The expanding role of leukotriene receptor antagonists in chronic asthma

Article · January 2007with6 Reads
DOI: 10.1016/S1081-1206(10)60963-5 · Source: PubMed
To provide a comprehensive review of studies that evaluate the effects of leukotriene receptor antagonists in adult chronic asthma. A literature search using MEDLINE, Clinical Evidence, and the Cochrane Library was performed using the following keywords: randomized controlled trial, asthma, cysteinyl leukotriene, leukotriene receptor antagonist, antileukotriene, montelukast, zafirlukast, pranlukast, inflammation, lung function, exacerbations, and symptoms. Relevant peer-reviewed articles (mostly randomized controlled trials, meta-analyses, and reviews) published up to July 2006 were selected and extracted. Leukotriene receptor antagonists are beneficial across a range of asthma severities and may have a particular role in exercise-induced asthma, aspirin-sensitive asthma, and individuals with concomitant allergic rhinitis. In the management of chronic asthma, leukotriene receptor antagonists have emerged as a useful oral nonsteroidal anti-inflammatory adjunct both as monotherapy and in combination with other classes of drugs. Monitoring their effects in terms of lung function alone may result in clinicians missing beneficial effects on inflammatory biomarkers, airway hyperresponsiveness, and exacerbations.
    • Several in vitro experiments have suggested that CysLTs may induce airway smooth muscle proliferation [14,15], alter fibroblast function [16,17] and induce extracellular matrix [18,19]. Taking into account the important role of leukotrienes in airway inflammation, and especially in asthma, several anti-LTs modifiers have been evaluated in the management of this pathology [20][21][22]. Leukotriene modifiers include three different groups of drugs: (i) specific inhibitors of FLAP; (ii) inhibitors of ALOX5; and (iii) CysLT1 receptor inhibitors. However, the role of these compounds in upper airway remodeling remains unclear.
    [Show abstract] [Hide abstract] ABSTRACT: Background: Cysteinyl leukotrienes (CysLTs) play a crucial role in the pathogenesis of airway remodeling. The use of CysLTs receptor antagonists has been included in the management of asthma and rhinitis. However, despite the action of these compounds on leukotriene production has been well documented, their role in airway remodeling remains unclear. Objective: We aimed to investigate the capability of the leukotriene receptor antagonist Montelukast to inhibit MMPs release after CysLTs stimulation in nasal tissue fibroblasts. Methods: Fibroblasts were isolated from sinunasal tissue collected from five patients suffering of chronic rhinosinusitis without nasal polyposis. Cells were cultured and stimulated first with LTC 4 and LTD 4 (10´1010´10 , 10´810´8 , 10´610´6 M) using as pre-stimulus 10 ng/mL of: IL-4, IL-13, or TGF-beta1 and in presence or absence of Montelukast (10´1010´10 , 10´810´8 , 10´610´6 M). To evaluate the regulation of MMP-1 and TIMP-1 we used enzyme immunoassays and to evaluate CysLT1 receptor we used real time PCR. Results: LTD 4 but not LTC 4 induced production of mRNA for CysLT1 receptor in a dose dependent manner and with an additive effect when the cells where primed with TGF-β 1. TNF-α, IL-4, and IL-13 did not influence the expression of the receptor. Levels of MMP-1 but not of TIMP-1 were statistically enhanced in cells primed with TGF-β 1 and stimulated with LTD 4. Montelukast significantly decreased Cys-LT 1 receptor and MMP-1 concentrations in a dose-dependent way in cells stimulated with LTD 4 and TGF-β 1 separately and when they were applied together. Conclusion: The leukotriene pathway may play an important role in extra-cellular matrix formation in an inflamed environment, such as chronic sinusitis and, consequently, leukotriene receptor antagonists such as Montelukast may be of great benefit in management of this disease.
    Full-text · Article · May 2016
    • Excessive activation of different bronchoconstrictor GPCRs, such as muscarinic, serotonin, endothelin B, leukotriene, and proton-sensing OGR1 receptors in ASM, contributes to AHR of asthma (Deshpande and Penn, 2006;Saxena et al., 2011). Drugs targeting specific GPCRs are used as therapies for AHR in asthma (Shore and Moore, 2003;Currie and McLaughlin, 2006;Hanania et al., 2010;Moulton and Fryer, 2011), yet asthma still affects 23 million Americans, causing significant morbidity. The strategy of inhibiting a single GPCR is limited because airway constriction can be induced by different GPCRs simultaneously, thereby having bronchoconstrictor signal redundancy.
    [Show abstract] [Hide abstract] ABSTRACT: We recently reported that phosphoinositide 3-kinase γ (PI3Kγ) directly regulates airway smooth muscle (ASM) contraction by modulating Ca(2+) oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 μg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kγ-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca(2+) transient and increased Ca(2+) oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kγ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kγ by 70% only reduced the initial Ca(2+) transient by 20 to 30% but markedly attenuated Ca(2+) oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kγ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kγ inhibitor can ameliorate AHR in a murine model of asthma.
