Issues in Pharmacotherapy Practice

Breathing Easier: The Role of Leukotriene Modifiers in Chronic Asthma Management

Marie-France Beauchesne, B.Pharm., M.Sc.(Pharm), Pharm.D. 

Faculty of Pharmacy, University of Montreal, Pharmacy Department, Sacre-Coeur Hospital, Montreal, Quebec, Canada. E-mail: beauchem@pharm.umontreal.ca


Download a PDF version of this article | Send FEEDBACK to the Editors about this article


Abstract

Objective: To review clinical trials evaluating the efficacy of leukotriene modifiers in the treatment of chronic asthma. 

Data Source: A MEDLINE search was performed (1966 - March 2000) to identify relevant English-language publications, including preclinical studies, clinical trials, and review articles. 

Study Selection and Data Extraction: Controlled-clinical trials of zileuton, zafirlukast, and montelukast in adults and children with asthma were selected to review the efficacy of leukotriene modifiers in asthma management.  Information on the safety and efficacy of zileuton, zafirlukast and montelukast, including pharmacokinetic and pharmacologic data are summarized. 

Data Synthesis and Results: Leukotrienes elicit many features of asthma such as bronchoconstriction and airway hyperreactivity. In pre-clinical studies, leukotriene modifiers have been shown to attenuate asthmatic responses following various challenges such as exercise, allergen, and acetylsalicylic acid.  In placebo-controlled trials, leukotriene modifiers improve pulmonary function, reduce asthma symptoms and short-acting ß2-agonist use in patients with moderate asthma.  The benefits of leukotriene modifiers are generally modest when used as monotherapy, but provide additive benefits when used in conjunction with inhaled corticosteroids. Overall, beclomethasone appears to be superior to montelukast when used in patients with mild-to-moderate asthma while salmeterol appears to be superior to zafirlukast for long-term asthma control.  Montelukast may permit a reduction of the required dose of inhaled corticosteroids. 

Conclusions: Leukotriene modifiers represent useful adjuncts to inhaled corticosteroids when moderate to high doses of these latter agents are no longer sufficient to control asthma.  Leukotriene modifiers may also be considered as first-line monotherapy in patients with mild persistent asthma who choose not to use inhaled corticosteroids.

J Inform Pharmacother 2000;1:300-309.

Introduction

Asthma is a chronic inflammatory disorder of the airways characterized by paroxysmal or persistent symptoms such as dyspnea, chest tightness, wheezing, sputum production and cough associated with variable airflow obstruction and a variable degree of airway hyperresponsiveness to endogenous or exogenous stimuli (1).  Chronic inflammation is now recognized as the key feature in the pathogenesis of asthma and contemporary management strategies are aimed at reducing airway inflammation.

The goals of asthma management, as outlined in the 1999 Canadian Asthma Consensus Report are to: (i) maintain normal or near normal pulmonary function (forced expiratory volume in 1 second; [FEV1] or peak expiratory flow; [PEF] >85%) with a PEF diurnal variation less than 15%; (ii) reduce the occurrence of daytime asthma symptoms to less than 4 days per week and night-time symptoms to less than 1 night per week; (iii) maintain normal physical activity; (iv) limit exacerbations to mild and infrequent; (v) prevent absenteeism and to; (vi) reduce the need for short-acting ß2-agonist to a frequency of less than 4 doses per week (1).

To achieve these goals of therapy, medications to treat asthma include the 'relievers' and the 'controllers'. Reliever medications (short-acting ß2-agonist) are used as needed for prompt relief of asthma symptoms. Controller medications, are generally taken regularly are used to prevent exacerbations. The latter agents include the corticosteroids, leukotriene modifiers, long-acting ß2-agonist, theophylline and anti-allergic agents (disodium cromoglycate and nedocromil sodium). Inhaled corticosteroids are the mainstay of asthma therapy and should be introduced for patients with moderate asthma symptoms (1).

Leukotriene modifiers were introduced a few years ago for chronic asthma management. Agents currently available are Zileuton (Zyflo®; not available in Canada), Zafirlukast (Accolate®) and Montelukast (Singulair®). Montelukast is approved for use in adults and children 6 years of age or older, zafirlukast in adults and children 7 years of age and older (in the United States) and zileuton in adults only (12 years of age and older). This article reviews leukotriene modifiers, with a focus on their efficacy in controlled clinical trials in the management of chronic asthma.

