治疗遗传性血管性水肿新药艾替班特概述

艾替班特和缓激肽结构类似,与其竞争性地结合缓激肽B2受体,具有良好的药动学特性,对急性发作期遗传性血管性水肿（HAE）的患者疗效佳.同时在发病的第一时间内,患者可以安全地自我治疗.目前的文献报道提示,艾替班特治疗获得性血管性水肿（AAE）的效果与治疗HAE一样安全、有效,或许将来艾替班特也可用于AAE的治疗.     

艾替班特在HAE研究中取得进展

德国Jerini AG公司宣布已完成艾替班特（Icatibant）（Ⅰ）Ⅲ期试验的患者随机选录工作。（Ⅰ）为缓激肽B2受体拮抗剂，可能对治疗遗传性血管性水肿（HAE）有效。该项研究被命名为FAST-2（血管性水肿皮下注射治疗），共在欧洲31个研究中心选录了74位研究对象，将（Ⅰ）与氨甲环酸（tranexamic acid）进行比较。     

新药研究与开发

FDA批准艾替班特用于治疗遗传性血管性水肿急性发作Shire药业宣布FDA已批准其艾替班特（icatibant,Firazyr）注射液上市,用于治疗18岁以上成人遗传性血管性水肿（HAE）急性发作。艾替班特治疗HAE急性发作的疗效和安全性已在双盲、随机、对照的FAST1、2和3的3次临床试验中评估。总共人选223名患者．平均年龄38岁,64％为女性,95％为白种人。     

艾替班特对多柔比星致大鼠急性肾损伤的保护作用及机制分析

摘要：目的:探讨缓激肽B2受体拮抗药艾替班特对多柔比星（Dox）致大鼠急性肾损伤的作用及机制分析。方法:30只大鼠随机分为对照组、Dox组和艾替班特组。除对照组外,各组均给予Dox 20 mg·kg?-1?ip,艾替班特组再给予艾替班特180μg·kg-1?ip,连续3 d。后称取质量,取血测定SCr、BUN、白蛋白（Alb）和TG,取肾组织用于组织病理学检查,Western Blot技术检测肾脏组织FABP4表达。结果:Dox组大鼠体质量较对照组明显降低（P<0.05）,艾替班特组和Dox组比较无明显变化（P>0.05）。与对照组相比,Dox组Alb明显降低,BUN、SCr和TG明显升高（P<0.01或P<0.05）;与Dox组比较,艾替班特组Alb明显升高,BUN和SCr明显降低（P<0.05）。Dox组肾间质炎细胞浸润、充血,肾小管肿胀;艾替班特组较Dox组有所缓解。免疫组化结果显示FABP4主要表达于大鼠肾小管上皮细胞胞质,与对照组相比,Dox组FABP4蛋白表达明显增加（P<0.01）;与Dox组相比,艾替班特组FABP4蛋白表达降低（P<0.05）。结论:艾替班特可减轻Dox所致大鼠急性肾脏损伤,其机制与脂代谢紊乱有关。     

艾替班特

艾替班特（icatibant）是由德国 Jerini 公司 (美国为Shire plc公司) 研发的一种对缓激肽B2 受体选择性的竞争性拮抗剂。2011 年 8 月艾替班特获美国 FDA 批准上市,商品名为 Firazyr。该药为注射剂,用于18 岁及以上人群治疗遗传性血管水肿(HAE)的急性发作。艾替班特的英文化学名称：D-arginyl-L-arginyl-L-prolyl-L-[(4R)-4-hydroxyprolyl]-glycyl- L-[3-(2-thienyl)alanyl]-L-seryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L-[(3aS,7aS)-octahydroindol-2-ylcarbonyl]-L-arginine;分子式：C₅₉H₈₉N₁₉O₁₃S;分子量：1304.52;CAS登记号：130308-48-4。     

FDA批准新药Firazyr(艾替班特注射剂)

