Leukotriene receptor antagonists in asthma therapy,☆☆

https://doi.org/10.1067/mai.2003.21Get rights and content

Abstract

In persons with asthma, the cysteinyl leukotrienes possess multiple inflammatory properties in vitro and have long been considered to be a potentially important mediator of asthma and an attractive target for therapeutic intervention. Controlled clinical trials have documented the efficacy of leukotriene receptor antagonists in asthma treatment, but reservations about their use for asthma therapy center on two main issues: the heterogeneity of patient responses and their reduced potency relative to other asthma medications. For example, leukotriene receptor antagonists also have been shown to be less efficacious than inhaled corticosteroids for several end points, including symptom relief, reduced markers of inflammation, and improved pulmonary function. This review explores several underappreciated aspects of asthma therapy: heterogeneity of patient responses to medication, the failure of symptoms to correlate with commonly used end points, and the potential of delivery to distal airways for producing important and novel benefits. (J Allergy Clin Immunol 2003;111:S62-70.)

Section snippets

Heterogeneity of responses to different asthma medications

The variability in clinical response produced by the LTRA montelukast was documented in a study comparing it with low-dose beclomethasone dipropionate for the treatment of patients with mild-to-moderate asthma.5 Whereas 34% of patients did not have an improvement in FEV1 after treatment with the LTRA, 22% had no response to 400 μg/d of beclomethasone.5 Similar percentages of asthmatic patients had no responses to a variety of asthma medications in a variety of other settings as well: 34% of

Asthma end points and the importance of asthma symptoms as an end point

Many end points have been used in clinical trials, including wheeze, dyspnea, cough, chest tightness, nocturnal awakenings, rescue medication use, rescue medication–free days, symptom-free days, measures of pulmonary function (eg, FEV1, PEFR variability, and airway hyperresponsiveness), asthma exacerbations, and indices of airway inflammation (eg, inflammatory cells in sputum, bronchoalveolar lavage, biopsy specimens, and exhaled nitric oxide). These end points have been used while trying to

Modeling asthma symptoms

A National Institutes of Health National Heart, Lung, and Blood Institute workshop on symptom perception and respiratory sensation in asthma has divided the many symptoms asthmatic patients have (such as wheeze, chest tightness, dyspnea, inability to exhale, cough, and nocturnal symptoms) into two general categories that can be modeled experimentally.23 These categories are (1) wheeze (bronchospasm), which can be modeled by an external resistance (mechanical loading), and (2) the inability to

Effects of luekotriene D4 on asthma symptoms and pulmonary function

Studies performed almost 2 decades ago examined the effects of leukotriene D4 (LTD4) inhalation on symptoms and pulmonary function in patients with asthma.25, 26 In one study,25 all 6 of the challenged asthmatic patients had wheeze and chest tightness, whereas 3 of 6 had an increase in residual volume. In another study,26 small airway function, flow at 30% vital capacity obtained from a partial flow volume curve, showed a more profound decrement than did FEV1, the classic clinical measure of

Relationship between dyspnea in asthma and pulmonary function

Examination of the disparate perceptions of dyspnea in asthmatic patients before and after the administration of a β-agonist compared with measures of pulmonary function (Table III)27 revealed that only sGaw was correlated with the Borg perception of dyspnea.

. Relationship between perception of dyspnea (Borg) before and after a β-agonist and different measures in lung function in patients with asthma

Lung functionr ValueP value
Change in sGaw0.47.007
Change in airway resistance0.31.086
Airway

Small airways and lung parenchyma in asthma

Small airway dysfunction is important in asthma. A marked increase in peripheral airway resistance occurred in patients with mild asthma who had a normal FEV1 and only a small decrease in forced midexpiratory flow rates.30 More intriguing is the loss of airway-parenchymal interdependence (the ability to decrease airway resistance when increasing thoracic lung volume) measured in sleeping patients with nocturnal asthma (Fig 3).31

. Effect of sleep on airway-parenchymal interdependence in patients

Treatment strategies to target asthma symptoms and the distal lung

If asthmatic symptoms are a result of the dysfunction of both large airways (as reflected by changes in sGaw) and the distal lung, LTRAs could be effective in both areas. These possibilities should be tested experimentally. First, it should be determined whether a relationship exists between LTRAs and sGaw on asthma symptoms as it does for β-agonists.27 Second, the effects of LTRAs on distal lung pathophysiology, including air trapping, peripheral airway resistance, and the loss of

CONCLUSIONS

The CysLTs produce many of the pathophysiologic manifestations associated with asthma, and leukotriene-active drugs have shown clinical benefits in many different aspects of asthma therapy. The heterogeneity of patients' responses to different asthma medications is an issue that appears to be common to most, if not all, asthma medications. Some asthma end points that might be affected by LTRAs, such as those associated with specific aspects of asthma symptoms and some associated with the

Questions and discussion

Qutayba Hamid: Stephen, is there a good way to measure peripheral airway obstruction?

Stephen Peters: The short answer to this question is no, in that all the commonly used techniques have disadvantages. For example, one of the most direct and accurate techniques involves measuring flow and pressure through a wedged bronchoscope, but this is an invasive technique. One could look at peripheral airway obstruction more indirectly, for example, by quantitating air trapping before and after

Discussion of important clinical measurements for managing asthma (Marc Peters-Golden, Chairman)

Marc Peters-Golden: In this discussion, let us try to propose practical clinical recommendations for what is important to measure and how the measurements can be used to better manage the asthmatic patient. In other words, in a clinical study or in patient care, what are the things we need to know?

Stephen Peters: Looking at asthmatic patients on 2 different days shows a lack of correlation between patient symptoms and FEV1, which is not surprising. Juniper et al28 used the asthma control

Summary (Marc Peters-Golden)

Endpoints. A variety of end points are used to monitor asthma in clinical practice and in clinical trials, but the correlation among these various end points is at best imperfect, and at worst, downright poor. This underscores the importance of monitoring multiple end points.

Symptoms. Indisputably important to patients, symptoms are perceived through variables in psychosocial factors (influencing the recognition of symptoms and the willingness to report them), perceptual ability, and lifestyle

References (33)

  • EF Juniper et al.

    Measuring asthma control in group studies: do we need airway calibre and rescue beta2-agonist use?

    Respir Med

    (2001)
  • JG Teeter et al.

    Relationship between airway obstruction and respiratory symptoms in adult asthmatics

    Chest

    (1998)
  • RC Murphy et al.

    Leukotriene C: a slow-reacting substance from murine mastocytoma cells

    Proc Natl Acad Sci U S A

    (1979)
  • PM O'Byrne et al.

    Antileukotrienes in the treatment of asthma

    Ann Intern Med

    (1997)
  • JM Drazen et al.

    Treatment of asthma with drugs modifying the leukotriene pathway

    N Engl J Med

    (1999)
  • TF Reiss et al.

    Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group

    Arch Intern Med

    (1998)
  • Cited by (0)

    Supported in part by grants A124509, HL51810, and HL67663.

    ☆☆

    Reprint requests: Stephen P. Peters, MD, PhD, Thomas Jefferson University Hospital, Gibbon Building, 111 S 11th St, Suite 4260, Philadelphia, PA 19107.

    View full text