波生坦治疗婴儿先心病合并肺动脉高压的临床观察研究

发布时间：2018-05-17 00:39

  本文选题：内皮素受体拮抗剂 + 波生坦　； 参考：《山东大学》2014年硕士论文

【摘要】：研究背景： 肺动脉高压作为先天性心脏病(左向右分流型)常见的、严重的并发症,它严重威胁着患儿的生命,患有严重肺动脉高压患儿行手术治疗的危险性及死亡率显著增加,目前临床尚缺乏特效的治疗方法。因此,对肺动脉高压的治疗方法进行深入研究非常必要。 研究证明内皮素-1(Endothelin-1,ET-1)为目前所被发现的、作用最强的缩血管物质,近年来发现ET-1不但为一种强效缩血管肽(血管内皮细胞释放的),同时亦是促血管平滑肌细胞(SMC)有丝分裂原。ET-1作为一种强力的内源性血管收缩剂和致丝裂素,参与了多种心血管疾病的病理生理过程,也是先天性心脏病患者发生PAH的重要原因之一,因此抑制内皮素-1具有控制PAH的作用。近年来研究发现,左向右分流型先天性心脏病(先心病)肺动脉高压患者血浆内皮素-1水平升高,应用DNA-RNA原位杂交法发现肺动脉高压患者肺组织ET-1mRNA含量明显增高[2]。目前认为ET-1导致肺动脉高压形成的可能机制：ET-1与平滑肌细胞表面的内皮素受体A(ETA)和B(ETB)结合,可引起肺动脉收缩、同时可促进肺动脉中层SMC的增生、分泌胶原等细胞外间质增多,从而导致肺动脉管壁增厚,管腔狭窄,肺动脉高压形成。而ET-1受体拮抗剂既可拮抗ET-1发挥的促肺动脉SMC增殖、肥大作用,又能拮抗ET-1的致缺氧性肺动脉高压大鼠肺血管收缩及血管平滑肌细胞增殖作用。 波生坦是第一个获得批准用于PAH的口服治疗药物,波生坦治疗儿童PAH的非对照的开放式BREATHE-3研究首次证实,波生坦可安全应用于儿童PAH的治疗,明显改善儿童PAH患者的血流动力学参数。2009年7月,波生坦在2岁以上的儿童PAH患者中的应用得到了EMA的许可,推荐的初始剂量为2mg/kg bid。目前正在开展的FUTURE-3研究旨在评价3个月至12岁的儿童PAH患者每日服用2次与每日服用3次波生坦的药代动力学、耐受性、安全性和疗效,初步结果令人鼓舞。 波生坦最常见的副作用是转氨酶升高,主要是因为该药竞争性抑制胆盐运输所致,但是至今尚无永久性肝功能损害的报道。波生坦上市后的监测报告表明,儿童发生肝损害的几率比成人要低,在3%左右。建议治疗期间至少每月监测1次肝功能。如转氨酶增高≤正常值高限3倍,可继续用药观察；3～5倍之间,可将剂量减半或暂停用药,每2周监测1次肝功能,待转氨酶恢复正常后再次使用；5～8倍之间,暂停用药,每2周监测1次肝功能,待转氨酶恢复正常后可考虑再次用药；但当达8倍以上时,需立即停用,终生不再考虑重新用药。 波生坦为非选择性的双重内皮素受体拮抗剂,它不但与血管中的内皮素受体A(ETA)结合,同时亦与脑、上皮细胞及平滑肌细胞中的内皮素受体B(ETB)相结合。ET-1可竞争抑制ET1与ETA及ETB的结合,从而阻止ET-1强效的内源性血管收缩作用和纤维化、致炎作用。目前国内外针对特发性肺动脉高压及缺氧、肺部炎症等导致PAH报道较多,同时治疗经验多针对成人及较大年龄组儿童,而针对婴幼儿先天性心脏病合并肺动脉高压的治疗方面研究较少,尤其3个月以下小婴儿先天性心脏病合并肺动脉高压的治疗方面更值得研究。 资料及方法： 病例选择：选择2012.01-2013.06在我院治疗的3个月以下合并肺动脉高压的先天性心脏病患者30例,所有患儿均经过心电图、胸部X光片、超声心动图检查,确诊为CHD合并肺动脉高压。同时设年龄3个月以下健康小婴儿10例,超声心动图检查排除肺动脉高压,为对照组。 