Leukotriene Biosynthesis and their Role in Asthma  

Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid (AA). In response to various stimuli (e.g. allergen exposure), AA is released from cell-membrane phospholipids by the action of phospholipase A2 (2,3).  Leukotrienes are generated when the enzyme 5-lipooxygenase, and its cofactor 5-lipooxygenase-activating protein metabolizes AA.  Arachidonate is initially converted to an unstable intermediate, LTA4, which is then metabolized by two pathways leading to the formation of LTB4 or LTC4.  Leukotriene C4 is actively transported out of cells and rapidly converted to LTD4 and then to LTE4.  Collectively, LTC4, LTD4, and LTE4 are referred to as the cysteinyl LTs (CysLTs) because of their chemical structure (cysteinyl residues) (2-4). Leukotriene E4 is mostly recovered in the urine and serves as a marker for LT activity (2).

The CysLTs produce their effect by binding and activating specific receptors. Two subtypes have been identified, CysLT1 and CysLT2 receptors (2,5).  The CysLT1 receptor is present on airway cells such as smooth muscle cells and mucus cells. Activation of the CysLT1 receptor results in smooth muscle constriction; LTC4 and LTD4 are equally potent bronchoconstrictors while LTE4 is only 10% as potent as LTC4 and LTD4 (2,3).  The CysLT2 receptor is found in the vascular smooth muscle of the human lung but its function has not been evaluated in humans in vivo (2,5).

Cysteinyl LTs elicit many features of asthma, including contraction of airway smooth muscle, enhanced airway hyperreactivity, increased vascular permeability (leading to airway edema), mucus secretion, and recruitment of neutrophils in the airways (3,4).  Zafirlukast and montelukast are selective and specific antagonists of the CysLT1 receptor (5).  In vitro, zafirlukast antagonizes the activity of LTC4, LTD4 and LTE4.  Montelukast inhibits the activity of LTD4 in receptor-binding studies (6).

Zileuton is a 5-LO inhibitor which binds at or closely to the active site of 5-LO and prevents the metabolism of AA to LTs. The clinical implication of this difference in mechanism of action is unknown (3,6).

Pharmacokinetics of Leukotriene Modifiers

The absolute oral bioavailability of zafirlukast has not been determined (7).  However, as mean bioavailability is reduced by about 40% in the presence of food, zafirlukast needs to be taken on an empty stomach (7).  Protein binding of zafirlukast is extensive (>99%) mostly to albumin. Zafirlukast is extensively metabolized in the liver, mainly by the cytochrome P450 isoenzyme CYP2C9.  Zafirlukast is primarily eliminated in the feces and urinary excretion accounts for less than 10% of an oral dose. The metabolites are less potent than the parent drug and mean terminal half-life of zafirlukast is about 10 hours (7).  Zafirlukast is a CYP2C9 and CYP3A4 inhibitor in vitro and thus reduces the metabolism of S-warfarin (more potent isomer) necessitating INR monitoring for those patients on concomitant therapy.  Although the clinical impact of these interactions do not seem to be significant, coadministration of theophylline, erythromycin and terfenadine reduce zafirlukast serum concentrations, whereas aspirin increases them (7).  Increased serum theophylline concentrations were reported when theophylline was coadministered with zafirlukast (8).  Although this drug interaction was not identified when zafirlukast was marketed, careful monitoring is required when these two drugs are used concurrently.

The bioavailability of montelukast is approximately 64% and the drug may be administered with or without food (9).  Montelukast is primarily eliminated in the feces as metabolites.  The mean terminal half-life of montelukast is between 2.7 to 5.5 hours (9).  There appear to be no clinically significant drug interactions with montelukast. Pharmacokinetic studies have failed to demonstrate significant drug interactions with theophylline, warfarin, digoxin, terfenadine, prednisone, prednisolone, and oral contraceptives (10).

