白三烯受体拮抗剂治疗哮喘的进展和临床评价

目的:评价白三烯受体拮抗剂在治疗哮喘中的进展和临床应用.方法:检索国内外文献,对有关抗白三烯药物的文献进行分析、总结.结果:近年来,高选择性白三烯受体拮抗剂进展十分迅速,其通过抑制白三烯合成和白三烯受体而对抗哮喘.结论:该类药物为一类新型、安全和有效的抗炎和平喘药物,在防治成人和儿童的长期哮喘上展现了良好的治疗前景.     

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。     

白三烯受体拮抗剂在支气管哮喘患儿中的应用研究

目的研究探讨白三烯受体拮抗剂在小儿支气管哮喘患者中的应用及其疗效。方法本院哮喘专科门诊支气管哮喘轻、中度患儿40例,按随机法分为实验组和对照组,每组20例。实验组给予白三烯受体拮抗剂,对照组给予糖皮质激素。评价各组临床症状缓解时间、症状消失时间、有效率、不良反应等,并进行统计学分析。结果两组临床症状缓解时间、症状消失时间、有效率、不良反应等明显不同(P<0.05)。结论在支气管哮喘患儿治疗中,白三烯受体拮抗剂治疗效果显著,且无明显不良反应,值得推广应用。     

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。     

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.     

白三烯受体拮抗剂对哮喘模型肺组织VEGF表达水平的影响

目的　探讨白三烯受体拮抗剂对哮喘模型肺组织血管内皮生长因子 (VEGF)表达的影响及其对哮喘模型气道重塑的预防和治疗作用 ,提供哮喘防治新途径的可靠实验依据。方法　 10 8只健康雄性豚鼠随机分为 3组 :哮喘发作组、治疗组、对照组 ,每组 36只。以卵蛋白 (OVA)致敏和激发建立豚鼠哮喘模型。肺组织病理切片以SP法免疫组化标记VEGF ,图像分析VEGF表达水平。结果　OVA激发后 4周 ,哮喘发作组肺组织VEGF表达水平显著高于治疗组及对照组 (P <0 0 5 ) ,白三烯受体拮抗剂治疗哮喘使肺组织VEGF的表达水平降低。结论　白三烯受体拮抗剂可以降低哮喘豚鼠肺组织VEGF表达水平 ,从而减少血管增生 ,延缓哮喘气道重塑的发生。     

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     

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.     

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.     

白三烯受体拮抗剂对哮喘患儿血清ECP的影响

目的:观察白三烯受体拮抗剂在治疗哮喘患儿过程中抗炎作用的临床效果。方法:对60例哮喘患儿随机分为观察组和对照组各30例。观察组吸入布地奈德(普米克)气雾剂同时口服孟鲁司特,对照组只吸入布地奈德气雾剂。所有病例治疗前及治疗4周后测定血清嗜酸细胞阳离子蛋白浓度(ECP)水平。结果:治疗前两组患儿血清ECP水平较高,两组之间无差异(P<0.05)。治疗4周后,两组ECP水平均较治疗前降低,但观察组ECP水平下降明显,差异具有显著性意义(P<0.01)。结论:白三烯受体拮抗剂在治疗哮喘患儿中起抗炎作用。     

The signal transduction system of the leukotriene D4 receptor

During the past several years, substantial progress in understanding the receptors and signal transduction processes for peptidyl leukotrienes has been reported. Receptors have been identified and characterized, the major steps in the signal transduction pathway have been described, and the genetic and epigenetic regulatory processes have been characterized. Very recent studies have defined the mechanisms by which LTE4 acts as a partial agonist at the LTD4 receptor. The cloning of the genes for the proteins involved in the major steps of the signalling process has also been initiated. Stanley Crooke and co-authors summarize this recent progress and present their current notions about the LTD4 receptor signalling process.     

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.     

