N-carbamylglutamate in the treatment of hyperammonemia

描述（由申请人提供）：本项目的总体目标是确定n -氨甲酰- l-谷氨酸（NCG）治疗急性高氨血症(丙酸血症（PA）、甲基丙二酸血症（MMA）、氨甲酰磷酸合成酶1缺乏症（CPSD）和鸟氨酸转氨基甲酰基酶缺乏症（OTCD）是否会改变疾病的临床结果。具体目标是：1。目的：确定NCG治疗严重、新生儿发病的PA和MMA患者的急性高氨血症是否能改善神经发育结局，以及是否安全。2. 探讨NCG治疗急性高氨血症是否能加速重度PA、MMA患者及部分CPSD、OTCD患者高氨血症的消退和临床恢复，是否安全。3. 为了确定在代谢稳定的患者中，3天的NCG治疗对尿原性的影响是否可以预测目的1和目的2中观察到的结果。这是一项双盲、安慰剂对照试验，在全国七家儿童医院进行。Aim 1的主要结果测量是使用适合年龄的特定神经发育工具评估神经认知发展。Aim 2的主要结局包括NCG对高氨血症的消退速度及其临床症状和住院时间的影响。目的3的结果是评估NCG对尿毒率的短期影响与NCG的长期临床反应之间的相关性，以及由目的1和2确定的急性临床情况。我们的假设是，NCG将改善这些疾病的临床结果。这些研究旨在为NCG的有效性和安全性提供科学证据，可用于扩大该药物的适应症，从而获得FDA的批准。

DESCRIPTION (provided by applicant): The overall objective of this project is to determine whether treatment of acute hyperammonemia with N-carbamyl-L-glutamate (NCG) in propionic acidemia (PA), methylmalonic acidemia (MMA), carbamyl phosphate synthetase 1 deficiency (CPSD) and ornithine transcarbamylase deficiency (OTCD) changes the clinical outcome of disease. The specific aims are: 1. To determine whether NCG treatment of acute hyperammonemia in severe, neonatal-onset PA and MMA improves neurodevelopmental outcome, and whether it is safe. 2. To determine whether NCG treatment of acute hyperammonemia accelerates the resolution of hyperammonemia and clinical recovery in patients with severe PA and MMA and in those with partial CPSD and OTCD, and whether it is safe. 3. To determine whether, in metabolically stable patients, the effect of a 3-day NCG treatment on ureagenesis is predictive of the outcomes observed in Aims 1 and 2. This is a double blind, placebo controlled trial performed in seven children's hospitals across the country. The primary outcome measure for Aim 1 is neurocognitive development assessed using age-appropriate specific neurodevelopmental instruments. Primary outcomes of Aim 2 include the effect of NCG on the pace of resolution of hyperammonemia and its clinical symptoms and the length of hospitalization. The Aim 3 outcome is an assessment of the correlation between the short-term effect of NCG on ureagenesis rate and the clinical response to NCG long term and in acute clinical settings as determined by Aims 1 and 2. Our hypothesis is that NCG will improve clinical outcome in these disorders. These studies are designed to provide scientific evidence for NCG efficacy and safety which can be used to expand the indication of this drug, leading to FDA approval.