Leukotriene Receptor Antagonist Therapy Research Articles

The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model

Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling. The cysteinyl leukotrienes (LTC(4), D(4) and E(4)) are known to play important roles in the pathobiology of asthma. To evaluate the effect of low dose montelukast (MK) on the development of airway remodeling using a chronic murine model of allergic airway inflammation with subepithelial fibrosis, BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on days 0 and 14, received intranasal OVA periodically on days 14-75. MK treated mice received montelukast sodium intraperitoneally on days 26-75. The OVA sensitized/challenged mice developed an extensive eosinophil cell inflammatory response, goblet cell hyperplasia, mucus occlusion, and smooth muscle hypertrophy of the airways. In addition, in OVA sensitized/challenged mice, dense collagen deposition/fibrosis was seen throughout the lung interstitium surrounding the airways, blood vessels, and alveolar septae. The cysteinyl leukotriene 1 (CysLT1) receptor antagonist, MK significantly reduced the airway eosinophil infiltration, goblet cell hyperplasia, mucus occlusion, and lung fibrosis except airway smooth muscle hypertrophy in the OVA sensitized/challenged mice. The OVA sensitized/challenged mice had significantly increased epithelial desquamation compared with control mice. MK markedly reduced epithelial desquamation of airways in OVA/MK treated animals compared with OVA sensitized/challenged mice. MK treatment did not affect the levels of CysLT in lung tissue. Our results show that the important role of cysteinyl leukotrienes in the pathogenesis of asthma. Lower dose of CysLT1 receptor antagonism has a significant anti-inflammatory effect on allergen-induced lung inflammation and fibrosis but not airway smooth muscle hypertrophy in an animal model of asthma.

The linkage between Churg-Strauss syndrome and leukotriene receptor antagonists: fact or fiction?

Epidemiologic evidence has shown that the worldwide prevalence of asthma is increasing. The leukotriene receptor antagonists (LTRAs) represent a new class of therapy for asthma. They have been developed in the last decade and play a pivotal steroid-sparing role in treating the inflammatory component of asthma. Consequently, reports of Churg-Strauss syndrome (CSS), a rare form of systemic vasculitis, have been recognized as a potential side effect in individuals with moderate to severe asthma on LTRA therapy. The serious nature of this disorder is worthy of prompt recognition by clinicians and aggressive therapy to avoid the subsequent longstanding effects of vasculitis. To validate the postulated linkage between the LTRAs and CSS, this review comprehensively evaluates reported cases in the literature and supports a pathophysiological relationship between the LTRAs and the development of CSS.

Acute asthma: under attack.

The burden of asthma (death, disability, and an increasing prevalence) makes it a major public health problem worldwide. In an effort to decrease this burden, investigators are studying many aspects of this disease. The role of race, ethnicity, infections, and pollutants as triggers, as well as the risk factors are now being defined. Research into methods to decrease acute exacerbations and improve emergency and in-hospital management, using standardized protocols and incentives for follow-up care, has yielded valuable information but has met with limited success. Adherence to the national guidelines has been poor and to some extent can be attributed to the lack of a practical method of measuring the degree of lung inflammation and cumbersome treatment protocols. Exhaled nitric oxide is a noninvasive marker of inflammation and may provide a rational method to titrate corticosteroid and leukotriene receptor antagonist therapy. The best route and dosing regimen for corticosteroid administration (oral vs intramuscular vs nebulized) are the subject of several studies, with no clear-cut winner. The burden of asthma in developing countries with limited financial resources has also triggered a search for simpler, cheaper, and practical methods for beta-agonist delivery using indigenous spacers. Recent research in asthma has unveiled our incomplete knowledge of the disease but has also provided a sense of where efforts should be expended. Research into the genetics and pharmacogenetics of asthma and into the societal factors limiting the delivery of optimal care is likely to yield useful and practical information.

LTRA inhibition of exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) affects between 70% and 80% of asthmatic patients. Shortly after strenuous exercise, several inflammatory mediators, including the cysteinyl leukotrienes, induce bronchoconstriction. Evidence of this phenomenon includes the increase in urinary leukotriene E4 excretion after exercise and the inhibition of EIB by the leukotriene synthesis inhibitor zileuton. Similarly, the leukotriene receptor antagonists (LTRAs) montelukast and zafirlukast have significantly reduced the decrease in pulmonary function after exercise and shortened the time to recovery. Because exercise is generally a less predictable event in children, EIB can be more difficult to manage in pediatric than in adult asthmatic patients. However, LTRA use may temper this problem. Montelukast administered once daily at bedtime protected pediatric patients against EIB throughout the entire day. Zafirlukast attenuated EIB within 4 hours of dosing in 6- to 17-year-old patients who had mild to moderate asthma. Currently, inhaled ss2-agonists are widely prescribed for EIB, but when used long term, their efficacy may wane because of tolerance. In contrast, one of the advantages offered by LTRA therapy is the absence of tolerance.

Effect of leukotriene receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: an integrated analysis of zafirlukast trials

BACKGROUNDAsthma exacerbations contribute substantially to morbidity, and their reduction is an important therapeutic objective. In this integrated analysis the risk of asthma exacerbations was assessed during treatment with the leukotriene...

Role for cysteinyl leukotriene receptor antagonist therapy in asthma and their potential role in allergic rhinitis based on the concept of "one linked airway disease".

This review focuses on the shared pathophysiology of asthma and allergic rhinitis. The similarities illustrate the "one linked airway disease" concept, a unifying theory of these upper and lower airway inflammatory disorders. Since leukotrienes are mediators in both conditions, studies have been performed to assess the potential therapeutic role of cysteinyl leukotriene antagonists. The purpose of this paper is to provide an overview of the accumulating data concerning these agents in treating asthma and allergic rhinitis. Relevant publications obtained from a literature review. Relevant publications on the topics of leukotrienes, leukotriene receptor antagonists, asthma, and allergic rhinitis were critically evaluated. Studies to date have documented the efficacy of cysteinyl leukotriene receptor antagonists for asthma. The pathophysiology of allergic rhinitis and its similarities to asthma suggest that these agents could play a significant therapeutic role in managing this upper airway disorder. Because the leukotriene antagonists are oral agents, they may be valuable in treating not only either condition but also both at the same time when they coexist. They appear to be beneficial when prescribed as the initial medicine and when used in conjunction with other therapies.