致敏大鼠大脑皮层和肺组织中白三烯B4含量一致性升高

目的:检测大鼠哮喘模型脑皮层和肺组织中白三烯(LT)的含量变化,以及抗哮喘药物对该变化的影响。方法:卵白蛋白致敏大鼠,观察支气管肺泡灌洗液(BALF)和肺组织及脑组织切片的炎症性变化,同时用反向高效液相(RP-HPLC)方法检测肺组织及大脑皮层匀浆LT的含量变化。结果:哮喘大鼠BALF内炎症细胞数量和组织学检查评分显著高于正常对照组(P<0.05),地塞米松(DXM,0.5mg/kg)和富马酸酮替芬(KF,5mg/kg)减轻这些炎症变化,RP-HPLC发现在哮喘大鼠肺组织及大脑皮层匀浆中LTB_4含量比正常大鼠显著升高(P<0.05),DXM和KF均可减低肺组织及大脑皮层匀浆液中的LTB_4水平,LTC_4在哮喘大鼠肺组织匀浆液中的含量较正常组显著升高(P<0.05),脑皮层内的含量无变化,DXM和KF均可降低哮喘大鼠肺组织匀浆液中LTC_4的水平(P<0.05)。结论:哮喘大鼠抗原攻击后脑皮层和肺组织中的LTB_4含量都一致性升高,DXM和KF可抑制这种变化。     

Anti-leukotrienes for asthma.

The field of cysteinyl leukotriene research has moved forward considerably in the past two years. Significant recent advances have been made in three areas: genetic control of the cysteinyl leukotriene response, in which alterations in both the promoter region and in transcribed mRNA have been described; the mechanisms by which cysteinyl leukotrienes promote the development of inflammation; and extensions in the clinical arena that support broader positioning of leukotriene modifiers in the therapy of asthma and allergic diseases.     

Cysteinyl leukotrienes and leukotriene B mediate vasoconstriction to arginine vasopressin in rat basilar artery

Arginine vasopressin (AVP) has been reported to be involved in the development of cerebral vasospasm after haemorrhage and cerebral oedema following ischaemia. Endogenously produced 5-lipoxygenase metabolites are able to contract isolated endothelium-preserved arterial strips and modulate vascular permeability. The present study addresses the role of 5-lipoxygenase and its products, namely cysteinyl leukotrienes (CysLTs) and leukotriene (LT) B4, in the contraction induced by AVP in rat basilar artery. Contractile responses to LTD4, LTC4, LTB4 or AVP were assessed in spiral preparations of rat endothelium-intact basilar artery. Contractions to AVP were determined in the absence or presence of 5-lipoxygenase inhibitors or CysLT1 or BLT receptor antagonists. Contractile responses to leukotrienes and AVP are expressed as a percentage of the contraction induced by 80 mmol/L KCl. Leukotriene D4, LTC4 and LTB4 acted as vasoconstrictor agents in rat basilar artery, causing contractions (all at concentrations of 1 micromol/L) of 42 +/- 13, 54 +/- 15 and 25 +/- 6% of the response to 80 mmol/L KCl, respectively. A concentration-response curve was constructed for AVP over the range 1 pmol/L to 10 nmol/L and an EC50 value of 0.19 +/- 0.02 nmol/L (n = 30) was determined. The presence of the 5-lipoxygenase inhibitors ZM 230487 (10 nmol/L and 0.1 and 1 micromol/L) and AA 861 (1, 3, 10, and 30 micromol/L), the CysLT1 receptor antagonist MK 571 (3, 10 and 30 micromol/L) or the BLT receptor antagonists CP 105696 and LY 255283 (3, 10 and 30 micromol/L for both) in the organ bath significantly attenuated the contractions induced by AVP in rat basilar artery (P < 0.05). The experimental results of the present study provide the first evidence for the involvement of CysLTs and LTB4 in the in vitro constriction induced by AVP in rat basilar artery. In the context of previously reported involvement of AVP in the development of cerebral vasospasm and oedema, the present study draws attention to the potential role played by the 5-lipoxygenase pathway in these pathological processes.     

Facile preparation of leukotrienes C(4), D(4) and E(4) containing carbon-13 and nitrogen-15 for quantification of cysteinyl leukotrienes by mass spectrometry

With the recent ability to use combined liquid chromatography/electrospray tandem mass spectrometry to analyze for several eicosanoids in biological samples in a single and rapid experiment, heavy isotope-labeled eicosanoids are needed as internal standards in order to quantify eicosanoid analytes. The present study describes a practical preparation of cysteinyl leukotrienes (leukotriene C(4), D(4) and E(4)) with three (13)C atoms and one (15)N atom in the cysteinyl residue. The method involves solid-phase peptide synthesis to make glutathione with heavy isotopes in the cysteinyl residue and reaction of this tripeptide with commercially available leukotriene A(4) methyl ester to give labeled leukotriene C(4) methyl ester, which is hydrolyzed to labeled leukotriene C(4). Labeled leukotriene E(4) is prepared in the same way with the use of labeled cysteine. Labeled leukotriene D(4) is prepared by treatment of labeled leukotriene C(4) with commercially available γ-glutamyl transpeptidase.