内皮素受体拮抗剂在肺动脉高压治疗中的作用

肺动脉高压(PAH)是常见的临床疾病,内皮素(ET)在PAH的发生机制中发挥了重要的作用,临床研究显示,ET受体拮抗剂治疗PAH疗效良好,该类药物可能成为治疗PAH的有效药物.     

内皮素受体拮抗剂治疗肺动脉高压的临床应用进展

内皮素（ET）-1是强有力的内源性血管收缩剂，在肺动脉高压的发病机制中发挥重要作用。ET受体分为两种类型：ETA和ETB。本文综述近年来非选择性ET受体拮抗剂和选择性ETA受体拮抗剂治疗肺动脉高压的临床应用进展。证明ET受体拮抗剂可以改善肺动脉高压患者的运动耐量，降低肺血管阻力，增加心输出量，改善心功能。其主要副作用是血清转氨酶增高。     

内皮素受体拮抗剂用于肺动脉高压的治疗进展

肺动脉高压（PAH）是一类以肺血管阻力进行性升高为主要特征的心肺血管疾病,最终可导致右心衰竭甚至死亡。早期发现PAH患者中内皮素明显高于正常,可引起肺血管的持续收缩及重构。内皮素受体拮抗剂可阻断该通路进而起到降低肺高压的作用。但目前国内临床上对于该类药物了解甚少。本文参考国内外文献对内皮素受体拮抗剂在PAH中的作用机制及临床应用作简要综述,旨在指导临床用药,使更多患者获益。     

使用选择性内皮素A受体拮抗剂sitaxsentan治疗肺动脉高压

目的:测定选择性内皮素A(ETA)受体拮抗剂sitaxsentan治疗肺动脉高压(PAH)的最佳剂量,为了便于观察,试验还包括了一个公开标签(OL)的波生坦(bosentan)治疗组。背景:内皮素是PAH的介导者。在一项初步的PAH研究中,选择性ETA受体拮抗剂sitaxsentan改善了6分钟步行(6MW)距离,世界卫生组织(WHO)功能分级(FC)以及血流动力学情况。方法:在此项双盲、安慰剂对照、为期18周的试验中,有247例PAH患者(原发性的,与结缔组织病或者先天性心脏病相关的)被随机纳入研究;245例患者接受了治疗:安慰剂组(n=62),sitaxsentan治疗组50mg(n=62)或者100mg…     

内皮素受体拮抗剂治疗肺动脉高压症临床评价

目的：伴随对肺动脉高压症发病机制的解释，一类内皮素受体桔抗剂于近期问市，本文阐述其在治疗肺动脉高压症的进展与临床评价，方法：采用国内、外文献综述方法。结果及结论：内皮素受体拮抗剂近年来进展迅猛，其抑制ET-1的收缩血管和促进细胞增殖作用，使动脉高压和心力衰竭问题已不再难于逾越，成为解脱肺动脉高压症之门一把金“药匙”．     

内皮素系统在肺动脉高压中的作用

内皮素（ET）具有强力而持久的血管收缩作用，同时促进细胞的生长和促有丝分裂。ET-1与内皮素受体（ETR）结合发挥作用，ET-1过度表达引起多种心脑血管疾病。广泛的临床前和临床试验表明，ETR拮抗剂具有预防和治疗肺动脉高压（PAH）的作用，使患者的血流动力学改善，运动耐力和功能分级提高，提高了生存率。目前，非选择性ETR拮抗剂波生坦经FDA批准用于治疗休息或者轻微运动（WHO功能分级评为Ⅲ和Ⅳ级）PAH。     

内皮素受体拮抗剂治疗肺动脉高压的研究进展

近年来肺动脉高压的药物治疗多从调控内源性血管收缩因子（如内皮素-1、血栓素A2）和增殖介质（前列腺素和一氧化氮）的失衡入手。本文综述了基于内皮素-1途径的内皮素受体拮抗剂,如波生坦、安立生坦以及新近上市的macitentan,该类药物具有全身副作用小和口服优势,日益受到关注。     

白三烯受体拮抗剂对慢性肺心病肺动脉高压的治疗研究

目的探讨在慢性肺心病肺动脉高压发病中白三烯的作用,评价其受体拮抗剂对慢性肺心病肺动脉高压的治疗效果。方法以白三烯受体拮抗剂扎鲁司特对慢性肺心病并肺动脉高压的患者进行治疗,40例患者分为两组：对照组和扎鲁司特治疗组,观察两组治疗前后肺动脉压、右室肥厚和动脉血氧分压的变化及超声心动图检测肺动脉压及右心室内径、血气分析,测定PaO2等指标。结果扎鲁司特治疗组治疗后与治疗前比较PaO2升高、肺动脉压降低;扎鲁司特治疗组治疗后与对照组比较PaO2升高、肺动脉压降低更大。结论白三烯受体拮抗剂能扩张血管、降低肺动脉压,抑制支气管痉挛并使动脉血氧分压上升,对慢性肺心病具有一定的治疗作用。     

