Journal of Allergy and Clinical Immunology
Leukotriene receptor antagonists in asthma therapy☆,☆☆
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.
Lung function r Value P value Change in sGaw 0.47 .007 Change in airway resistance 0.31 .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
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)
- et al.
Analysis of montelukast in mild persistent asthmatic patients with near-normal lung function
Respir Med
(2001) - et al.
Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. The Zafirlukast Trialists Group
Clin Ther
(1997) - et al.
Zafirlukast improves asthma symptoms and quality of life in patients with moderate reversible airflow obstruction
J Allergy Clin Immunol
(1998) - et al.
Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma
J Allergy Clin Immunol
(1999) - et al.
Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma
J Allergy Clin Immunol
(2000) - et al.
Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial
J Allergy Clin Immunol
(2001) - et al.
Asthma
Lancet
(1995) - et al.
Significant variability in response to inhaled corticosteroids for persistent asthma
J Allergy Clin Immunol
(2002) - et al.
Do inhaled corticosteroids affect perception of dyspnea during bronchoconstriction in asthma?
Chest
(2001) - et al.
The perception of dyspnea in patients with mild asthma
Chest
(2001)
Measuring asthma control in group studies: do we need airway calibre and rescue beta2-agonist use?
Respir Med
Relationship between airway obstruction and respiratory symptoms in adult asthmatics
Chest
Leukotriene C: a slow-reacting substance from murine mastocytoma cells
Proc Natl Acad Sci U S A
Antileukotrienes in the treatment of asthma
Ann Intern Med
Treatment of asthma with drugs modifying the leukotriene pathway
N Engl J Med
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
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.