Zileuton is well absorbed after oral administration and its bioavailability is not altered by food (10).  Zileuton is primarily eliminated as a glucuronide conjugate and a small fraction is metabolized by the CYP2C9, CYP1A2, and CYP3A isoenzymes (10).   The metabolites of zileuton are excreted in the feces and urine, and most of the pharmacologic activity is due to the parent drug. The mean terminal half-life of zileuton is 2.5 hours (10).  Zileuton reduces the clearance of warfarin and theophylline so INR and theophylline serum concentrations should be closely monitored when these agents are used concurrently with zileuton (10).  Zileuton also increases terfenadine serum concentrations and although no cardiac side effects have been reported, most authorities consider it is preferable to avoid concomitant use of these agents (11).

Clinical Trials

Challenge Studies and Dose-Ranging Trials

Challenge studies are usually performed by measuring pulmonary function changes in response to inhalation of a test substance (e.g. histamine) or exercise. Leukotriene modifiers have been compared with placebo in various challenge studies in asthmatics (12-27).  Overall, zileuton (12-18), zafirlukast (19-23) and montelukast (24-27) have been shown to attenuate the bronchoconstrictor response to exercise, allergen, aspirin, LTD4, sulfur dioxide, platelet-activating-factor and exposure to cold/dry air.  Results from these trials support the role of LTs in the pathophysiology of asthma and suggest that these agents may be useful in long-term asthma management.

In studies evaluating the effects of various dosages of zafirlukast, most benefits have been achieved with a regimen of 20 mg twice daily (7).  Dose-ranging trials for montelukast have established 10 mg/day at bedtime as the optimal dose of the drug in adults, while 5 mg/day at bedtime has been identified as the appropriate dose for children (9).  Placebo-controlled trials evaluating two different doses of zileuton demonstrate that 600 mg four times daily provides better asthma control than 400 mg four times daily (28-30).  The manufacturer of zileuton recommends using a total daily dose of 2.4 g.

Placebo-Controlled Clinical Trials

The efficacy of zafirlukast 20 mg twice daily over 13 weeks was evaluated in a placebo-controlled trial in 762 adult patients with mild-to-moderate asthma (FEV1 >55% predicted (mean 79%); mean ß2-agonist use 4 puffs/day) (31).  Zafirlukast increased FEV1 by 6.3% (difference of 3.3% vs. placebo; p<0.05) and improved patient reported endpoints (daytime asthma symptoms, nighttime awakenings, ß2-agonist use (p<0.05) (Table 1).  Patients on zafirlukast reduced their use of ß2-agonist by about 1 puff/day and had fewer asthma exacerbations (difference of 3.8% vs. placebo; p<0.05).

A 12-week placebo-controlled trial of Montelukast 10 mg once daily was conducted in 681 adult asthmatics with mild-to-moderate asthma (FEV1 50-85%, mean 68%; mean ß2-agonist use 5.4 puffs/day) (32).  Twenty-three percent of asthmatics were receiving inhaled corticosteroids. Montelukast improved pulmonary function (increase of 8.9% in FEV1 vs. placebo; p<0.001) and asthma symptoms (Table 1).  Use of ß2-agonist was reduced by about 1 puff/day with montelukast.  No significant difference in oral corticosteroid rescue was found between the groups and concomitant use of inhaled corticosteroid did not influence the response to treatment with montelukast.  Near-maximal effects on ß2-agonist use, daytime asthma symptoms and morning PEF were achieved within one day of treatment with montelukast.

The efficacy of montelukast 5 mg once daily was evaluated over 8 weeks in 336 children 6 to 14 years of age with mild-to-moderate asthma (FEV1 50-85%, mean 72%; average of 3.3 doses/day of short-acting ß2-agonist) (33).  Thirty-nine percent of patients on montelukast and 33% of children on placebo were receiving inhaled corticosteroids.  Montelukast provided modest improvements in FEV1 (difference of 4.65% vs. placebo; p<0.001 (Table 1).  Use of ß2-agonist was reduced by less than 1 puff/day (p=0.08). Most patient-reported endpoints were similar in subjects on montelukast and placebo at the end of the study.  The effects of montelukast on FEV1 and ß2-agonist use were similar between patients receiving or not receiving concomitant treatment with inhaled corticosteroids.