内皮素受体拮抗剂在肺动脉高压治疗中的应用

内皮素是强的缩血管因子,肺动脉高压患者内皮素表达明显增加,内皮素受体拮抗剂已经作为靶向药物治疗肺动脉高压,其疗效及前景备受瞩目。波生坦、安立生坦分别为口服的双重和选择性内皮素受体拮抗剂(ERAs),均能显著降低肺动脉高压,改善患者的生存,Macitentan是一种新型的口服非肽类双重ERAs,现已完成Ⅲ期临床研究,疗效可观;西他生坦是选择性的内皮素受体拮抗剂,因其肝脏毒性已经退市。对于这些双重或选择性内皮素受体拮抗剂的选择问题至今仍存在分歧,长期疗效、联合用药及肝脏安全性等问题都需要更多循证医学证实。     

新型内皮素受体拮抗剂马西替坦

内皮素受体拮抗剂与内皮素受体结合后,可以抑制由内皮素引起的血管收缩,同时还可减轻由内皮素活化造成的血管平滑肌的增殖和纤维化,从而达到治疗与内皮素相关疾病的目的.马西替坦是由瑞士Actelion公司研发的新型内皮素受体拮抗剂,具有组织靶向性,对ETA受体、ETB受体具有双重抑制作用,可用于治疗肺动脉高压、肺纤维化等疾病,在一系列临床研究中显示出良好的治疗前景,且安全性及耐受性均较好.     

CPU0507, an endothelin receptor antagonist, improves rat hypoxic pulmonary artery hypertension and constriction in vivo and in vitro

1. The Aim Of The Present Study Was To Test The Efficacy Of The Novel Endothelin (Et) Receptor Antagonist CPU0507 In Treating Rat Hypoxic Pulmonary Hypertension (Ph) In Vivo And In Vitro And To Explore The Role Of The Et-1 System In The Disease. 2. Male Sprague-dawley Rats (220 +/- 20 G) Were Divided Into Four Groups: (I) Control; (Ii) Untreated Hypoxic (28 Days Hypoxia); (Iii) Hypoxic Rats Treated In The Last 5 Days Of Hypoxia With Nifedipine(5 Mg/kg Per Day, P.o.); And (Iv) Hypoxic Rats Treated In The Last 5 Days Of Hypoxia With CPU0507 (20 Mg/kg Per Day, S.c.). Effects Of Treatments On Haemodynamics And Biochemical Data, As Well As Functional Assessments Of The Isolated Pulmonary Artery, Were Determined In Vivo And In Vitro. 3. It Was Found That CPU0507 Reduced The Elevated Pulmonary Arterial Pressure And Right Heart Weight Index And Restored Abnormalities In Nitric Oxide (No), Malondialdehyde And No Synthase (Nos) In The Serum And Superoxide Dismutase, Hydroxyproline And Nos In Pulmonary Homogenates. In Addition, CPU0507 Restored Altered Pulmonary Vasoconstrictor And Vasodilator Responses. Vascular Constriction And Dilatation Of Untreated Pulmonary Arteries Were Reverted Effectively Towards Normal Following Exposure Of Artery Rings To CPU0507 In Vitro. 4. In Conclusion, The Results Indicate That Hypoxic Ph Is Relieved Significantly By CPU0507 In Vivo And In Vitro And The Effects Are Presumed To Be Mediated By Suppression Of The Et-reactive Oxygen Species Axis.     

Ambrisentan,an endothelin receptor type A-selective endothelin receptor antagonist,for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ET_A-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.     

Sitaxsentan,a selective endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Sitaxsentan, a highly selective endothelin-A (ET_A) receptor antagonist (6500-fold more selective for ET_A receptors than endothelin-B (ET_B) receptors), may benefit patients with pulmonary artery hypertension (PAH) by blocking the vasoconstrictor effects of ET_A receptors while maintaining the vasodilator/clearance functions of ET_B receptors. In its first randomised, placebo-controlled study, Sitaxsentan to Relieve Impaired Exercise-1 (STRIDE-1), sitaxsentan improved exercise capacity assessed by 6 min walk, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association class II, III and IV patients with idiopathic PAH, PAH related to connective tissue disease or PAH related to congenital heart disease. In STRIDE-1, doses of 100 and 300 mg/day p.o. were evaluated. Although both doses showed equivalent efficacy, the lower dose had a more tolerable safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg/day doses, both in de novo patients and in patients previously treated with the ET_A/ET_B receptor antagonist bosentan. Long-term comparative studies are necessary to determine whether there is a clinically meaningful difference between selective ET_A receptor antagonism and ET_A/ET_B receptor antagonism.     