    Article · Apr 2012
    • Several in vitro trials have documented zileuton, a hydroxyurea derivative, may have potential beneficial effects in sickle cell disease pathology including effects on nitric oxide, sickle red blood cell retention and adhesion in the pulmonary circulation, and decreased interleukin-13 secretion[108][109][110][111][112]. Montelukast, however, would be the preferred leukotriene modifier in patients with sickle cell disease and asthma 8 Anemia because it has well-established effects on the improvements of asthma symptoms and it can be given once daily[107,113,114]. The safety profile of montelukast is similar to placebo and its safety record extends over 10 years of use in millions of patients.
    [Show abstract] [Hide abstract] ABSTRACT: Objective. To review issues related to asthma in sickle cell disease and management strategies. Data Source. A systematic review of pertinent original research publications, reviews, and editorials was undertaken using MEDLlNE, the Cochrane Library databases, and CINAHL from 1947 to November 2010. Search terms were [asthma] and [sickle cell disease]. Additional publications considered relevant to the sickle cell disease population of patients were identified; search terms included [sickle cell disease] combined with [acetaminophen], [pain medications], [vitamin D], [beta agonists], [exhaled nitric oxide], and [corticosteroids]. Results. The reported prevalence of asthma in children with sickle cell disease varies from 2% to approximately 50%. Having asthma increases the risk for developing acute chest syndrome , death, or painful episodes compared to having sickle cell disease without asthma. Asthma and sickle cell may be linked by impaired nitric oxide regulation, excessive production of leukotrienes, insufficient levels of Vitamin D, and exposure to acetaminophen in early life. Treatment of sickle cell patients includes using commonly prescribed asthma medications; specific considerations are suggested to ensure safety in the sickle cell population. Conclusion. Prospective controlled trials of drug treatment for asthma in patients who have both sickle cell disease and asthma are urgently needed.
    Full-text · Article · Mar 2011
    • It is used as the sodium salt, but doses are expressed in terms of the base; montelukast sodium 10.38 mg is equivalent to about 10 mg of montelukast. In the management of chronic asthma (Currie and McLaughlin 2006) and as prophylaxis for exercise-induced asthma, montelukast sodium is given in doses equivalent to 10 mg of montelukast once daily in the evening. It should not be used to treat an acute asthma attack.
    [Show abstract] [Hide abstract] ABSTRACT: Simple, sensitive and accurate stability indicating analytical method for montelukast has been developed and validated by using RP-HPLC techniques and applying the proposed method in the assay of Montelukast ® tablets (SIGMA Pharmaceuticals), since there is no official monograph. The procedure was developed and validated under acidic, basic, oxidative and photo-irradiation conditions. Chromatography was performed with mobile phase containing a mixture of acetonitrile and 0.01M potassium dihydrogen phosphate buffer pH 4.0 (7:3 v/v) with flow rate of 1.0 mL per min, C 18 column and UV detection at 355 nm. developed method satisfies the system suitability criteria, peak integrity, and resolution for the parent drug and its degradants. The method was validated for linearity (correlation coefficient = 0.9999), accuracy, and precision. Experimental design was used for validation of robustness and intermediate precision. The proposed method was simple, highly sensitive, precise and accurate. And the run time was less than 15 min which indicates the method is useful for routine quality control analysis and stability testing. Montelukast was determined to be more sensitive to the acidic conditions and photodegradation on light exposure, oxidation may also appear. But it was stable in alkaline medium.
    Full-text · Article · Apr 2010
    • The aspirin-induced airway inflammatory response is characterized by profound eosinophilia releasing large amounts of cysteinyl leukotrienes: bronchoactive mediators that can be quantified by urinary leukotriene E 4 [43, 69] . Despite a timeconsuming procedure requiring close monitoring for potential anaphylaxis, aspirin challenge is a useful tool for intervention studies with drugs targeting the aspirininduced airway responses, e.g., anti-leukotriene therapy [70].
    [Show abstract] [Hide abstract] ABSTRACT: The respiratory function of the lung can easily be measured in a variety of circumstances, and thus distinguishing obstructive from restrictive lung diseases, quantifying the severity of functional impairment, and treatment response. In this regard, peak-flow, spirometry, but also body plethysmography are the most important techniques. Inhalation challenge tests are performed to measure the response of the airways to substances that may be causing asthma or wheezing. Non-invasive airway sampling may further enhance our understanding of the underlying inflammatory processes in the airways causing pathological changes in lung function, whereas measurements of exhaled nitrogen and biomarkesr in exhaled breath condensate are from particular interest. All of these will be facets of this chapter.
    Chapter · Jan 2009 · Acta Pharmaceutica Sciencia
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