Nitric Oxide Precursors and Congenital Heart Surgery

一氧化氮前体与先天性心脏病手术

• 批准号: 6836044
• 负责人: FREDERICK E BARR
• 金额: $ 43.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836044
• 关键词: adolescence (12-20); arginine; arginosuccinate synthetase deficiency; blood tests; carbamoyl phosphate synthetase deficiency; child (0-11); citrulline; clinical research; clinical trial phase I; clinical trial phase II; congenital heart disorder; drug screening /evaluation; electroencephalography; enzyme activity; genetic polymorphism; genotype; heart surgery; human subject; human therapy evaluation; nitric oxide; nitric oxide synthase; ornithine carbamoyltransferase; patient oriented research; pediatric pharmacology; polymerase chain reaction; postoperative complications; urea cycle

DESCRIPTION (provided by applicant): Increased pulmonary vascular tone (PVT) can complicate the postoperative course after 6 specific surgical procedures for congenital heart defects. These include the unrestrictive ventricular septal defect (VSD) repair, the atrioventricular septal (AVSD) repair, the arterial switch procedure for transposition of the great arteries (TGA), and the Norwood I, bidirectional Glenn shunt, and Fontan procedures for single ventricle lesions. PVT is partially controlled by nitric oxide (NO). Arginine, the precursor to NO, is a product of the urea cycle. In the preliminary data section of this application, we present data on 169 infants and children who have undergone one of these 6 surgical procedures. We specifically found that urea cycle function and plasma arginine levels were significantly decreased in all patients. Furthermore, patients with increased PVT had significantly lower arginine levels compared to patients with normal PVT. Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme, carbamyl phosphate synthetase I (CPSl T1405N), appeared to affect postoperative plasma arginine levels and pulmonary vascular tone. The hypothesis of this study is that genetic polymorphisms in the rate limiting urea cycle enzyme CPSl and other important enzymes in the urea cycle influence the availability of nitric oxide precursors and that perioperative enhancement of urea cycle function with the key urea cycle intermediate, citrulline, will increase plasma arginine and NO metabolites and prevent elevations in PVT. Specific Aims: 1. In an observational study in infants and children undergoing one of 6 congenital heart surgeries test the hypothesis that genetic polymporphisms in the urea cycle enzymes carbamyl phosphate synthetase I (CPSl), ornithine transcarbamylase (OTC), argininosuccinate syntheatse (ASS), argininosuccinate lyase (ASL), and enodothelial nitric oxide synthase (eNOS) influence arginine and NO availability and postoperative pulmonary vascular tone 2. In a phase 1/11clinical trial, determine the pharmacokinetics and safety profile of 3 doses of intravenous citrulline in children undergoing cardiopulmonary bypass for correction of congenital heart defects. 3. In a phase III randomized clinical trial of infants and children undergoing one of 6 congenital heart surgeries test the hypothesis that intravenous citrulline increases postoperative arginine and NO metabolite levels and prevents increased postoperative PVT.

描述（由申请人提供）： 肺血管张力（PVT）增加后，在6个特定的先天性心脏缺陷后，术后病程使术后病程复杂化。其中包括不受限制的心室间隔缺陷（VSD）修复，房屋中的间隔（AVSD）修复，大动脉转座（TGA）的动脉开关程序（TGA）以及诺伍德I（Norwood I），双向Glenn shunt和Fontan shunt和Fontan手术。 PVT由一氧化氮（NO）部分控制。精氨酸是NO的前体，是尿素周期的产物。在本应用程序的初步数据部分中，我们介绍了169名接受过这6个手术程序之一的婴儿和儿童的数据。我们特别发现所有患者的尿素周期功能和血浆精氨酸水平均显着降低。此外，与正常PVT患者相比，PVT增加的患者的精氨酸水平明显降低。最后，在限制尿素循环酶，磷酸氨基磷酸盐合成酶I（CPSL T1405N）的速率上，遗传单核苷酸多态性（SNP）似乎会影响术后血浆精氨酸水平和肺血管张力。这项研究的假设是，尿素周期酶CPSL和尿素周期中的其他重要酶的遗传多态性会影响一氧化氧化物前体的可用性，并且毛刺循环的毛骨循环功能增强功能与关键尿素周期的尿素周期功能相关，将增加尿素循环，柠檬酸盐和无质量质量质量质量为蛋白质蛋白蛋白蛋白蛋白蛋白含量和含量为蛋白含量。具体目的：1。在接受6种先天性心脏手术之一的婴儿和儿童进行的观察性研究中，检验了尿素周期酶中遗传多孢子型在尿素周期酶中的磷酸磷酸磷酸合成酶I（CPSL），鸟氨酸盐氨基氨基酶（OTC），ArginInoscination（ArginInoscination）（ArginInoscination）（Ass）溶解（Ass）溶解酶（Ass）含素（Ass）含素（Ass）含素（Ass）。 ENODPOLIAL NITRIC氧化物合酶（ENOS）会影响精氨酸，没有可用性和术后肺血管张力2。在第1阶段的1/11氯化试验中，确定3剂的药代动力学和3剂静脉柑橘类静脉ci亵葡萄瓜的药代动力学和安全性，用于造成心脏损害的儿童，可用于治疗先生性心脏脱位。 3。在第三阶段的随机临床试验中，接受了6种先天性心脏手术之一的婴儿和儿童进行了一种假设，即静脉注射瓜氨酸会增加术后精氨酸且无代谢物水平，并防止术后PVT增加。