Chronic Stable Asthma

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In addition to their anti-inflammatory effects and benefits in patients with a variety of lab-induced models of asthma, leukotriene modifiers have significant efficacy in patients with chronic persistent asthma, compared with placebo, both as monotherapy and as add-on therapy to other controllers.

Leukotriene Modifiers as Monotherapy

Multiple studies have shown that, when asthma patients who used inhaled p-agonists as their only asthma medication were treated with a leukotriene modifier (pranlukast, zafirlukast, montelukast, or zileuton), asthma improved such that they had improvement in airway obstruction, decreased need for rescue treatment with p-agonists, relief of asthma symptoms, and decreased frequency of asthma exacerbations that required systemic corticosteroid therapy (111,112,128,129).

In studies of four to six weeks duration, patients with moderate asthma (mean FEV1 of 65% predicted) treated only with p-agonists were given placebo in a single-blind manner for a run-in period of 7 to 14 days, followed by an active treatment period of four to six weeks (followed in some cases by a withdrawal period). In most of the trials, during the first month of treatment, the FEV1 improved significantly by 10% to 15% and the degree of improvement was statistically significant with active agent compared with placebo. Improvement encompassed decreases in asthma symptoms, nighttime awakenings, and p-agonist use and increases in morning and evening peak flow rates. In the trials with zileuton (112) and zafirlukast (128), patients receiving higher doses of either drug had a significantly greater increase in FEV1 than did patients receiving placebo; patients receiving lower doses had an increase of intermediate magnitude.

Long-term studies with each of the leukotriene modifiers have had similar findings. For instance, when 401 patients were randomized in a double-blind fashion to three months of therapy with placebo or with one of two doses of zileuton, there was a significant increase in FEV1 with zileu-ton compared with placebo (16% with zileuton 600 mg four times a day vs. 8% with placebo), a significant decrease in asthma symptoms, a significant decrease in p-agonist use, and a significantly lower percentage of patients who required treatment with corticosteroids (6% vs. 16%). Furthermore, six months of treatment with zileuton reduced peripheral eosinophil counts by more than 20% (108). Although most of the improvement in airway function occurs within two to four weeks after the initiation of drug therapy, the improvement in FEV1 was maintained over the course of the trial, extending previous findings that patients do not become tolerant of the effects of 5-LO inhibition or blockade.

The effect on FEV1 also appears to be greater in patients with more severe airway obstruction. Zafirlukast improved FEV1 by only 40 mL in patients whose baseline FEV1 was more than 80% predicted, compared with an increase of 800 mL in those whose FEV1 was less than 45% predicted (128). Among patients using inhaled corticosteroids, pranlukast allowed a 50% reduction in the dose of inhaled corticosteroid compared with placebo, without loss of asthma control (130). In general these agents have been shown to improve asthma control and can reduce days lost from school or work, unscheduled medical care episodes, and days with asthma symptoms (131-133).

Treatment once daily with montelukast appears to confer the same benefit as more frequent treatment with other agents (134). Furthermore, the leukotriene receptor antagonists have been systemically studied in children and are approved for use in children as young as two years of age (135-137). In children with moderate persistent asthma, treatment with montelukast (one 5-mg tablet at bedtime) was associated with improved lung function at baseline, decreased asthma symptoms, and decreased need for asthma rescue medication use. Asthma-specific quality of life improved a ''clinically significant" amount in children receiving active treatment, while such an effect was not observed in children treated with placebo. These effects were present in patients also receiving inhaled corticosteroids as an asthma treatment. Montelukast, given as a single 5-mg tablet daily, inhibited the bronchospasm induced by exercise by an average of 50%; these effects were observed up to 24 hours after the last medication dose, indicating a prolonged effect. In children with exercise-induced asthma, zafirlukast, 40 mg/day, was effective in preventing exercise-induced bronchospasm (138).

How do leukotriene modifiers fare as monotherapy in comparison to other controller therapies? Several studies have compared the effectiveness of leukotriene modifiers and inhaled corticosteroids (124,139,140). In a study comparing montelukast and beclomethasone as monotherapy in patients with moderate asthma, there were greater peak expiratory flow rate and quality of life, fewer nocturnal awakenings and asthma attacks, more asthma-control days, and fewer days with asthma exacerbations following treatment with either active agent than with placebo (141). Both classes of therapy caused similar decreases in peripheral blood eosinophil counts. Although beclomethasone in general had a greater mean effect on FEV1 than montelukast (percentage change from baseline in FEV1 was 13.1% with beclomethasone, 7.4% with montelukast), montelukast had a faster onset of action and a greater initial effect. While other studies corroborate the findings that inhaled corticosteroids show greater improvement in FEV1 and peak flow than leukotriene modifiers, they demonstrate no significant difference in exacerbation rates or days of asthma control (140,142145). While inhaled corticosteroids often demonstrated greater effects on inflammatory indicators, several investigators found that both of these agents were effective at reducing airway inflammation and airway hyper-responsiveness (146); inhaled steroid use resulted in greater adrenal suppression and a rise in osteocalcin levels, an important marker of bone turnover (115).

