治疗遗传性血管水肿新药艾替班特的药理作用与临床研究新进展

艾替班特作为缓激肽B2受体抑制剂,对18岁及以上成人遗传性血管水肿(HAE)急性发作具有很好的疗效,且不良反应较少,可由患者自助给药,便于携带及紧急情况下使用。本文利用MEDLINE对关键词艾替班特、缓激肽B2受体抑制剂和HAE进行检索,并对检索到的体外、体内试验结果进行综述,通过文献回顾了艾替班特在治疗HAE中的作用机制、药效学、药代动力学、临床评价和安全性,更多的研究有待进一步评价。     

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)。     

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。     

遗传性血管性水肿一例

遗传性血管性水肿是C_1抑制物的遗传缺陷,是一种常染色体的显性遗传病,发病率约为1/50万。约有30％发生喉水肿窒息而死亡。女患,59岁,医师。曾于20a(年)前因蚊虫叮咬面部后,引起前额部、面部水肿,数日后自行消退。20多年来,经常在四肢,尤其在头面部及前臂、手背等裸露部位发生水肿,每次发作均无一定规律,并能自行消退。于1988—04—02水肿再发,开始在上肢、手部、颜面,发展迅速,自感病情危笃,于午后3时求医。体检:患者颜面、颈部及全身均见严重水肿,头部     

缓激肽B2受体拮抗剂艾替班特降低卡托普和对培养新生大鼠心肌细胞 …

AIM: To study whether endogenous kinins are negative modulators in the growth of cardiomyocytes and their possible cellular and molecular mechanisms. METHODS: Cultured neonatal rat cardiomyocytes were used. Intracellular RNA and protein synthesis were measured by [3H]uridine incorporation and [3H]leucine incorporation, respectively. The expression level of proto-oncogene c-myc, c-fos mRNA was observed by Northern blotting. RESULTS: Exposure of cardiomyocytes to captopril (Cap, 100 mumol.L-1) for 48 h inhibited the rates of [3H]Urd and [3H]Leu incorporations by 25% and 26%, respectively, and for 2 h inhibited c-myc, c-fos mRNA expression by 75% and 55%, respectively. Treatment of angiotensin II (Ang II, 1 mumol.L-1) for 48 h significantly increased the rates of [3H]Urd and [3H]Leu incorporations and for 1 h induced c-myc, c-fos mRNA overexpression, which were reduced by pretreatment with Cap (100 mumol.L-1). Icatibant acetate (Hoe 140, a specific antagonist of bradykinin B2 receptor) 0.1-10 mumol.L-1 blocked the effects of Cap in a concentration-dependent manner. CONCLUSION: Endogenous kinins exhibited a negative modulatory effect on growth of cardiomyoctes via BK B2 receptor.     

达那唑治疗遗传性血管性水肿的疗效与安全性

目的评价达那唑治疗遗传性血管性水肿（HAE）的疗效和安全性。方法收集1985至2010年于北京协和医院就诊,应用达那唑≥1年、随访时问≥1年或随访次数≥5次并有完整随访记录的HAE患者的临床资料进行回顾性分析。疗效评估指标为用药前后皮肤水肿、腹痛、喉头水肿发作频率、血清补体第1成分抑制因子（C1INH）含量与功能、血清补体第4成分（C4）含量。安全性评价指标为用药前后肝功能、体重、女性患者月经情况变化。结果24例患者符合纳入标准。男、女性各12例,就诊年龄（36±15）岁,病程（15±8）年。达那唑初始剂量均为200mg,2～3次／d,口服1～4周逐渐减至维持剂量,男性维持剂量为（169±94）mg／d,女性为（130±56）mg／d。24例患者服用达那唑时间的中位数和四分位数间距为5（1．1～10．3）年。服用达那唑之前,24例患者体表水肿、喉头水肿和腹痛发生率分别为100％（24例）、70．8％（17例）和62．5％（15例）,治疗后分别降至41．6％（10例）、12．5％（3例）和8．3％（2例）,差异均有统计学意义（均P〈0．01）。服用达那唑1～4周后,24例患者血清C1INH含量和功能分别由治疗前的（0．08±0．06）g／L和（0．14±0．04）U／ml升至（0．12±0．07）g/L（P=0．05）和（0．26±0．05）U／ml（P〈0．01）,但未恢复至正常水平。22例患者有血清C4含量检测结果记录,2004年前后就诊者分别为17和5例,服用达那唑前后C4含量分别为（23．5±12．6）、（56．9±30．0）mg/L和（0．06±0．01）、（0．08±0．01）g/L,差异均有统计学意义（均P〈0．05）。2例患者分别在服药30和45d后血清丙氨酸转氨酶由25和20U／L升至138和74U／L,并出现脱发、油脂分泌增多、烦躁等症状,给予保肝治疗后恢复正常。6例体重较服药前增加。6例女性患者分别出现停经、月经周期延长或缩短、月经量减少或增多等症状,将达那唑剂量减至200mg,1次／d或隔日1次后,月经紊乱得到明显改善。结论达那唑治疗HAE有效且安全。建议将血清G4水平作为调整达那唑剂量的指标。     