Zileuton was studied in 122 adult asthmatics with a mean FEV1 of 63% predicted and using an average of 5.8 puffs/day of short-acting ß2-agonist at baseline (29).  The FEV1 increased after the first doses of zileuton and remained improved over the 6-month study period (Table 1).  Subjects receiving zileuton had fewer asthma symptoms, lower requirements for short-acting ß2-agonist or corticosteroids rescue, and fewer asthma exacerbations.

Table 1: Summary of Placebo-Controlled Clinical Trials

Outcome*

Zafirlukast (31)

Montelukast (32,33)

Zileuton (29)

FEV1

3.3% (p<0.05)

adults: 8.9% (p<0.01) children: 4.7% (p<0.01)
 

8% (p=0.004)

Daytime Asthma Symptoms

13.2% (p>0.01)

adults: decrease (p=NR) children: no difference
 

decrease (p<0.05)

Nocturnal Asthma Symptoms

-0.47 nights/week (p<0.05)

adults: -0.87 nights/week (p=NR)
children: no difference
 

decrease (p<0.05)

b2-agonist Use

0.77 puffs/day

adults: decrease (p=NR) children: no difference

1.1 puffs/day (p<0.01)

Corticosteroid Rescue

NR

adults: no difference children: no difference

13.3% (p<0.001)

Asthma Exacerbations

3.8% (p<0.05)

adults: 31% fewer days with worsening symptoms (p<0.001)
children: 5.1% less days with worsening asthma symptoms (p=0.049)

11% (p=0.043)

*difference vs. placebo
NR = not reported, FEV1 = forced expiratory volume in one second

Overall, LT modifiers have been demonstrated to improve asthma control with improved pulmonary function tests and reduction of symptoms in patients with mild-to-moderate disease who are receiving short-acting ß2-agonist only.  However, the clinical benefits of LT modifiers achieved in placebo-controlled trials are generally modest and monotherapy with these agents is most likely insufficient to achieve the goals of asthma care in patients with moderate or severe asthma.

Comparative Clinical Trials.

The effects of montelukast 10 mg once daily, placebo, and beclomethasone 200 mcg twice daily were evaluated over 12 weeks in 895 patients with moderate asthma (FEV1 50-85%, mean 66%, mean short-acting ß2-agonist use 5.5 puffs/day) (34).  Patient response to montelukast or beclomethasone was superior to placebo and the effect of beclomethasone was superior to montelukast. Mean response differences between beclomethasone and montelukast were 5.8% for FEV1, -0.67 puffs/day for ß2-agonist use, and -0.7 nights/week for nocturnal awakenings favoring beclomethasone.  Montelukast had a faster onset of action (within one day); however, the effects of beclomethasone surpassed that of montelukast after 7 to 10 days of therapy.  The incidence of adverse effects was reported to be similar in the three treatment groups.  In a 3-week washout period at the end of the study, there was no apparent rebound worsening of asthma symptoms and FEV1 values returned to baseline in patients receiving montelukast or beclomethasone who were switched to placebo.

Using an intention-to-treat study design, the steroid-sparing effect of montelukast 10 mg once daily was evaluated in 226 asthmatics aged 17-70 years with an FEV1 >70% (mean 84%) requiring moderate to high doses of inhaled corticosteroids (300-3000 mcg daily) (35).  Dosages of inhaled corticosteroids were tapered over 6 weeks before entering a 12-week period of double-blind treatment.  Inhaled corticosteroid dose was adjusted every two weeks according to a composite clinical score.  Twenty-one percent of patients (48/226 patients enrolled) did not complete the 12-week period.  Montelukast therapy was associated with a reduction in the mean inhaled corticosteroid dose from 976 mcg/day to 526 mcg/day (47% absolute reduction) compared with placebo (from 1079 mcg/day to 727 mcg/day; 30% absolute reduction), without significant changes in FEV1, asthma symptoms, and ß2-agonist use.  Those patients receiving montelukast had fewer failed rescue episodes (16% vs. 30% with placebo; p=0.01).  Failed rescue episodes were defined as the number of patients who failed to regain clinical stability after an increase in dose of corticosteroids.  This study suggests that montelukast may have a steroid-sparing effect, although the absolute difference in the reduction of corticosteroid dose at the end of 12 weeks appeared to be small (absolute difference of 98 mcg/day or 17.6%; 95% CI: 0.3 to 34.8%; p=0.046).  Considering the wide 95% CI and the proximity of the lower limit to zero, it is difficult to establish a clinically relevant difference compared to placebo.  Differences in potencies between various inhaled corticosteroids was not taken into account when comparing the percentage change in the corticosteroid dose.  Finally, the number of patients on different types of inhaled corticosteroids was not reported and equivalent doses were not calculated when comparing groups.