分组：超声心动图确诊CHD合并肺动脉高压患儿按随机数字法分成两组： 波生坦组：在常规治疗基础上加用内皮素受体拮抗剂波生坦口服的患儿作为治疗组,具体方案：波生坦2mg/kg.次,每日两次,疗程7天；后改为4mg/kg.次,每日2次,疗程3周,以后逐渐减量至停药,总疗程为8周。 卡托普利组：接受常规治疗加卡托普利1mg/kg.d口服；常规治疗包括：地高辛口服、安体舒通口服。 对照组：10例年龄3个月以下健康查体小婴儿,超声心动图排除肺动脉高压。 方法： 1、观察组患儿均进行超声心动图检查,估测肺动脉收缩压≥60mm Hg,肺动脉平均压≥45mm Hg,且心功能在纽约心脏病协会(NYHA)分级Ⅱ级以上。 2、三组患儿分别于入组前签署知情同意书,实验组患儿于治疗前、治疗后4周、8周分别抽取静脉血2ml,检测患儿肝功能、血小板及心肌酶谱变化；以观察波生坦对患儿血小板、肝脏功能等的影响； 3、观察组患儿治疗前、治疗后4周、8周及对照组患儿分别抽取静脉血2ml,采用ELISA法测定患儿血浆ET-1水平；检测波生坦对肺动脉高压患儿血浆ET-1的影响； 4、观察组患儿用药前、用药后4周及8周,超声心动图测定肺动脉收缩压变化；通过30ml奶液喂养时间的变化进行患儿运动耐量评估。所记录数据进行组间比较,以评价波生坦临床治疗效果。 统计学处理： 所有资料数据采用均数±标准差表示,采用SPSS17.0对所得结果进行统计学分析,P0.05为有统计学意义。 结果： 1.口服波生坦治疗先天性心脏病相关PAH的患儿,经治疗后肺动脉收缩压明显降低。波生坦组患儿治疗剂量2mg/kg.次,每日2次,口服4周及8周后进行心脏彩色超声心动图监测,肺动脉收缩压即有明显改善,用药后4周、用药后8周与治疗前比较差异均有显著性意义(P0.001),由此说明波生坦可显著降低PH患儿的平均肺动脉压；卡托普利可使患儿的平均肺动脉压下降,用药后4周、用药后8周与治疗前比较差异有统计学意义(P0.05)。 2.经过波生坦治疗,患儿运动耐量能明显得到改善。小婴儿运动行为较少,目前尚无较为特效评估小婴儿运动耐量的良好办法,一般在吃奶时小婴儿可以精力集中,故测量患儿1次完成30ml奶液(婴幼儿配方奶及母乳)的喂养时间,可作为评估患儿运动耐量方便、可行,且较为准确的衡量标准。口服波生坦(内皮素受体拮抗剂)治疗,可使患儿30ml奶液的喂养时间明显缩短,治疗4周后,喂养时间由原来的平均20.55min降为16.05min,有显著意义(P0.01)。 3.肺动脉高压时,血浆ET-1水平升高,表明肺动脉压力升高时,血管内皮细胞合成和释放增加,与对照组相比,有显著差异(P0.05)。波生坦组用药后4周、用药后8周与治疗前比较差异均有显著性意义(P0.01),由此可见,波生坦可显著降低血浆ET-1水平(P0.01)；卡托普利可使儿血浆E T-1水平下降,但用药后4周及8周与治疗前比较差异均无显著性意义(P0.05)。 4.本实验在短期、小剂量口服波生坦治疗的过程中,未见有不良反应的发生,患儿耐受性好。口服治疗4周及8周后,复查患儿肝功能均在正常范围。 结论： 1.先心病肺动脉高压患儿血浆ET-1水平与对照组比较明显升高,表明当肺动脉压力升高时,血管内皮细胞合成及释放ET-1增加。 2.本研究首次在小于3个月的婴儿应用波生坦,且波生坦与卡托普利比较可更明显降低先天性心脏病相关PAH患儿肺动脉压力。 3.波生坦能显著改善先天性心脏病相关PAH患儿的心脏功能,提高运动耐量。 4.短期、小剂量口服波生坦治疗小婴儿先天性心脏病合并肺动脉高压,患儿肝肾功能无明显异常。证实波生坦治疗小婴儿肺动脉高压安全、有效。
[Abstract]:Background of Study :

