白三烯受体拮抗剂的作用与临床应用评价

目的 :介绍白三烯受体拮抗剂的作用进展和临床应用的评价。方法 :采用国内、外文献综述方法。结果和结论 :近年来 ,高选择性白三烯受体拮抗剂进展十分迅速 ,通过抑制白三烯合成和白三烯受体而对抗哮喘 ,对白三烯受体的选择性高 ,有良好的耐受性和药代动力学性质 ,成为一类新型、安全和有效的抗炎和平喘药物 ,在防治成人和 12岁以上儿童的长期哮喘上展现了良好的治疗前景     

白三烯受体拮抗剂在儿童支气管哮喘治疗中的地位

支气管哮喘(简称哮喘)是由多种细胞和细胞组份参与的慢性气道炎症性疾患,白三烯(Leukotrienes,LTs)是哮喘发病机制中重要的炎性介质.白三烯受体拮抗剂是近年来出现的一种新的治疗哮喘的药物.越来越多的临床证据显示白三烯受体拮抗剂对哮喘治疗具有肯定的效果.白三烯受体拮抗剂在临床上尤其是在儿科临床的应用得到了广泛的重视.     

白三烯受体拮抗剂合理应用评价

目的：评价白三烯受体拮抗剂的临床应用概况。方法：收集国内外相关文献，从白三烯受体拮抗剂的作用机制、应用状况、不良反应等方面对常用的白三烯受体拮抗剂进行分析评价。结果及结论：白三烯受体拮抗剂成为哮喘临床治疗中最有效的介质拮抗剂，目前已普遍应用于临床。     

孟鲁司特治疗变应性鼻炎伴哮喘的疗效观察

目的:评价白三烯受体拮抗剂治疗变应性鼻炎伴哮喘患者的疗效及安全性.方法:选择120例变应性鼻炎伴哮喘患者,随机平均分成两组,每组60例.一组应用白三烯受体拮抗剂治疗(实验组),一组应用局部激素治疗(对照组).比较治疗前后的症状积分、肺功能及嗜酸性粒细胞阳离子蛋白(ECP)水平.结果:实验组与对照组患者治疗后均能明显减轻患者的鼻炎及哮喘症状,改善患者肺功能,并使血清ECP水平下降.实验组未出现一例不良反应,对照组有3例出现鼻腔干燥感、有1例出现鼻出血,有1例出现声嘶.结论:白三烯受体拮抗剂是治疗变应性鼻炎伴哮喘的有效、安全的药物.     

白三烯拮抗剂在治疗支气管哮喘中的作用

白三烯,特别是半胱氨酸白三烯在支气管哮喘的发病中起着关键作用,目前有关支气管哮喘治疗的最新进展主要集中在白三烯拮抗剂。现已批准应用于临床的白三烯拮抗剂主要有白三烯受体拮抗剂和５－脂氧酶抑制剂。本文综述了这两类药物的体内外效应,药物动力学,以及近年来白三烯拮抗剂在各类型哮喘中的应用经验。推荐白三烯拮抗剂作为一种控制剂,可应用于轻中度持续性哮喘病人。     

白三烯调节剂在哮喘治疗中的应用

白三烯包括半胱氨酰白三烯（cysteinyl leukotrienes, CysLT）和白三烯B4（leukotriene B4, LTB4）等,是哮喘的主要炎症介质,参与哮喘发病的多种病理生理机制。白三烯调节剂已用于哮喘治疗,其中CysLT受体-1（CysLT receptor-1, CysLT1）拮抗剂可口服、单药治疗轻度持续性哮喘,但疗效通常不如吸入糖皮质激素。重症哮喘患者联合使用CysLT1拮抗剂和吸入糖皮质激素既能有效控制哮喘,又能减少吸入糖皮质激素的剂量。确定对CysLT1拮抗剂治疗反应良好的哮喘患者亚群有助于更好地发挥CysLT1拮抗剂的作用。CysLT1拮抗剂还有抗重塑作用,可防止哮喘患者的气道结构改变。本文主要就白三烯调节剂在哮喘治疗中的应用作一综述。     

白三烯受体拮抗剂在哮喘治疗中的作用

支气管哮喘(哮喘)是气道的慢性炎症性疾病,许多炎症细胞及其释放细胞因子及炎症介质参与此过程[1].其中花生四烯酸的代谢产物,尤其是白三烯(LTs)的作用日益受到重视.近年来研究提示LTs是哮喘发病过程中最重要的炎症介质之一.自第一个白三烯D4(LTD4)受体拮抗剂异丁司特于1989年在临床应用以来,白三烯受体拮抗剂LTRA的开发研究十分活跃.1996年新一代LTKA zafirukast(商品名安可来)作为抗哮喘、抗炎、抗过敏药物在国外上市.有关此类具有拮抗LTs作用的药物,成为当前治疗的新发展或可能是一种新趋势[2].     