A clinical trial examined the use of montelukast 10 mg once daily in combination with beclomethasone 200 mcg twice daily to determine whether concomitant therapy would yield additional clinical benefits in patients with incompletely controlled asthma (36).  Overall, 193 patients were randomly allocated to the montelukast plus beclomethasone group and 200 patients were assigned to the beclomethasone group (placebo tablets once daily and inhaled beclomethasone 200 mcg twice daily).  At baseline, patients in both groups had a mean FEV1 of 71.5% and reported to use about 3.5 puffs/day of short-acting ß2-agonist.  Primary endpoints that were measured in the study were FEV1 and patient-reported daytime asthma symptoms.  The addition of montelukast resulted in improvements in FEV1 (5.08% vs. 0.72% in the montelukast plus beclomethasone and beclomethasone only groups, respectively, p<0.001), daytime asthma symptom scores (-0.13 vs. -0.02, respectively, p=0.041) and nocturnal awakenings (-1.04 vs. -0.45, respectively, p=0.010); however, total ß2-agonist use was similar in both groups (-5.51% change from baseline vs. 6.04; p=0.08).  Montelukast provided additional clinical benefits; however, inclusion of a group on a higher dose of inhaled corticosteroids would have been of interest to determine whether the addition of montelukast is comparable in efficacy to increased doses of corticosteroids.

The efficacy of zileuton was compared with theophylline (target trough serum concentration between 8-15 mcg/ml) in 377 adult asthmatics (mean FEV1 about 60% predicted) using approximately 6.5 doses of ß2-agonist daily (37).  After 13 weeks of treatment, FEV1 measurements were similar in patients receiving zileuton and theophylline (increase from baseline of 30.2% vs. 33.7% with zileuton 2.4 g/day and theophylline, respectively).  Improvement in morning and evening peak flow measurements, ß2-agonist requirements (decrease of 1.5 puffs/day vs. 2 puffs/day with zileuton 2.4 g/day and theophylline, respectively), use of rescue corticosteroids, symptom and quality of life scores were not different in subjects on theophylline and zileuton.  Overall, the efficacy of zileuton and theophylline was similar in patients with mild-to-moderate asthma.

The efficacy of salmeterol 42 mcg twice daily and zafirlukast 20 mg twice daily was compared over a 4-week period, in a 189 adults with persistent asthma (FEV1 50-80%, mean 68%) (38).  Approximately 80% of patients in each treatment group were receiving a stable regimen of inhaled corticosteroid at the time of study enrolment.  Overall, salmeterol provided greater improvements in pulmonary function and symptom control. Salmeterol increased morning peak flow (primary endpoint) by 29.6 L/min while zafirlukast improved this value by 13.0 L/min. Zafirlukast and salmeterol provided similar improvements in FEV1, nocturnal awakenings, ß2-agonist use and asthma exacerbations.  The incidence of adverse events was similar in each treatment group.  This study was the first published report in which the efficacy of salmeterol and zafirlukast were compared directly.  Even though most patients were receiving inhaled corticosteroids, the use of salmeterol is not recommended without concomitant inhaled corticosteroids.  Both treatment groups were comparable at baseline, but the dose of inhaled corticosteroid received during the study was not specified.  Finally, this short-term trial is not sufficient to draw conclusions about the efficacy of one agent over the other as an add-on therapy with inhaled corticosteroids.  Long-term trials are required to characterize the efficacy of long-acting ß2-agonist over LT modifiers in chronic asthma management.

