N-carbamylglutamate in the treatment of hyperammonemia

描述(申请人提供)：本项目的总体目标是确定N-氨基甲酰-L-谷氨酸盐(NCG)治疗丙酸血症、甲基丙二酸血症、氨基甲酰磷酸合成酶1缺乏症和鸟氨酸转氨酶缺乏症的急性高氨血症是否会改变疾病的临床结果。具体目的是：1.确定NCG治疗重症新生儿PA和MMA急性高氨血症是否能改善神经发育结局，以及它是否安全。2.确定NCG治疗急性高氨血症是否能促进重症PA、MMA和部分CPSD、OTCD患者高氨血症的消退和临床恢复，以及其安全性。3.为了确定在代谢稳定的患者中，为期3天的NCG治疗对尿失禁的影响是否可以预测AIMS 1和AIMS 2观察到的结果。这是一项在全国七家儿童医院进行的双盲安慰剂对照试验。目标1的主要结果衡量标准是使用适合年龄的特定神经发育工具评估神经认知发展。目标2的主要结果包括NCG对高氨血症及其临床症状和住院时间的缓解速度的影响。目标3的结果是评估NCG对尿失禁发生率的短期效果与长期和急性临床环境下NCG的临床反应之间的相关性。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，这些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.