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Leukotriene-receptor antagonists. Clinical models of asthma

 

Allergen-induced asthma

In sensitized patients, inhalation of a specific allergen results in acute bronchoconstriction that usually subsides spontaneously within 2 hours; this phenomenon is known as the early asthmatic response. In many asthma patients, the early response resolves only to be followed by a second episode of airway narrowing that begins 3 to 4 hours after allergen challenge. This late response can last as long as 24 hours. Cysteinyl leukotrienes are produced during the early asthmatic response, and the degree of leukotriene production correlates directly with the magnitude of the early asthmatic response. Several studies involving LTRAs have shown that most of the bronchospasm associated with the early asthmatic response is attenuated and that the late asthmatic response is partially attenuated by these agents.

It is less clear that the leukotriene-receptor antagonists now available can suppress the airway inflammation seen during the late asthmatic response. In a recent placebo-controlled, double-blind crossover trial, Calhoun and colleagues challenged airways directly by using a bronchoscope to instill a dilute solution of allergen in segmental airways. They subsequently lavaged the same airways to assess the cellular response. They reported that zafirlukast administration (20 mg bid for 7 days) reduced several indices of the inflammatory allergic response, but the reduction in eosinophil count was not statistically significant. This lack of statistical significance might be due to large intersubject variation and the small sample size (n = 11) of the study. Similarly, a short course of montelukast (10 mg daily) has been shown to protect against allergen-induced airway narrowing but does not significantly suppress sputum eosinophil counts or eosinophil cationic protein levels in asthma patients (n = 9).

allergen-induced-asthma

Acetylsalicylic acid-induced asthma

As many as 10% of asthmatic adults have ASA-induced asthma. In some susceptible people, severe, life-threatening asthma can follow ingestion of ASA or other nonsteroidal anti-inflammatory drugs (NSAIDs). At present, the most effective therapy for ASA-induced asthma is avoidance of ASA or other NSAIDs. There is, however, good reason to speculate that leukotriene-receptor antagonists might have a useful role in treatment of ASA-sensitive asthma. Research suggests that ASA triggers attacks of wheezing in susceptible individuals by blocking cyclooxygenase metabolic degradation of arachidonic acid and directing larger amounts of this substrate down the lipoxygenase (leukotriene-producing) pathway. Leukotriene-receptor antagonists have been shown to protect against bronchospasm associated with oral ASA challenge, protection that ranges from moderate to complete. Montelukast has also been reported to improve the symptom control and pulmonary function of patients with severe ASA-sensitive asthma when it was added to their maintenance regimen of inhaled and, in some cases, oral steroids.

Exercise-induced bronchospasm

Cysteinyl leukotrienes appear to have an important role in causing exercise-induced bronchoconstriction. In eight asthma patients with documented exercise-induced bronchospasm, administration of 20 mg of zafirlukast as a single dose 2 hours before exercise reduced the mean maximum decrease in forced expiratory volume in 1 second (FEV1) after exercise to 22%, compared with a 36% decrease after placebo.

In a recent report, montelukast (10 mg daily for 12 weeks) was associated with significant inhibition (47.4%) of the exercise-induced fall in FEV1 when described in terms of improvement in the area under the FEV1 curve. This protective effect was well sustained, and there was no evidence of tolerance or rebound worsening of lung function after 3 months of continuous montelukast therapy. The same cannot be said of long-acting β2-agonists, which lose some effectiveness over time when given continuously to prevent exercise-induced symptoms.

Role of leukotriene-receptor antagonists in chronic asthma

While the efficacy of LTRAs in various clinical models of asthma has been well documented, studies of leukotriene-receptor antagonists in asthma management that are most clinically relevant to family physicians involve patients with chronic asthma. Currently, zafirlukast and montelukast are available in Canada and USA for managing asthma. Both of these drugs are selective and competitive receptor antagonists of leukotriene D4 and leukotriene E4. No studies have compared montelukast and zafirlukast with each other. Before instituting new therapy in patients with suboptimal asthma control, physicians should evaluate medication compliance, inhaler technique, and environmental control measures.