Aspirin-Intolerant Asthmatics

The efficacy of zileuton was evaluated in a cross-over study of 40 aspirin-intolerant asthmatics (AIA) (39).  Most patients were receiving corticosteroids at baseline.  Zileuton improved FEV1 (difference with placebo after 6 weeks of treatment: 0.19 L; p<0.01), reduced daily ß2-agonist use (difference with placebo of 0.64 puffs/day; p<0.05), and lowered the scores for loss of smell and rhinorrhea.  However, asthma symptoms, peak nasal inspiratory flow rates and nasal congestion scores were similar with zileuton and placebo.

Safety

The incidence of adverse effects is mostly similar in patients receiving LT modifiers and placebo in the clinical trials reviewed. An exception to this is the reversible elevations in liver function tests seen in 2-9% of patients in studies of zileuton (28,29).  One patient experienced jaundice, hives, and increased liver function tests which resolved after discontinuation of zileuton (28).  Patients on zileuton should have liver function tests performed before starting therapy, every month in the first three months, every 2-3 months for the rest of the first year of treatment, and periodically thereafter (10).  Infrequent asymptomatic elevations in serum liver enzymes has been reported with higher than recommended doses of zafirlukast (7).

Concern about the association between Churg-Strauss syndrome and the use of LT modifiers has been raised.  Churg-Strauss syndrome is an eosinophilic vasculitis that has been reported in patients with moderate or severe asthma receiving zafirlukast and montelukast.  Most patients were undergoing corticosteroid withdrawal after the addition of a LT modifier.  It has been postulated that this reaction is not directly related to LT modifiers, but may be an unmasking of the syndrome following corticosteroid withdrawal.  A causal relationship between this syndrome and LT modifiers remains unproven and the occurrence of this event is rare (40).  Patients with moderate to severe asthma should be monitored for signs and symptoms of the Churg-Strauss syndrome when corticosteroids are tapered or discontinued following the addition of a LT modifier.  Leukotriene modifiers are generally well tolerated, but there is limited experience with long-term use of these agents

Discussion

The role of LT modifiers in asthma management is currently being defined.  The Expert Panel of the National Asthma Education and Prevention Program states that zafirlukast and zileuton (montelukast was not available at the time of writing of the Expert Panel Report) should be considered as alternative long-term therapies to low-dose inhaled corticosteroids, sodium cromoglycate or nedocromil for patients with mild persistent asthma, but the place of LT modifiers in asthma therapy has not been entirely established (41).  The 1999 Canadian Asthma Consensus Report describe the role of LT modifiers as an alternative to low-dose inhaled beclomethasone in patients with mild asthma who cannot tolerate or choose not to use inhaled corticosteroids, although no studies in this population have been published; as an alternative to increased doses of inhaled corticosteroids or as an alternative add-on therapy in place of long-acting ß2-agonist (1).  Unfortunately, few comparative trials are available.  To further define their place in therapy, trials comparing LT modifiers with standard therapy, such as inhaled corticosteroids in mild chronic asthma; long-acting bronchodilators in moderate-to-severe asthma; and comparisons to higher doses of inhaled corticosteroids in moderate-to-severe asthma are required.  Relevant studies should evaluate primary clinical endpoints that include oral steroid rescue, unscheduled medical visits, hospitalizations, and asthma exacerbations.  These trials are underway and their results may enable clinicians to rank LT modifiers within the armamentarium of asthma therapies.

Leukotriene modifiers differ in terms of frequency of administration, whether they can be taken with food or not, in their safety profile and in their potential for drug interactions.  Zileuton is given four times daily, whereas zafirlukast is administered twice daily and montelukast once daily.  Zileuton and montelukast may be administered without regards to meals, whereas zafirlukast must be taken on an empty stomach.  Zileuton may cause hepatic toxicity and unlike other agents, periodic monitoring of liver function tests is necessary.  Zileuton and zafirlukast may influence the elimination and clinical effects of other medications (e.g. warfarin) whereas no drug interactions have been identified with montelukast to date.  Finally, whether one agent is superior to another is unknown since no clinical trials have directly compared the efficacy of leukotriene modifiers.  Overall, montelukast has many advantages over other agents of this class and may be the LT modifier of choice.

