83. Israel E, Rubin P, Kemp JP, The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993; 119:1059-1066 [Abstract/Free Full Text]
84. Israel E, Cohn J, Dube L, Drazen JM Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group . JAMA. 1996; 275:931-936 [Abstract/Free Full Text]
85. Schwartz HJ, Petty T, Dube LM, Swanson LJ, Lancaster JF A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group. Arch Intern Med. 1998; 158:141-148 [Abstract/Free Full Text]
86. Accolate. Manufacturer's prescribing information. Carolina, Puerto Rico: Zeneca Pharmaceuticals; 1999
87. Adkins JC, Brogden RN Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma. Drugs. 1998; 55:121-144 [CrossRef][Medline]
88. Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI.,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. ACCOLATE Asthma Trialists Group. Am J Respir Crit Care Med. 1994;204;150:618-623
89. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby LA, Bonuccelli CM Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group. Clin Ther. 1997; 19:675-690 [CrossRef][Medline]
90. Nathan RA, Bernstein JA, Bielory L, Zafirlukast improves asthma symptoms and quality of life in patients with moderate reversible airflow obstruction. J Allergy Clin Immunol. 1998; 102:935-942 [CrossRef][Medline]
91. Suissa S, Dennis R, Ernst P, Sheehy O, Wood-Dauphinee S 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]
92. Pearlman DS, Ostrom NK, Bronsky EA, Bonuccelli CM, Hanby LA The leukotriene D4-receptor antagonist zafirlukast attenuates exercise-induced bronchoconstriction in children. J Pediatr. 1999; 134:273-279 [CrossRef][Medline]
93. Jones TR, Labelle M, Belley M, Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist. Can J Physiol Pharmacol. 1995; 73:191-201 [Medline]
94. Singulair. Manufacturer's prescribing information. Whitehouse Station, NJ: Merck & Co, Inc; 1999
95. Knorr B, Larson P, Nguyen HH, Montelukast dose selection in 6- to 14-year-olds: comparison of single-dose pharmacokinetics in children and adults. J Clin Pharmacol. 1999; 39:786-793 [Abstract]
96. Laviolette M, Malmstrom K, Lu S, Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med. 1999; 160:1862-1868 [Abstract/Free Full Text]
97. Löfdahl C-G, Reiss TF, Leff JA, 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]
98. Villaran C, O'Neill SJ, Helbling A, Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol. 1999; 104:547-553 [CrossRef][Medline]
99. Kemp JP, Dockhorn RJ, Shapiro GG, Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr. 1998; 133:424-428 [CrossRef][Medline]
100. Knorr B, Nguyen HH, Seidenberg BC, Reiss TF, the Montelukast Pediatric Study Group. Montelukast, a leukotriene receptor antagonist, provides additional clinical benefit in asthmatic children aged 6 to 14 years using inhaled corticosteroids. Presented at the European Respiratory Society; October 9-13, 1999; Madrid, Spain
101. Hui KP, Barnes NC Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet. 1991; 337:1062-1063 [CrossRef][Medline]
102. Reiss TF, Sorkness CA, Stricker W, Effects of montelukast (MK-0476), a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids. Thorax. 1997; 52:45-48 [Abstract/Free Full Text]
103. Kips JC, Joos GF, De Lepeleire I, MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human. Am Rev Respir Dis. 1991; 144:617-621 [Medline]
104. Virchow JC, Hassall SM, Summerton L, Harris A Improved asthma control over 6 weeks with zafirlukast in patients on high dose inhaled corticosteroids. Eur Respir J 1997; 10:437s
105. Tamaoki J, Kondo M, Sakai N, Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. Am J Respir Crit Care Med. 1997; 155:1235-1240 [Abstract]
106. Chen XS, Sheller JR, Johnson EN, Funk CD Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature. 1994; 372:179-182 [CrossRef][Medline]
107. Wechsler ME, Garpestad E, Flier SR, Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA. 1998; 279:455-457 [Abstract/Free Full Text]
108. Katz RS, Papernik M. Zafirlukast, and Churg-Strauss syndrome. JAMA. 1998;279:1949. Letter; comment
109. Knoell DL, Lucas J, Allen JN Churg-Strauss syndrome associated with zafirlukast. Chest. 1998; 114:332-334 [Abstract/Free Full Text]
110. Franco J, Art Pulmonary eosinophilia associated with montelukast. Thorax. 1999; 54:558-560 [Abstract/Free Full Text]
111. Drazen JM, Israel E Asthma: a solution to half the puzzle? Am Rev Respir Dis. 1991; 144:743-744 [Medline]
112. In KH, Asano K, Beier D, Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest. 1997; 99:1130-1137 [Medline]
113. Bradding P, Redington AE, Djukanovic R, Conrad DJ, Holgate ST 15-lipoxygenase immunoreactivity in normal and in asthmatic airways. Am J Respir Crit Care Med. 1995; 151:1201-1204 [Abstract]
114. Sanak M, Simon HU, Szczeklik A Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet. 1997; 350:1599-1600 [CrossRef][Medline]
115. Cowburn AS, Sladek K, Soja J, Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest. 1998; 101:834-846 [Medline]
116. Bisgaard H Long-acting beta2-agonist in management of childhood asthma: a critical review of the literature. Pediatr Pulmonol. 2000; 29:221-234 [CrossRef][Medline]
117. Bisgaard H, Munck SL, Nielsen JP, Petersen W, Ohlsson SV Inhaled budesonide for treatment of recurrent wheezing in early childhood. Lancet. 1990; 336:649-651 [CrossRef][Medline]
118. Bisgaard H, Gillies J, Groenewald M, Maden C The effect of inhaled fluticasone propionate in the treatment of young asthmatic children: a dose comparison study. Am J Respir Crit Care Med. 1999; 160:126-131 [Abstract/Free Full Text]
119. 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]
120. Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanovic R The relationship between airway inflammation and asthma severity. Am J Respir Crit Care Med. 2000; 161:9-16 [Abstract/Free Full Text]
121. Kamada AK, Szefler SJ, Martin RJ, Issues in the use of inhaled glucocorticoids. Am J Respir Crit Care Med. 1996; 153:1739-1748 [Medline]