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。     

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。     

以腹水为主要表现的遗传性血管性水肿1例

遗传性血管性水肿（HAE）是一种罕见的常染色体显性遗传病,1888年由Oslar首次报道,其发病机制为C1酯酶抑制物（complement 1 esterase inhibitor,C1-INH）基因缺陷导致血浆C14NH含量和（或）功能低下,发病率为1／5万。HAE典型的临床表现为反复发作的、局限性、自限性皮肤及黏膜下水肿,水肿累及胃肠道黏膜及其他腹部脏器时,可表现为剧烈绞痛,与外科急腹症很难鉴别,1／3的患者被误施手术,水肿累及上呼吸道,可因窒息导致死亡。现报道1例以月经时反复出现腹水为主要临床特征的患者。     

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.     

Parallel comparison of three methodologies for measuring functional C1-inhibitor in Hereditary angioedema patients

Hereditary angioedema (HAE) types I and II are characterized by functional C1 inhibitor (fC1-INH) deficiency which results in bradykinin overproduction. Sensitive, specific and robust methods to quantitate fC1-INH in human samples are required for diagnosing HAE and/or to measure pharmacodynamic activity of C1-INH drugs in clinical studies. To date, three methods have been reported in literature to measure fC1-INH: conventional chromogenic assay measuring residual C1-esterase activity, and immunoassays based on functional binding to either activated complement C1s or Factor XIIa/kallikrein.We used three qualified/validated fit-for purpose methods to quantitate fC1-INH in human plasma and to conduct a parallel comparison for diagnostic purposes and as a read-out for pharmacodynamic activity. Sensitivity and specificity were determined from the Receiver Operator Characteristics (ROC) curve analysis of the three fC1-INH methods through testing of fifty healthy control vs. HAE plasma samples. fC1-INH profile of fifteen HAE subjects, who underwent different treatment regimen in a cross-over Shire C1-INH clinical study, was analyzed in these three methods in parallel. A correlation analysis performed between these methods using data generated from clinical samples showed that profiles obtained from different fC1-INH methods matched for individual HAE subjects.Our findings suggest that functional binding immunoassay methods serve as reliable alternates for conventional chromogenic method to quantitate fC1-INH in human plasma samples with a better dynamic range of detection and ease of use. Of the two immunoassays used in this study, FXIIa-binding method gave better sensitivity, specificity, and correlation to the chromogenic method as a diagnostic method to distinguish HAE samples from healthy controls.     

Effects of the bradykinin antagonist,icatibant (Hoe 140), on pancreas and liver functions during and after caerulein-induced pancreatitis in rats