Studies by Edelman et al. (95) and Villaran et al. (147) showed montelukast to be more effective than the long-acting p-agonist salmeterol in the acute and chronic treatment of exercise-induced asthma. In a four-week study comparing zafirlukast and salmeterol in patients with persistent asthma with established p-adrenergic responsiveness, both salmeterol and montelukast improved pulmonary function, asthma symptoms, and supplemental albuterol use (148). While salmeterol treatment resulted in significantly greater improvements from baseline than zafirlukast for morning peak flow (29.6 vs. 13.0L/min), percentage of symptom-free days (22.4% vs. 8.8), and percentage of days and nights with no supplemental albuterol use (30.5% vs. 11.3), there was no significant difference in the improvement in FEV1. In another study comparing salmeterol with zafirlukast over four weeks in 301 patients with persistent asthma, salmeterol was more effective than zafirlukast in improving pulmonary function and symptom control. However, asthma exacerbation rates and adverse event profiles were similar between the two drugs (149).

When zileuton was compared with twice-daily theophylline in a three-month trial, the two drugs resulted in similar increases in FEV1 and had similar safety profiles. Theophylline gave somewhat greater symptomatic relief in the first two months of the trial, but there was no significant difference in maximal effect (150). When zafirlukast and cromolyn were compared to each other and to placebo in the treatment of patients with mild asthma, the medications were found to be superior to placebo but comparable to each other in terms of symptom scores and p-agonist usage (151,152).

Leukotriene Modifiers as Add-On Therapy

Several investigators have demonstrated that leukotriene modifiers decrease the need for oral corticosteroid rescue therapy and permit the safe reduc-

Figure 2 Effect of zafirlukast compared with placebo on a.m. and p.m. peak expiratory flow in 368 adults who had persistent asthma symptoms despite >1200 mg of inhaled corticosteroids. Zafirlukast significantly improved a.m. and p.m. peak flows. Source: From Ref. 155.

tion of inhaled glucocorticoid doses (153,154). Virchow and colleagues (155) showed that zafirlukast improves both pulmonary function and asthma symptoms in patients taking high-dose inhaled corticosteroids, and also resulted in a reduction in asthma exacerbations (Fig. 2). Laviolette et al. (156) demonstrated that the addition of montelukast to inhaled beclomethasone in patients marginally controlled with beclomethasone alone led to a significant improvement in FEV1, daytime asthma symptom scores, and nocturnal awakenings (Fig. 3). For patients with asthma and persistent symptoms despite budesonide treatment, concomitant therapy with montelukast significantly improves asthma control with fewer nighttime awakenings, and results in greater improvements in rescue p-agonist use (157). Another double-blind, 16-week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma (158). The addition of montelukast was an effective and well-tolerated alternative to doubling budesonide dose with respect to peak flow, symptoms, exacerbations, and asthma-specific quality of life.

How does the combination of a leukotriene modifier and an inhaled corticosteroid compare with combination therapy of a long-acting p-agonist and an inhaled corticosteroid? While the LABA/ICS combination generally results in greater improvements in FEV1 and peak flow, there were no

Figure 3 Mean FEV1 percent change from baseline in subjects receiving montelukast + beclomethasone (closed diamonds), beclomethasone alone (closed triangles), montelukast alone (closed circles), or placebo (open squares). Both montelukast and beclomethasone resulted in greater improvement in FEV1 than placebo. The addition of montelukast to beclomethasone yielded greater results than the use of either agent alone. Source: From Ref. 156.

Figure 3 Mean FEV1 percent change from baseline in subjects receiving montelukast + beclomethasone (closed diamonds), beclomethasone alone (closed triangles), montelukast alone (closed circles), or placebo (open squares). Both montelukast and beclomethasone resulted in greater improvement in FEV1 than placebo. The addition of montelukast to beclomethasone yielded greater results than the use of either agent alone. Source: From Ref. 156.

Figure 4 Percentage of patients experiencing an asthma exacerbation during treatment with either montelukast plus fluticasone versus salmeterol plus fluticasone. There was no significant difference in exacerbation rates between the two groups. Source: From Ref. 159.

differences between groups with respect to asthma exacerbations (159,160) (Fig. 4). Wilson et al. (161) also compared the efficacy of salmeterol and montelukast as second-line therapy in patients with asthma not controlled by inhaled steroids. While both montelukast and salmeterol produced significant improvements in asthma control when given with inhaled cortico-steroid therapy, montelukast also produced significant effects on adenosine monophosphate bronchial challenge and blood eosinophil count, suggesting additive anti-inflammatory activity. This benefit was even observed when montelukast was added to the combination of long-acting p-agonist and inhaled corticosteroid (120).

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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