Effect Of Leukotriene Receptor Antagonist Research Articles

Leukotriene Modifier vs Inhaled Corticosteroid in Mild-to-Moderate Asthma: Clinical and Anti-inflammatory Effects

Evidence for the anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited. There are also no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids. This study was designed to assess the clinical efficacy and anti-inflammatory effects of leukotriene receptor antagonist plus low-dose inhaled corticosteroids compared to those of a high-dose inhaled corticosteroid in patients with mild-to-moderate asthma. Forty-nine patients with newly diagnosed asthma were recruited. They were randomly assigned to groups that received, for a 6-week period, either (1) budesonide, 600 microg bid (1,200 microg/d) or (2) budesonide, 200 microg (400 microg/d), and zafirlukast, 20 mg bid. The variables of asthma control were recorded daily. Sputum induction and methacholine provocation tests were performed. The results indicated that the administration of a low-dose inhaled corticosteroid plus zafirlukast was as effective as that of a high-dose inhaled corticosteroid regarding clinical improvement and anti-inflammatory effects (ie, eosinophil percentage, and eosinophilic cationic protein [ECP] and cysteinyl leukotriene C4 levels in induced sputum). Nineteen (group 1, 8 patients; group 2, 11 patients) of 49 patients (38.8%) had returned to normal airway responsiveness after treatment. Among these patients, 16 patients (84.2%) had normal ECP levels and 10 patients (52.6%) had normal percentages of eosinophils. ECP level, but not the eosinophil percentage, was significantly associated with symptom scores. The peak expiratory flow rate (PEFR) showed a significant correlation with the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) instead of with symptom scores. The addition of a leukotriene modifier to treatment with low-dose inhaled corticosteroids is equivalent to treatment with high-dose inhaled corticosteroids in patients with newly diagnosed mild-to-moderate asthma. In addition to symptoms and PEFR, the monitoring of ECP and PC20 may be of great value in achieving optimal control of asthma.

422 Protective effects of leukotriene receptor antagonist- montelukast against protamine sulfate induced bladder injury

422 Protective effects of leukotriene receptor antagonist- montelukast against protamine sulfate induced bladder injury

Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma.

Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C4 synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild-type (A) polymorphism of this enzyme. We carried out a retrospective analysis of 8 randomised, placebo-controlled trials performed in our department in mild-to-moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils. For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) (n = 78): 2.21 and 2.07-fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36-fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold-differences of 1.07 (95%CI 0.63-1.81) and 1.02 (95%CI 0.70-1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes. Polymorphisms of leukotriene C4 synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists in mild-to-moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide.

Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation

The understanding that asthma pathophysiology includes an inflammatory component has spurred the more aggressive use of anti-inflammatory therapies and created a need for effective tools to measure inflammation. Biomarkers of airway inflammation proposed are obtained by methods that are direct but highly invasive (bronchial biopsy, bronchoalveolar lavage), moderately direct, and less invasive (indirect sputum, exhaled air, breath condensate) or indirect and least invasive (blood, urine). Several studies described in this review have implicated the cysteinyl leukotrienes (CysLTs) as inflammatory mediators in a wide range of diseases, implying that their biological activities reach far beyond acute bronchoconstriction, the activity traditionally ascribed to them. The validity of examining sputum for “biomarkers” has improved the understanding of asthma pathophysiology, optimization of asthma treatment and management, and investigation of the relation between CysLTs and airway inflammation in asthma. Nitric oxide is also a surrogate marker of asthma and reflects airway inflammation. The anti-inflammatory effects of the leukotriene receptor antagonists and the markers of their activity continue to grow. (J Allergy Clin Immunol 2003;111:S49-61.)

Effects of leukotriene receptor antagonists on bronchial hyperresponsiveness: A meta-analysis

Effects of leukotriene receptor antagonists on bronchial hyperresponsiveness: A meta-analysis

The roles of leukotrienes and the effects of leukotriene receptor antagonists in the inflammatory response and remodelling of allergic asthma

The roles of leukotrienes and the effects of leukotriene receptor antagonists in the inflammatory response and remodelling of allergic asthma

Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability, exudation of macromolecules and edema. The cysteinyl leukotrienes also have potent chemoattractant properties for eosinophils, causing an influx of eosinophils into the airway mucosa, which further fuels the inflammatory process. In addition, the cysteinyl leukotrienes are potent secretagogues and reduce ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast and pranlukast inhibit bronchoconstriction in asthmatic patients undergoing allergen, exercise, cold air or aspirin challenge. They attenuate the hallmarks of asthmatic inflammation, including eosinophilia in the airway mucosa and peripheral blood. Moreover, exhaled nitric oxide concentrations, another correlate of airway inflammation, are decreased during montelukast treatment in children. Cysteinyl leukotriene synthesis is not blocked by corticosteroid therapy. This important observation suggests that the leukotriene receptor antagonists represent a novel therapeutic approach, one that may provide benefits that are additive with corticosteroid therapy. This supposition is supported by clinical observations that treatment with leukotriene receptor antagonists significantly improve asthma control when added to inhaled corticosteroid therapy. Moreover, the bronchodilator properties of the leukotriene receptor antagonists are additive with those of beta agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma.