It has been found earlier that the bradykinin antagonist, icatibant (Hoe 140), prevents the pancreatic oedema and the ensuing hypotension and haemoconcentration, and facilitates the removal of activated enzymes from the tissue during caerulein-induced acute pancreatitis. For a potential therapeutic use of the compound in clinical situations it is essential to investigate whether the associated increase in enzyme activities in the blood serum has any adverse effects on the pancreas itself or on other organs.Normal amylase secretion into the biliopancreatic duct stimulated by a low dose of caerulein (0.4 nmol kg^–1 h^–1, i.v.) was not affected by icatibant (100 nmolkg^–1, s.c.). Acute pancreatitis, induced by a high dose of caerulein (4 nmol kg^–1 h^–1 for 2 h, i.v.), resulted in elevations in the activities of amylase and lipase in the pancreatic tissue and in the blood serum lasting for at least 4 h after the end of the caerulein infusion. While the rise in enzyme activities in the blood serum was augmented in icatibant-treated rats only at the end of the caerulein-infusion, the enzyme accumulation in the pancreas was significantly reduced by icatibant for at least 4 h after the end of the caerulein infusion. The secretion of amylase and lipase into the biliopancreatic duct was significantly increased only during the first 20 min of acute pancreatitis; in rats pre-treated with icatibant, no significant increase could be observed. Twenty-four hours after induction of pancreatitis, a low-dose caerulein stimulation of the exocrine function of the pancreas led to a reduced but sustained secretion of amylase regardless of whether the animals had received icatibant or not. During the first 45 min of pancreatitis, blood glucose concentrations were significantly reduced, but returned to values not different from those obtained in saline-infused controls. This effect was not affected by icatibant. No changes in the response to an i.v. glucose tolerance test were found on the day after induction of acute pancreatitis. The serum activities of glutamic pyruvic transaminase and -glutamyl transpeptidase determined up to 24 h after induction of pancreatitis were not different from saline controls. Icatibant had no effect on the activities of these enzymes.It is concluded that during caerulein-induced acute pancreatitis normal exocrine secretion of pancreatic enzymes into the pancreatic duct ceases almost immediately. Pre-treatment with icatibant significantly reduces the accumulation of activated enzymes in the pancreatic tissue for several hours after induction of pancreatitis while a concomitant augmentation in enzyme activities in the blood serum lasts much shorter. There is no indication of adverse effects on the function of the endocrine or exocrine pancreas and that of the liver, either during the acute stages of pancreatitis or during the recovery period.     

Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia–reperfusion injury

Bradykinin B1 receptors are exclusively expressed in inflamed tissues. For this reason, they have been related with the outcomes of several pathologies. Ischemia–reperfusion injury is caused by the activation of inflammatory and cytoprotective genes, such as macrophage chemoattractant protein-1 and heme oxygenase-1, respectively. This study was aimed to analyze the involvement of bradykinin B1 and B2 receptors (B1R and B2R) in tissue response after renal ischemia–reperfusion injury. For that, B1R (B1−/−), B2R (B2−/−) knockout animals and its control (wild-type mice, B1B2+/+) were subjected to renal bilateral ischemia, followed by 24, 48 and 120 h of reperfusion. At these time points, blood serum samples were collected for creatinine and urea dosages. Kidneys were harvested for histology and molecular analyses by real-time PCR. At 24 and 48 h of reperfusion, B1−/− group resulted in the lowest serum creatinine and urea levels, indicating less renal damage, which was proved by renal histology. Renal protection associated with B1−/− mice was also related with higher expression of HO-1 and lower expression of MCP-1. In conclusion, the absence of B1R had a protective role against inflammatory responses developed after renal ischemia–reperfusion injury.     

Putative roles of kinin receptors in the therapeutic effects of angiotensin 1-converting enzyme inhibitors in diabetes mellitus

The role of endogenous kinins and their receptors in diabetes mellitus is being confirmed with the recent developments of molecular and genetic animal models. Compelling evidence suggests that the kinin B₂ receptor is organ-protective and partakes to the therapeutic effects of angiotensin 1-converting enzyme inhibitors (ACEI) and angiotensin AT₁ receptor antagonists. Benefits derive primarily from vasodilatory, antihypertensive, antiproliferative, antihypertrophic, antifibrotic, antithrombotic and antioxidant properties of kinin B₂ receptor activation. Mechanisms include the formation of nitric oxide and prostacyclin and the inhibition of NAD(P)H oxidase activity involving classical and novel signalling pathways. Kinin B₂ receptor also ameliorates insulin resistance by increasing glucose uptake and supply, and by inducing glucose transporter-4 translocation either directly or through phosphorylation of insulin receptor. The kinin B₁ receptor, which is induced by the cytokine network, growth factors and hyperglycaemia, mediates hyperalgesia, vascular hyperpermeability and leukocytes infiltration in diabetic animals. However, emerging data highlight reno- and cardio-protective effects mediated by kinin B₁ receptor under chronic ACEI therapy in diabetes mellitus. Thus, the Janus-faced of kinin receptors needs to be taken into account in future drug development. For instance, locally acting kinin B₁/B₂ receptor agonists if used in a safe therapeutic window may represent a more rationale strategy in the prevention and management of diabetic complications. Because kinin B₂ receptor antagonists may further increase insulin resistance, the persisting dogma that restricts the development of kinin receptor analogues to antagonists (that is still relevant to abrogate pain and inflammation) needs to be revisited.