Leukotriene modifiers provide additive benefits to inhaled corticosteroids.  In clinical practice, these agents are used in combination with other therapies (i.e. medium or higher doses of inhaled corticosteroids) as an alternative to increasing the corticosteroid dose, or to reduce the corticosteroid dose required to maintain asthma control.  Leukotriene modifiers are usually considered as second-line adjunctive therapies to moderate or higher doses of inhaled corticosteroids since more data and clinical experience are available with using long-acting ß2-agonist.  Because they reduce LT-induced airway inflammation, LT modifiers should be the treatment of choice in patients with mild persistent asthma who choose not to use inhaled corticosteroids.  Inhaled corticosteroids may prevent the decline in lung function that occurs in patients with asthma, whereas the effect on airway remodeling has not been confirmed with LT modifiers (1).  Monotherapy with LT modifiers is insufficient to achieve the goals of asthma therapy in patients with moderate or severe disease.

Clinical trials evaluating montelukast in exercise-induced asthma have demonstrated that it is useful for this indication when used on a regular basis (24,42-45).  Leukotriene modifiers are of particular interest in patients with aspirin-induced asthma, which involves a LT-mediated process, but comparative trials remain to be completed.  These agents currently have no role for the acute management of asthma exacerbations.  Finally, the use of LT modifiers is pregnancy and lactation is not recommended at this time since human data is not available and clinical experience is limited (45).

Leukotriene modifiers have the advantages of being administered orally, of having few side effects and in the case of montelukast, having no drug or food interactions.  Unfortunately, asthma control is not improved in all patients receiving LT modifiers.  It appears that only 30-50% of patients will respond to therapy, and characteristics which predict response are unknown.  Since LT modifiers have a rapid onset of action, a 2-week trial is generally sufficient to determine if patients will benefit from therapy.  An exception is when LT modifiers are used in an attempt to reduce the corticosteroid dose, where the trial period is usually longer.