Pulmonary arterial hypertension is a common and serious complication of congenital heart disease ( left - to - right shunt ) . It is a serious threat to the life of children . The risk and mortality rate of patients with severe pulmonary hypertension are significantly increased . There is a lack of special treatment methods at present . Therefore , it is necessary to study the treatment of pulmonary hypertension .

Endothelin - 1 ( ET - 1 ) is one of the most potent vasoconstrictors in patients with congenital heart disease . ET - 1 is a potent endogenous vasomotor and mitogen . ET - 1 is one of the important causes of PAH . In recent years , it has been found that the level of ET - 1 mRNA in pulmonary tissues of patients with congenital heart disease ( CHD ) increased significantly in patients with congenital heart disease . ET - 1 is combined with endothelin receptor A ( ETA ) and B ( ETB ) on the surface of smooth muscle cells .

For the first time , Bosentan was the first non - control open BREATHE - 3 study approved for PAH , which was first confirmed to be safe for use in the treatment of children ' s PAH and significantly improved the hemodynamic parameters of patients with PAH . In July 2009 , the initial dose recommended was 2 mg / kg bid . The currently ongoing study was intended to evaluate the pharmacokinetics , tolerability , safety and efficacy of 3 patients with PAH for 3 months to 12 years , and the preliminary results were encouraging .

The most common side effects of bosentan are the elevation of transaminase due mainly to the competitive inhibition of bile salt transport , but there has been no permanent liver function damage . The monitoring report after Posetin ' s marketing shows that the incidence of liver damage in children is lower than that of adults , and is about 3 % . It is suggested that the liver function should be monitored at least once a month during the treatment period . For example , the elevation of transaminase is 3 times higher than the normal value , and the observation of medication can be continued ;
between 3 and 5 times , the dosage can be reduced by half or the medicine is paused , and once every 2 weeks , the liver function is monitored , and after the transaminase returns to normal , the medicine is used again ;
between 5 and 8 times , the medicine is suspended , the liver function is monitored once every two weeks , and after the transaminase is returned to normal , the medicine can be taken into account again ;
However , when up to 8 times , the product is stopped immediately , and the life - life is no longer considered for re - use .

Bosentan is a non - selective double endothelin receptor antagonist , which binds not only to endothelin receptor A ( ETA ) in blood vessels but also to endothelin receptor B ( ETB ) in brain , epithelial cells and smooth muscle cells .

Materials and Methods :

Case Selection : Select 30 cases of congenital heart disease with pulmonary hypertension after 3 months of treatment in our hospital in 2012 . 01 - 2013.06 . All the children were diagnosed as CHD with pulmonary hypertension by electrocardiogram , chest X - ray and echocardiography .

Group : Echocardiography was divided into two groups according to the random number method for children with CHD combined with pulmonary hypertension .

Posentan group : The treatment group was treated on the basis of routine therapy with endothelin receptor antagonist bosentan as the treatment group , and the specific protocol was as follows : bosentan 2mg / kg . times , twice daily , duration of treatment for 7 days ;
The treatment course was 4 mg / kg once a day , twice a day , 3 weeks in treatment course , and then gradually reduced to drug withdrawal , and the total course of treatment was 8 weeks .

captopril group : conventional therapy plus captopril 1mg / kg 路 d oral administration ;
Routine therapy includes : digoxin oral administration , oxintong oral administration .

Control group : 10 small infants with 3 months of age were examined by echocardiography to exclude pulmonary hypertension .

Method :

1 . All patients in the observation group were examined by echocardiography to estimate the pulmonary artery systolic pressure 鈮，

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