Leukotriene receptor antagonists in chronic urticaria.

. SOME patients with chronic idiopathic urticaria (CIU) do not respond to antihistamines and require long-term steroid administration or even cyclosporin to control their disease. Recently, several studies reported good results with antileukotriene drugs in CIU (1–4); however, a prospective investigation aiming to detect which patients are more likely to benefit from antileukotriene treatment has not been carried out yet. Twelve consecutive patients with unremitting, steroid-dependent urticaria were studied. Clinical features and results of the main laboratory investigations are shown in Table 1. Montelukast 10 mg once a day (n=5) or zafirlukast 20 mg twice a day (n=7) was started. The usual therapies were not changed at the start of the scheduled 3-week treatment period, but patients were left free to reduce or withdraw antihistamine treatment in the case of a remission of the disease. Patients recorded both the severity of urticaria and the drugs used, and were followed up weekly. The primary end point of the study was an adequate control of the disease, defined as absence or marked reduction of pruritus and urticaria without the need for systemic steroid therapy. One patient was excluded because of intolerance of both montelukast and zafirlukast (severe headache). Six of the remaining 11 patients (55%) responded to zafirlukast (n=3) or montelukast (n=3) (Table 1). In these subjects, leukotriene receptor antagonists (LRA) induced a nearly total remission of the disease: four could easily control their urticaria with cetirizine 10 mg every other day, and two could discontinue antihistamine treatment altogether. The effect of LRA was already appreciable after some days of treatment. Responders have now been followed up for 6–24 months; they are still taking LRA and are all still in remission. No clinical feature or specific ‘‘marker’’ (sex, age, duration of the disease, NSAID intolerance, autologous serum skin test [ASST] result, thyroid autoimmunity, or histamine-releasing activity of serum) was associated with the response to LRA (Table 1). Leukotrienes might well play a central pathogenic role in some patients with CIU. Their injection into human skin produces a wheal and flare reaction (5), and, on a molar basis, they are 100 times more potent than histamine; moreover, serum from some patients with CIU, particularly those positive on ASST, induces both histamine release and de novo production of sulfidoleukotrienes in human basophils (6). Interestingly, in one study (3), one nonresponder to LRA showed a complete response to the lipoxygenase inhibitor, zileuton, suggesting a possible pathogenic role for LTB4, a substance that enhances cutaneous microvascular permeability by a not yet identified neutrophil-derived mediator (7). Because zileuton is not available in Italy, we could not confirm these observations. Good result in 50% of cases of therapy resistance.

Leukotriene receptor antagonists in the treatment of asthma.

The role of leukotriene receptor antagonists in the treatment of persistent asthma is in evolution. Pivotal 8-12-week, randomized, controlled trials in both adults and children have shown efficacy, as defined by standard asthma outcomes. Tolerance to therapy did not develop, nor did rebound worsening of asthma symptoms once therapy was withdrawn. In a comparator trial of montelukast versus beclomethasone, the average percentage change from baseline in forced expiratory volume in 1 second was greater with the inhaled corticosteroid preparation; however, improvements in other asthma outcomes were similar. There was considerable heterogeneity of pulmonary response with both treatments, with good and poor responders in both groups. In an open-label, crossover comparison of montelukast versus cromolyn, both parents and children preferred montelukast, thus regimen adherence was greater with montelukast. Additional long-term, randomized, controlled trials will define the effectiveness of leukotriene receptor antagonists compared with established controllers, thus determining the leukotriene receptor antagonists' place in asthma management.

Leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria

About 30% of patients with chronic urticaria experience flares of hives and/or angioedema after ingesting either aspirin or nonsteroidal anti-inflammatory drugs. In such patients, cross-reactivity to all NSAIDs seems to occur suggesting a mechanism dependent on cyclooxygenase inhibition. To evaluate the preventive effect of leukotriene receptor antagonists on urticaria exacerbations induced by NSAIDs in a patient with chronic urticaria. A 59-year-old woman with a 2-year history of recurrent urticaria exacerbated by different NSAIDs including aspirin 500 mg (2 episodes), piroxicam 20 mg, and nimesulide 100 mg (1 episode each) was studied. Acetaminophen 375 mg and floctafenine 50 mg induced a marked flare of urticaria/angioedema in a single-blind, placebo-controlled challenge. The patient was totally urticaria free during a 3-week course of montelukast 10 mg once a day. After montelukast withdrawal, a gradual relapse of urticaria/angioedema occurred along with a further acute urticaria/angioedema episode after a single piroxicam, 20-mg tablet. Zafirlukast 20 mg twice daily was started. After some days the patient was urticaria-free again, and after 3 weeks she tolerated a 6-day course of injective piroxicam (20 mg once a day) without any problem. To date the patient is still urticaria-free. Leukotriene receptor antagonists may prevent the severe urticaria/angioedema exacerbations which follow the use of NSAIDs in some patients with chronic urticaria.

Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma.

Over the last few years, the demonstration of beneficial effects of leukotriene receptor antagonists in various forms of asthma has renewed clinical and pharmacologic interest in this class of lipid mediators. Several studies demonstrated an increased biosynthesis of cysteinyl leukotrienes (CysLT) in asthmatic patients. However, the reasons for the dysregulated production of CysLTs in asthmatic patients are not completely defined. An improved method of lipid mediator detection and the availability of cells isolated from human airways (by bronchoalveolar lavage [BAL] and bronchial biopsies) have allowed initial studies to address this issue. Eosinophils retrieved from inflamed airways of asthmatics have a larger arachidonic acid (AA) content than their blood counterpart. The high level of AA in these cells is primarily due to a remodeling of endogenous arachidonate pools with the accumulation of this fatty acid in a triglyceride-associated pool. In addition, elevated levels of a secretory form of phospholipase A2, the key enzyme initiating the cascade of CysLTs, are found in the BAL of asthmatics. Finally, eosinophils isolated from the BAL of asthmatics have an increased expression of LTC4 synthase. The level of expression of this enzyme correlates with the increased amount of CysLTs produced in the airways of these patients. Taken together, these data identify at least two possible mechanisms to explain the excessive CysLT production in asthmatics: 1) an increased content of AA in the glycerolipid pools of inflammatory cells 2) an enhanced activity of key biosynthetic enzymes involved in CysLT synthesis.

Leukotrienes, leukotriene receptor antagonists, and rhinitis.

A series of clinical studies have shown the ef®cacy of leukotriene (LT) receptor antagonists (LTRAs) in the treatment of bronchial asthma (1±6). LTRAs relieve bronchospasm, prevent exercise-induced asthma, and reduce bronchial hyperresponsiveness. LTRAs also have some anti-in ammatory activity in that they reduce the number of eosinophils in bronchoalveolar lavage uid (7), and the content of NO in the exhaled air of asthmatic children (8). LTRAs have been recently introduced for the treatment of asthma, but their place in the management of the disease has not yet been de®ned. As asthma and rhinitis are manifestations of similar in ammatory reactions in the lower and the upper airways, it is natural to speculate whether LTRAs may be useful also in the management of rhinitis. A bene®cial effect can be taken as evidence for a role played by LTs in the upper airways. In this paper, we present an overview of the published literature on the role of LTs in rhinitis and the effect of LTRAs. Considering the large number of studies on asthma, the number of reports on rhinitis is astonishingly low and, for that reason, this review is short.

Beneficial effects of a leukotriene receptor antagonist on thrombin-induced pulmonary edema in the rat

The effect of a selective leukotriene receptor antagonist, the peptide ICI 198,615, on thrombin-induced pulmonary edema was studied in rats. Administration of thrombin produced a significant increase in lung weight ( p < 0.05), wet weight to dry weight ratio ( WW DW ; p < 0.05 ), and relative lung water content ( p < 0.05). These increases were all significantly reduced ( p < 0.05) by ICI 198,615 (bolus 15 mg/kg, infusion 15 mg/kg/h). Thrombin infusion caused a significant increase in myeloperoxidase activity in the lung tissue ( p < 0.05). This increase was further accentuated by ICI 198,615, indicating that the effect of this antagonist is not due to reduction of leukocyte infiltration in the lungs. The results thus show that a leukotriene receptor antagonist effectively counteracts the increase in lung vascular permeability to protein caused by thrombin, and indicate that leukotrienes are important mediators of thrombin-induced pulmonary edema in the rat.