Leukotriene Inhibitors for Asthma

ABSTRACT & COMMENTARY

Synopsis: These data provide further evidence for the clinical applicability of leukotriene inhibitors in the treatment of asthma.

Source: Liu MC, et al. J Allergy Clin Immunol 1996;98:859-71.

Asthma is a common and increasing chronic disease, which, in its most severe form, is associated with significant dyspnea, reduction in exercise tolerance, sleep disturbance, and reduced quality of life, often with lost days from school or work. In recent years, the risk for fatal asthma has also increased, especially in the non-white population. While there are numerous therapeutic approaches to asthma, many of these are associated with significant side effects and, therefore, reduction in patient tolerance. Currently, treatment guidelines suggest the use of inhaled anti-inflammatory agents, like corticosteroids, as the bedrock of asthma therapy. It has been recognized for several decades that leukotrienes are important mediators of asthma and are capable of inducing bronchoconstriction, mucous hypersecretion, eosinophil migration into the airway, and airway edema (see Table). Leukotrienes are also measurably increased following either antigen challenge or acute asthmatic exacerbations. Agents that inhibit leukotriene production, either by the inhibition of the 5-lipoxygenase enzyme or by blocking leukotriene receptors, have recently become available and have been demonstrated to be effective when acutely administered, especially to aspirin, allergen, and exercise-induced asthma.

Table
Leukotrienes in asthma

Cysteinyl Leukotrienes

• Bronchoconstriction

• Mucous secretion

• Vascular permeability

• Produced by human lung following antigen challenge

Leukotriene inhibitors (Receptor Antagonists, Lipoxygenase inhibitors)

Block:

• Exercise-induced asthma

• Aspirin-sensitive asthma

• Atopic asthma

Improve:

• Pulmonary function

Modified from: Nathan RA. J Asthma 1996;33:353-366.

Liu et al now report on the chronic effects of a 5-lipoxygenase inhibitor, Zileuton, over a six-month period. Patients 18-62 years old with mild-to-moderate asthma were recruited with an average FEV1 of approximately 60%. All patients had to have at least a 15% improvement in FEV1 after inhalation of albuterol. Most medications used in the management of asthma and allergic disease were stopped prior to the start of the single-blind, lead-in phase. Patients were then randomized into three treatment groups: Zileuton 400 mg, Zileuton 600 mg, or placebo given four times daily. Assessment included serial spirometry, daily daytime and nighttime peak flow and symptoms, frequency of beta-agonist use, and asthma exacerbations treated with systemic corticosteroids. As has been previously demonstrated, Zileuton demonstrated acute bronchodilation, evident from two hours onward. Zileuton had its most pronounced effect in patients whose baseline FEV1 was less than 50%. By day eight, treatment with Zileuton resulted in significantly improved FEV1 compared to placebo. Patients receiving 600 mg of Zileuton had a mean increase in morning FEV1 of 18% at three months, compared to 12% in the 400 mg Zileuton, and 7% in the placebo. Significantly increased peak flows were noted in the 600 mg Zileuton group compared to other patients, as were decreases in daytime and nocturnal symptom scores, especially for shortness of breath, wheezing, cough, and nasal congestion.

The overall improvement in symptom score was maximal in the second half of the study and continued to be maintained. Overall, 38% of the placebo-treated patients had an exacerbation of asthma, compared to 31% and 27% in the Zileuton groups (P = 0.18, P = 0.104), and the use of rescue medications, especially systemic corticosteroids, was significantly reduced. There was also a decrease in blood eosinophil counts in both Zileuton- treated groups, compared to control. Adverse events were similar in both groups and did not appear to be related to dosing of Zileuton over the course of six months.

COMMENT BY ALAN M. FEIN, MD

The data offered by Liu et al provide further evidence for the clinical applicability of leukotriene inhibitors in the treatment of asthma. These agents demonstrated not only improved pulmonary function but, more importantly, improved symptoms and quality of life. Exacerbations requiring the use of systemic corticosteroids over a six-month period were also observed. Of great import was the lack of reported significant side effects. Zileuton had an acute effect, suggesting an acute bronchodilatory effect, which was maximal at five hours and thus probably related to inhibition of airway smooth muscle tone. However, as indicated by the sustained reduction of eosinophils, it also had an effect on the inflammatory component of asthma. This resulted in a sustained elevation of FEV1 and peak expiratory flow, which peaked by day 36. Daytime and nighttime symptom scores also followed suit. There were significant reductions in the need for corticosteroids.

These data follow previous work that has suggested a role for both leukotriene receptor antagonists, Zileuton and Zafirlukast, which have been demonstrated to limit both exercise- and allergic-mediated asthma, as well as seasonal rhinitis. The use of a 5-lipoxygenase inhibitor to maintain sustained improvement in pulmonary function over six months suggests that these agents will be an important part of the pharmacologic treatment of asthma.

Where do these agents fit in an overall management plan? The study of Liu et al enrolled patients with mild-to-moderate asthma, who were able to discontinue most of their medications during a qualification period. Their FEV1s were in the 60% range, and their mean age was 34, with 93% being Caucasian and 75% never smokers. This may represent a selected population, though perhaps somewhat broader than previous groups studied with these agents. Although chronic use of inhaled corticosteroids appear safe, there is a growing body of evidence which suggests that chronic effects may be seen over time, especially with bone density, adrenal suppression, and skin changes. Questions about the chronic use of beta-agonists have also been raised, especially regarding potential rebound symptoms and loss of efficacy over time. Thus, the availability of leukotriene antagonists represents a new approach, especially in the mild-to-moderate asthmatic. Whether these agents will have the same efficacy in "intrinsic asthmatics" or individuals with airway reactivity, complicating other illnesses like COPD and sarcoidosis, remains to be established. While we optimistically await these studies, it is clear that a whole new approach has been opened in the chronic management of asthma.