Montelukast

Reiss et al conducted a 12-week double-blind, placebo-controlled trial involving 681 patients with intermittent or persistent asthma and found that a single 10-mg daily dose of montelukast given at night increased morning FEV1 by 13% as compared with 4% in the placebo group. Montelukast (trade name Singulair) also decreased nocturnal awakenings due to asthma and need for short-acting β2-agonists.

In a short study (1.5 weeks), montelukast was compared with placebo in a crossover trial, and treatment with montelukast was associated with a 16% improvement in FEV1. In an 8-week trial of 336 children 6 to 14 years old with intermittent or persistent asthma, Knorr et al found that 5 mg of montelukast nightly increased mean morning FEV1 significantly more than placebo (approximately 8% vs 4%). Short-acting β2-agonist use decreased by 0.57 puffs daily among montelukast-treated children and increased by 0.22 puffs daily among placebo-treated children.

Noonan et al studied patients with mild to moderate asthma and concluded that montelukast administration was associated with dose-related improvements in asthma control end points. Improvements were seen in FEV1 and peak expiratory flow rate and in daytime symptom scores, use of as-needed inhaled β2-agonists, and asthma-specific quality of life. In a recent report (n = 226), Lofdahl et al reported that montelukast permitted a 47% reduction in inhaled corticosteroid dosage compared with a 30% reduction with placebo in a group of asthma patients previously well controlled on inhaled corticosteroids. Near maximal effects on several asthma control end points have been shown to occur within the first day of treatment with montelukast.

In another double-blind, placebo-controlled trial (n = 40), Leff et al showed that montelukast (10 mg daily) resulted in significant decreases in both sputum and blood eosinophils compared with placebo. Peak flow rate, symptoms, and β2-agonist use all improved significantly with montelukast use. Malmstrom et al have reported that both montelukast and beclomethasone (200 µg bid) provide important clinical improvements in need for rescue medication, symptom scores, and lung function as compared with placebo.

Montelukast

Zafirlukast

In a 6-week double-blind, placebo-controlled trial, Spector et al randomly assigned 255 patients with moderate asthma to receive one of three daily dosages of zafirlukast [marketed as Accolate] (10, 20, or 40 mg in divided doses) or placebo. These investigators reported significant improvements in both subjective (asthma symptom score) and objective FEV1, number of nocturnal awakenings, and use of rescue β2-adrenergic agonist drugs) measures of asthma control. Improvement was dose dependent, with the 10-, 20-, and 40-mg groups exhibiting a 7%, 6%, and 11% increase in FEV1, respectively (P <.05 for the 40-mg group vs placebo). In the placebo group, FEV1 increased by just 1%.

In a 13-week double-blind, placebo-controlled trial involving 672 asthmatic adults, zafirlukast administration at a dose of 20 mg bid was associated with significant reductions in daytime asthma scores (27%), in mornings with asthma (29%), and in β2-agonist use (22%). Morning peak expiratory flow rate and FEV1 increased significantly, by 6.9% and 6.3%, respectively, compared with placebo. Changes in symptoms, β2-agonist use, and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial.

Micheletto et al indicate that zafirlukast given as a single 20-mg dose is associated with reduced need for (inhaled) steroids as demonstrated by a decrease (-256.3 ± 120.7) in the angular coefficient for this trend compared with placebo (+12.4 ± 17, P < 0.025, n = 9). These investigators also reported significant reductions in nighttime awakenings and asthma symptoms. In a double-blind, placebo-controlled trial of 13 weeks duration, Kylstra et al studied the effect of zafirlukast (20 mg bid) on quality of life, event-free days, and peripheral eosinophils in 231 patients and found that zafirlukast significantly increased the number of symptom- and problem-free days, improved quality of life scores, and decreased the number of peripheral eosinophils.

 

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