基本药物治疗慢性阻塞性肺疾病的应用评价

目的:评价基本药物在慢性阻塞性肺疾病药物治疗中的效果和合理应用原则。方法:采用国内、外文献综述方法进行评价。结果与讨论:高选择性白三烯受体阻断药、黏痰调节剂、吸入型糖皮质激素等研究和临床应用进展迅速,通过抑制白三烯合成,拮抗白三烯受体和抗炎而对抗哮喘,在防治成人和12岁以上儿童的慢性阻塞性肺疾病和长期哮喘上展现了良好的治疗前景。     

白三烯抑制剂在哮喘治疗中的进展

目的:介绍白三烯抑制剂治疗哮喘的进展。方法:综述近年来国外有关文献,介绍和评价白三烯抑制剂的临床疗效,不良反应和用法用量。结果:白三烯抑制剂有效地治疗哮喘发作,且副作用较少。结论:白三烯抑制剂临床使用安全有效,是一类新的哮喘治疗药物。     

白三烯受体拮抗剂治疗哮喘后血清白细胞介素-5及支气管肺泡灌洗液嗜酸性粒细胞凋亡的变化

目的　探讨白三烯受体拮抗剂对嗜酸性粒细胞 (EOS)凋亡的诱导作用及其机制。方法　支气管哮喘患者 5 0例 (哮喘组 ,其中 30例急性发作期 ,2 0例非急性发作期 )采用酶联免疫吸附试验 (EL ISA)法测定经白三烯受体拮抗剂治疗前后血清白细胞介素 (IL) - 5水平。分离 5 0例支气管哮喘患者支气管肺泡灌洗液 EOS,测定经白三烯受体拮抗剂治疗前后 EOS的凋亡率。结果　白三烯受体拮抗剂对 IL - 5介导的 EOS存活有抑制作用。哮喘组在白三烯受体拮抗剂治疗后的血清 IL - 5水平比治疗前显著降低 (P<0 .0 1)。治疗后的 EOS凋亡率与治疗前比较差异有显著性 (P<0 .0 1)。结论　白三烯受体拮抗剂能有效诱导 EOS凋亡 ,凋亡 EOS通过拮抗 IL - 5机制获得     

Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: an update. Part II: clinical studies with leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma.

The demonstration that leukotrienes, mainly cysteinyl leukotrienes, have biological properties relevant to the pathogenesis of asthma has stimulated the development of many therapeutic compounds to block these deleterious effects. Two main classes of leukotriene modulators have been developed: CysLT1 receptor antagonists and leukotriene synthesis inhibitors. This article reviews the pharmacodynamics, the effects on baseline airway function, the protective effects in airway challenges as well as the results in chronic asthma of the different leukotriene modulators. In addition, the complementary anti-inflammatory effect of leukotriene modulators to that of corticosteroids and H1-histamine receptor antagonists is reviewed. Finally, a concise overview of the clinical responsiveness to this new class of drug, the safety and the drug interactions as well as the place in the strategies of treatment for asthmatic patients of the leukotriene modulators is also provided.     

Leukotrienes, antileukotrienes and asthma

Leukotrienes (LTs), including LTB(4) and cysteinyl-LTs (CysLTs) (LTC(4), LTD(4), and LTE(4)), are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs, which stimulate CysLT(1) and CysLT(2) receptor subtypes, are functionally involved in the pathophysiology of asthma. Selective CysLT(1) receptor antagonists are effective anti-asthmatic drugs. CysLT(1) receptor antagonists have been developed from leukotriene structural analogs, analogs of FPL 55712, a chromone carboxylic acid, and by random screening of corporate compound banks. This review will examine the biosynthesis, metabolism and mechanism of action of leukotrienes, their role in asthma, the therapeutic implications of the leukotriene pathway inhibition for asthma, and the medicinal chemistry strategies that have been exploited in the design of potent and selective CysLT(1) receptor antagonists.     