References

  1. Boulet L-P, Becker A, Berube D, Beveridge R, Ernst P. Canadian Asthma Consensus Report, 1999. CMAJ 1999;161(11 Suppl):S1-S62.
  2. Drazen JM. Leukotrienes as mediators of airway obstruction. Am J Respir Crit Care Med 1998;158:S193-S200.
  3. Horwitz RJ, McGill KA, Busse WW. The role of leukotriene modifiers in the treatment of asthma. Am J Respir Crit Care Med 1998;157:1363-71.
  4. O'Byrne PM. Leukotriene in the pathogenesis of asthma. Chest 1997;111:S27-S34.
  5. Aharony D. Pharmacology of leukotriene receptor antagonists. Am J Respir Crit Care Med 1998;157:S214-9. 
  6. Busse W. The role and contribution of leukotrienes in asthma. Ann Allergy Asthma Immunol 1998;81:17-29. 
  7. Adkins JC, Brogden RN. Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma. Drugs 1998;55:121-144. 
  8. Katial RK, Stelzle R, Bonner MW, Marino M, Cantilena LR, Smith LJ. A drug interaction between zafirlukast and theophylline. Arch Intern Med 1998;158:1713-1715. 
  9. Markham A, Faulds D. Montelukast. Drugs 1998;56:251-6. 
  10. Smith LJ. A risk-benefit assessment of antileukotriene in asthma. Drug Saf 1998;19:205-18. 
  11. Awni WM, Cavanaugh JH, Leese P, Kasier J, Cao G, Locke CS, Dube LM. The pharmacokinetic and pharmacodynamic interaction between zileuton and terfenadine. Eur J Clin Pharmacol 1997;52:49-54. 
  12. Meltzer SS, Hasday JD, Cohn J, Bleecker ER. Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor. Am J Respir Crit Care Med 1996;153:931-5. 
  13. Hui KP, Taylor IK, Taylor GW, Rubin P, Kesterson J, Branes NC, Barnes PJ. Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 1991;46:184-9. 
  14. Gomez FP, Iglesia R, Roca J, Barbera JA, Chung KF, Rodriguez-Roisin R. The effects of 5-lipoxygenase inhibition by zileuton on platelet-activating-factor-induced pulmonary abnormalities in mild asthma. Am J Respir Crit Care Med 1998;157:1559-64. 
  15. Israel E, Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Shapiro J, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 1993;148:1447-51. 
  16. Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G, Rubin P, Drazen JM. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med 1990;323:1740-4. 
  17. Fischer AR, McFadden CA, Frantz R, Awni WM, Cohn J, Drazen JM, Israel E. Effect of chronic 5-lipoxygenase inhibition of airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med 1995;152:1203-7. 
  18. Dekhuijzen PNR, Bootsma GP, Wielders PLML, van der Berg LRM, Festen J, van Herwaarden CLA. Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids. Eur Respir J 1997;10:2749-53. 
  19. Calhoun WJ, Lavins BJ, Minkwitz MC, Evans R, Gleich GJ, Cohn J. Effect of zafirlukast (Accolate) on cellular mediators of inflammation. Am J Respir Crit Care Med 1998;157:1381-9. 
  20. Roquet A, Dahlen B, Kumlin M, Ihre E, Anstren G, Binks S, Dahlen S. 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;155:1856-63. 
  21. Lazarus SC, Wong HH, Watts MJ, Boushey HA, Lavins B, Minkwitz MC. The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma. Am J Respir Crit Care Med 1997;156:1725-30. 
  22. Dahlen B, Zetterstrom O, Bjork T, Dahlen S-E. The leukotriene-antagonist ICI-204,219 inhibits the early airway reaction to cumulative bronchial challenge with allergen in atopic asthmatics. Eur Respir J 1994;7:324-31. 
  23. Smith LJ, Hanby LA, Lavins BJ, Simonson SG. A single dose of zafirlukast reduces LTD4-induced bronchoconstriction in patients on maintenance inhaled corticosteroid therapy. Ann Allergy Asthma Immunol 1998;81:43-9. 
  24. Kemp JP, Dockhorn RJ, Shapiro GG, et Nguyen HH, Reiss TF, Seidenberg BC, Knorr B. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 1998;133:424-8. 
  25. Reiss TF, Hill JB, Harman E, Zhang J, Tanaka QK, Bronsky 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. 
  26. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, Reiss TF. Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval. Clin Pharmacol Ther 1997;62:556-61. 
  27. DeLepeleire I, Reiss TF, Rochette F, Botto A, Zhang JZ, Kundu S, et al. Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma. Clin Pharmacol Ther 1997;61:83-92. 
  28. Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;199:1059-66. 
  29. Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipozygenase inhibitor in asthma: a 6-month randomized multicenter trial. J Allergy Clin Immunol 1996;98 :859-71. 
  30. Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. JAMA 1996;275:931-6. 
  31. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby L, Bonucceli CM. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multi-center study. Clin Ther 1997;19:675-90. 
  32. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998;158:1213-20. 
  33. 33. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss T, et al. Montelukast for chronic asthma in 6- to 14-year-old children. JAMA 1998;279:1181-6. 
  34. Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med 1999;130:487-95. 
  35. Lofdahl C-G, Reiss TF, Leff JA, Israel E, Noonan MJ, Finn AF, et al. Randomized, placebo-controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BUM 1999;319:87-90. 
  36. Lavallette M, Malmstrom K, Lu S, Chervinsky P, Puget J-C, Passé I, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999;160:1862-68. 
  37. Schwartz HE, Petty T, Dube LM, Swanson LJ, Lancaster JEFF. A randomized controlled trial comparing zileuton with theophylline in moderate asthma. Arch Intern Med 1998;158:141-8. 
  38. Busse W, Nelson H, Wolfe, J, Kalberg C, Yancey SW, Rickard KA. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999;103:1075-80. 
  39. Dahlen B, Nizankowska E, Szczeklik, Zetterstrom O, Bochenek G, Kumlin M, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998;157:1187-94. 
  40. Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and churg-strauss syndrome. Drug Saf 1999;21:241-51. 
  41. Clinical Practice Guidelines. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; April 1997. NIH publication 97-4051. 
  42. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339:147-52. 
  43. Villaran C, O'Neill SJ, Helbling A, van Noord JA, Lee TH, Chuchalin AG, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol 1999;104:547-53. 
  44. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, Ghanna, AF, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. Ann Intern Med 2000;132:97-104. 
  45. Jobin V, Beauchesne M-F, Cartier A. Management of asthma in pregnancy. Allergy and Asthma; December 1999/January 2000;14-26.

Copyright © 2000 by the Journal of Informed Pharmacotherapy. All rights reserved.