CPU0213, a non-selective ETA/ETB receptor antagonist, improves pulmonary arteriolar remodeling of monocrotaline-induced pulmonary hypertension in rats

1. The aim of the present study was to explore the effects of CPU0213, a dual endothelin ET(A)/ET(B) receptor antagonist, and nifedipine, a calcium antagonist, in relieving pulmonary hypertension (PH). Both endothelin receptor and calcium antagonists have been reported to be effective in alleviating the remodelling of pulmonary arteries induced by monocrotaline (MCT) in rats. 2. After an initial single dose of 60 mg/kg, s.c., MCT, CPU0213 was administered to rats at doses of 25, 50 or 100 mg/kg, p.o., for 28 days. In addition, nifedipine was administered to another group of rats at a dose of 10 mg/kg, p.o., for 28 days. The haemodynamics of the right ventricle, pulmonary vascular activity, remodelling of the pulmonary arterioles (< 150 microm) and biochemical changes were evaluated. 3. Right ventricular systolic pressure (RVSP), central venous pressure (CVP), the maximum rate of uprising pressure (dP/dT(max)) and the weight index of the right ventricle were significantly elevated in MCT-treated rats. In addition, increases in pulmonary endothelin-1, malonyldialdehyde (MDA) and hydroxyproline content and a reduction in superoxide dismutase activity was found after MCT treatment. The thickness and area of the pulmonary arterial wall were significantly increased in MCT-treated rats compared with control rats. At all three doses tested, CPU0213 ameliorated these changes in a dose-dependent manner and the effects were associated with a greater reduction in the remodelling of pulmonary arterioles. However, nifedipine was only partially effective in amelerioating biochemical and haemodynamic changes induced by MCT, significantly reducing RVSP, CVP, +dp/dt(max), tissue MDA, inducible nitric oxide synthase and hydroxyproline content, increasing -dp/dt(min) and having no effect on the other parameters investigated. In addition, nifedipine had no effect on remodelling of the arterial wall. 4. In conclusion, CPU0213 is more effective than nifedipine in suppressing the remodelling of pulmonary arterioles in PH induced by MCT treatment of rats. Furthermore, CPU0213 may have promise in treating PH secondary to connective tissue disease.     

内皮素-1受体拮抗剂的筛选和药理学研究

目的对军事医学科学院毒物药物研究所合成的系列内皮素受体拮抗剂进行筛选,并对有效化合物进行抗肺动脉高压的药理学研究。方法放射配体-受体结合实验测定受试化合物对ETA和ETB受体亚型的亲和力;在ET-1诱发离体大鼠主动脉环收缩、整体大鼠颈动脉压升高实验模型上进行生物活性筛选;在野百合碱诱发大鼠肺动脉高压实验模型上对受试化合物进行抗肺动脉高压的药效学研究。结果部分化合物与ETA受体的亲和力比与ETB受体的亲和力高万倍以上,并能有效地抑制ET-1诱发的离体大鼠主动脉环收缩,其中1μmol.L-1的受试化合物ETP-508可使ET-1累加浓度收缩效应曲线平行右移,且最大效应不变。此外,3.7μg.(0.5ml)-1.kg-1ET-1所致的大鼠体动脉压升高也可被2mg·kg-1ETP-508等化合物静脉注射所阻断;更进一步,ETP-508和BQ-485静脉给药(0.4mg.h-1)还可逆转80mg·kg-1野百合碱皮下一次注射诱发的大鼠肺动脉高压。结论以上结果提示,ETP-508和BQ-485是高选择性的ETA受体竞争性拮抗剂,能有效地抑制野百合碱诱发的大鼠肺动脉高压。     

Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence

In addition to its potent vasoconstricting effect, endothelin (ET)-1 induces proliferation of pulmonary vascular cells and appears to play a pathogenic role in the development of pulmonary arterial hypertension (PAH). Blockade of the ET receptors has been proposed for the treatment of this condition. Bosentan (Tracleer^®, Actelion Pharmaceuticals), an oral ET_A/ET_B receptor antagonist, has been shown to improve exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with PAH in short-term placebo-controlled trials. These improvements were sustained, and a long-term observational study on idiopathic PAH patients suggested a favourable effect on survival in this subset. In the present report, the pharmacology, clinical efficacy and safety profile of bosentan are summarised. The place of bosentan among the current therapies available for the treatment of PAH is also discussed.     

Endothelin receptor antagonists for the treatment of pulmonary arterial hypertension

Introduction: Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of endothelin are, therefore, of interest to improve the functional status of patients with PAH.

Areas covered: The rationale for the use of endothelin receptor antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested.

Expert opinion: The availability of the endothelin receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective endothelin-A receptor antagonism is more advantageous than dual receptor antagonism. Future studies of endothelin receptor antagonists will increasingly focus on the potential of a combination of different PAH therapeutic classes and will employ ‘harder’ clinical end points. This is of crucial importance to ensure that future developments are both worthwhile and acceptable to patients, physicians, health system payers and regulatory authorities.     

内皮素受体拮抗剂治疗心血管疾病研究进展

内皮素(ET)家族包括ET-1，ET-2和ET-3。ET-1通过与血管平滑肌细胞上的特异受体结合而产生血管收缩和细胞增殖效应，其异常表达参与了多种心血管疾病如慢性心衰、高血压、肾衰、肺动脉高压、脑血管痉挛等的病理机制。ET受体包括ETA和ETB2种亚型。动物实验和临床研究表明，非选择性ETA/B拮抗剂和选择性ETA拮抗剂对多种心血管疾病有较好的治疗作用。ET及其受体拮抗剂所具有的广泛的生物学效应和独特的作用机制，为临床治疗相关疾病提供了新途径。