<正>2011年8月25日,Shire医药公司宣布,美国FDA批准新药Firazyr(艾替班特注射剂)上市,用于治疗18岁以上患者遗传性血管水肿的急性发作(HAE)。     

美国FDA批准IcatibantAcetate用于治疗遗传性血管神经性水肿

2011年8月25日,美国食品药品监督管理局（FDA）批准英国沙尔（Shire）制药公司的新药醋酸艾替班特（通用名：IcatibantAcetate,商品名：FIRAZYR）注射剂上市,用于治疗18岁及以上成人遗传性血管神经性水肿（HAE）的急性发作。     

选择性缓激肽B2受体拮抗剂——Icatibant

Icafibant（JE-049）为一新型选择性强效肽类缓激肽B2受体拮抗剂，是合成的十肽化合物，对缓激肽受体具有基本上与缓激肽一样的亲和力，其体内给药后具有良好的稳定性。Jerini公司于2001年从Aventis Pharma（Sanofi—Aventis）公司获得icatibant的全球开发权。目前，本品用于治疗严重烧伤病人水肿的研究已进入Ⅰ期临床试验，用于治疗肝硬化顽固性腹水（RAIL）的研究已进入Ⅱ期临床试验，而用于口服治疗遗传性血管水肿（HAE）的研究已进入Ⅲ期临床试验。     

缓激肽对ACE—抑制剂抗心脏缺血影响的作用

缓激肽是九肽链蛋白质。缓激肽至少可被激肽酶Ⅰ和激肽酶Ⅱ所分解,主要的分解酶是激肽酶Ⅱ,激肽酶Ⅱ也叫血管紧张素转变酶。激肽酶Ⅱ脱掉末端羟基氨基酸组成脱精~9缓激肽。许多与B受体兴奋相关的生物进程受激肽的影响,B受体根据与拮抗剂的相关性分为B_1受体和B_2受体。B_1受体对代谢产物脱精~9缓激肽非常敏感,而B_2受体则对大多数缓激肽敏感。缓激肽是药效很强的舒张血管药。对疼痛、炎性痛觉过敏、鼻炎和内毒素性休克也有作用。既往对缓激肽的心肌作用未给予足够注意。1970年,wikens等报告,心脏组织局部缺血引起的pH值微小降低,可激活局部的激肽系统。1977年,Hashimoto等发现狗的冠脉阻塞之后,冠状     

缓激肽对转化生长因子-β1诱导的肺动脉平滑肌细胞迁移的影响简

摘要 目的 观察缓激肽对转化生长因子-β1（TG-β1）诱导的肺动脉平滑肌细胞（PASMCs）迁移的影响及其可能机制。方法原代培养PASMCs，应用Transwell小室检测缓激肽对PASMCs跨膜迁移能力的影响，同时应用划痕修复实验检测缓激肽对PASMCs横向迁移能力的影响。结果TGF β1显著增加了跨膜迁移的PASMCs数目（P＜0.05），缓激肽显著减少了PASMCs的跨膜迁移（P＜0.05），而B2受体抑制剂（HOE 140）对缓激肽抑制TGF β1诱导的PASMCs的跨膜迁移作用无显著改变（P＞0.05）。缓激肽显著降低PASMCs的划痕愈合指数（P＜0.05），而HOE 140对缓激肽抑制TGF β1诱导的PASMCs的横向迁移能力无显著改变（P＞0.05）。 结论缓激肽可以抑制TGF β1诱导的PASMCs跨膜和横向迁移能力，而这一效应可能不通过缓激肽B2受体介导。     

Switch to icatibant in a patient affected by hereditary angioedema with high disease activity: a case report

Icatibant, an antagonist of the bradykinin B2 receptor, was approved for the treatment of acute attacks of hereditary angioedema in the EU in 2008. This paper presents the case of a 65-year-old woman affected by frequent acute attacks of hereditary angioedema who benefitted from a change of therapy to icatibant, following years of treatment with C1-inhibitor.     

Icatibant. Attacks of hereditary angioedema: continue to use C1 esterase inhibitor

Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema.     