Leukotriene modifiers: novel therapeutic opportunities in asthma

Cysteinyl leukotrienes (Cys-LT) are powerful proinflammatory autacoids that cause long-lasting bronchoconstriction, plasma leakage, increased mucus production; their biological activity suggests a prominent role in the etiopathology of asthma and several Cys-LT receptor antagonists and synthetase inhibitors have been developed as new antiasthmatic drugs. Zafirlukast was discovered by a mechanism-based approach to drug discovery; early structure-activity relationship analyses of the prototype SRS-A antagonist FPL-55712, lead to the identification of an indole-containing lead compound that was more specific than FPL-55712. Modifications were made on the lipid-like tail, indole backbone and acidic head region of this lead compound, resulting in potent and selective leukotriene receptor antagonists such as ICI-198615 and 204219 (zafirlukast). On the basis of successful results in preclinical asthma models, zafirlukast was recommended for clinical development and became the first leukotriene-modifier to be approved for the treatment of asthma. Leukotriene biosynthesis inhibitors (LSI) also represent a promising approach to the treatment of asthma and may theoretically provide a broader protection than Cys-LT receptor antagonists by inhibition of the synthesis of the two major leukotrienes, the Cys-LT and the chemotactic LTB4. The LSI BAY X-1005 is the result of a broad chemistry program that identified 15-HETE as an endogenous inhibitor of leukotriene synthesis and REV 5901 as a lead prototypic quinoline-based 5-lipoxygenase (5-LO) inhibitor. Clinical studies demonstrated the effectiveness of BAY X-1005 in experimental conditions such as allergen provocation and cold-air induced asthma. However, no consistent treatment effect in the overall asthma population (mild to moderately severe asthmatics) lead to discontinuation of its development.     

Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulair?, Merck) and zafirlukast (Accolate?, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflo?, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.     

A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma

BACKGROUND: Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism. METHODS: The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network). RESULTS: A significant association of the coding polymorphism, 601A>G, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601A>G were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601A>G compared to wild-type CYSLTR2. CONCLUSIONS: Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.     

Role of inflammatory mediators in asthma.

Release of inflammatory mediators such as histamine and products of arachidonic acid metabolism has been demonstrated in bronchoalveolar lavage fluid of patients with asthma. Their precise cellular source is not clear but many cells types such as eosinophils, macrophages and mast cells may contribute to the generation of a wide variety of chemical mediators. These can mimic many of the features associated with asthma including bronchoconstriction, bronchial hyperresponsiveness and airway microvascular leakage. Development of specific mediator receptor antagonists or inhibitors of mediator synthesis may clarify the role of particular inflammatory mediators such as the sulphidopeptide leukotrienes or platelet-activating factor in asthma. It seems unlikely that only one particular mediator is responsible for all the manifestations of asthma.     

Cysteinyl leukotriene receptors

Cysteinyl leukotrienes (CysLTs) are important inflammatory mediators in asthma and allergic disorders. Two types of CysLT receptors, CysLT(1) and CysLT(2), which were originally defined pharmacologically based on their sensitivity to CysLT(1) specific antagonists, are responsible for most of the known CysLT biological actions. The regulation of CysLT receptor expression and signaling in disease processes is largely unclear. Recent molecular cloning of both receptor subtypes from several different species will greatly facilitate future research in understanding CysLT signal transduction mechanisms. Expression of the relatively better-studied CysLT(1) is verified in lung tissues and peripheral blood cells. Elucidating how this receptor mediates airway inflammation will deepen our understanding of asthma etiology. On the other hand, detection of CysLT(2) in the heart, brain, and adrenal glands will inject new excitement into the search for novel CysLT functions. This review summarizes receptor cloning, ligand binding, expression, signaling, and functions in an effort to bridge early pharmacological studies to future studies at the molecular level.     

Antileukotriene drugs: clinical application, effectiveness and safety

Cysteinyl leukotrienes (Cys-LTs) are potent proinflammatory mediators derived from arachidonic acid through the 5-lypoxigenase (5-LO) pathway. They exert important pharmacological effects by interaction with at least two different receptors: Cys-LT(1) and Cys-LT(2). By competitive binding to the Cys-LT(1) receptor, leukotriene receptor antagonist drugs such as montelukast, zafirlukast, and pranlukast, block the effects of Cys-LTs and alleviate the symptoms of many chronic diseases, especially bronchial asthma and allergic rhinitis. Evidence obtained by randomized clinical trials as also by direct experience derived from patients suffering from asthma and allergic rhinitis justifies a broader role for leukotrienes receptor antagonists (LTRAs). Recently published studies and case reports have demonstrated beneficial effects of LTRAs on other diseases commonly associated with asthma (exercise induced asthma, rhinitis, chronic obstructive pulmonary disease, interstitial lung disease, chronic urticaria, atopic dermatitis, allergic fungal disease, nasal polyposis, and paranasal sinus disease) as well as other diseases not connected to asthma (migraine, respiratory syncytial virus postbronchiolitis, systemic mastocytosis, cystic fibrosis, pancreatitis, vulvovaginal candidiasis, cancer, atherosclerosis, eosinophils cystitis, otitis media, capsular contracture, and eosinophilic gastrointestinal disorders). The aim of this review is to show the most recent applications and effectiveness in clinical practice of the LTRAs.