Icatibant: HOE 140, JE 049, JE049

Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin beta2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now Sanofi-Aventis). Jerini is seeking a partner for development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis, angioedema and burns. In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis.Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. Positive results from an icatibant formulation comparative study, in patients with acute attacks of hereditary angioedema, were announced in August 2004; IV and SC formulations showed no difference in efficacy and safety. It was announced in September 2004 by Jerini that a pivotal study, known as For Angioedema Subcutaneous Treatment (FAST) 1, had been initiated in the US and Canada. The protocol of a European study, to be known as FAST 2, is to be submitted to the authorities in September 2004. Jerini expects to launch the product in 2006. The US FDA granted icatibant, for the treatment of hereditary angioedema, fast-track designation in July 2004. In January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema. In November 2003, Jerini announced that effective December 2003, icatibant had orphan drug status in the US for the same indication.     

Therapeutic potential of icatibant (HOE-140, JE-049)

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.     

Icatibant: HOE 140, JE 049, JE049

Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin B2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now sanofi-aventis). Jerini AG is seeking a worldwide partner for the development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis and seeking a partner in Asia, North America, South America and Australia for angioedema. In August 2004, Aventis merged with Sanofi-Synthelabo to form sanofi-aventis. Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. It was announced in September 2004 by Jerini that a pivotal registration study, known as FAST 1 (For Angioedema Subcutaneous Treatment), had been initiated in the US and Canada. The protocol of a European study, known as FAST 2, was submitted to the authorities in September 2004. Jerini is currently conducting pivotal/registration trials for angioedema in the US, Canada and Europe. During the 3rd Annual BioPartnering North America Conference (BPN-2005), Jerini announced that it expects to complete registration trials in the second half of 2005/first half of 2006, with a launch of icatibant for HAE in 2007. The US FDA granted fast-track status to icatibant in July 2004 for the treatment of HAE. Effective December 2003, icatibant gained orphan drug status in the US for the same indication. Previously, in January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema.     

Therapeutic potential of icatibant (HOE-140, JE-049)

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.     

Icatibant as acute treatment for hereditary angioedema in adults

Introduction: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by recurrent, unpredictable episodes of cutaneous and/or mucosal edema. Bradykinin, released by the activation of the contact system, binds to bradykinin B2 receptors on the endothelial cell surface to enhance vascular permeaility, which leads to angioedema.

Areas covered: C1-INH-HAE therapy is aimed at the inhibition of bradykinin release, as well as at the blockage of its effects mediated by its receptor. Three controlled trials, three open-label extensions, and two open-label studies, and a prospective, observational study have confirmed the safety and efficacy of the bradykinin B2 receptor antagonist, icatibant administered as acute treatment for HAE attacks in adult patients with C1-INH-HAE.

Expert commentary: The ready-to-use, pre-filled syringes of icatibant can be self-administered easily, effectively, safely and, importantly, conviently. – This has resulted in patients being able to quickly treat an attack and realize a dramatic change for the better in their lives.     

Icatibant,the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

Introduction: HOE-140/Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency.

Areas covered: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin–receptor interactions.

Expert opinion: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.     

New promise and hope for treating hereditary angioedema

Background: While there is no approved effective therapy for the treatment of acute attacks of hereditary angioedema in the USA, four different drugs are completing or have recently completed Phase III clinical trials. Objective: To review the clinical status and future prospects of the new therapies under development for the treatment of hereditary angioedema. Methods: A review was carried out of the literature and presentations at meetings on the efficacy and safety of plasma-derived C1 inhibitor, recombinant human C1 inhibitor, the kallikrein inhibitor DX-88, and the B2 bradykinin receptor antagonist HOE-140. Results/conclusion: Each of these drugs has been shown to be effective and safe for the treatment of hereditary angioedema; however, subtle differences in their mechanisms of action and delivery may influence how physicians and patients utilize the different drugs. The availability of effective therapy is expected to reshape the management of hereditary angioedema.