N-carbamylglutamate in the treatment of hyperammonemia

N-氨甲酰谷氨酸治疗高氨血症

• 批准号: 8254226
• 负责人: Mendel Tuchman
• 金额: $ 83.12万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254226
• 关键词: Acute; Age; Ammonia; Anisotropy; Attenuated; Benzoates; Biological Markers; Blood; Brain; Brain Injuries; Carbamyl Phosphate; Cell Energetics; Cell membrane; Cessation of life; Chemicals; Childhood; Choline; Clinical; Clinical Research; Cognitive; Controlled Environment; Country; Creatine; Data; Defect; Development; Developmental Disabilities; Dietary Proteins; Diffusion Magnetic Resonance Imaging; Disease; Disease Outcome; Encephalopathies; Europe; FDA approved; Funding; Glutamates; Glutamine; Goals; Hereditary Disease; Hospitalization; Hyperammonemia; Inborn Errors of Metabolism; Inherited; Intelligence; Investigation; Length; Ligase; Liver; Liver Circulation; Liver Failure; Magnetic Resonance Imaging; Measurement; Measures; Metabolic Diseases; Modality; N acetyl L glutamate; N-acetylaspartate; N-carbamylglutamate; Neonatal; Nervous System Trauma; Neurocognitive; Neurologic; Neurons; Nitrogen; Ornithine carbamoyltransferase deficiency; Orphan; Outcome; Outcome Measure; Pathway interactions; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phenylacetates; Phenylbutyrates; Placebos; Production; Randomized; Recovery; Research Design; Resolution; Safety; Secondary to; Severities; Spectrum Analysis; Surrogate Markers; Symptoms; Testing; Urea; acylating agent; analog; design; double-blind placebo controlled trial; early childhood; functional status; improved; instrument; ketotic hyperglycinemia; methylmalonic aciduria; neonate; prevent; primary outcome; response; secondary outcome; small molecule; standard care; urea cycle; white matter

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. PUBLIC HEALTH RELEVANCE: Elevated ammonia levels in the blood can cause severe brain damage, developmental disabilities and can be fatal. N-acetylglutamate (NAG) is a small molecule in the liver that is essential for the urea cycle, keeping blood ammonia levels below levels that are toxic to the brain. We now have strong preliminary evidence that N- carbamylglutamate (Carbaglu), a chemical that is very similar to NAG, but that, unlike NAG, is not broken down in the body, can mimic the effect of NAG to decrease ammonia levels in patients with a number of inherited metabolic diseases. This project will investigate whether Carbaglu can improve the clinical outcome and reduce or prevent brain damage from ammonia in patients with four different genetic diseases associated with high ammonia levels. If the results confirm our hypothesis, these patients can be treated with Carbaglu to keep their ammonia level at normal or close to normal levels, protecting them from brain damage.

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.具体目的是：1。确定在严重，新生儿发作的PA和MMA中对急性高症治疗的治疗是否可以改善神经发育结果，以及它是否安全。 2。为了确定NCG治疗急性高症血症是否会加速严重PA和MMA的患者以及患有部分CPSD和OTCD的患者的高症和临床恢复，以及它是否安全。 3。为了确定在代谢稳定的患者中，3天NCG治疗对尿素发生的影响是否可以预测AIMS 1和2中观察到的结果。这是在全国七个儿童医院进行的双盲，安慰剂对照试验。目标1的主要结果度量是使用适合年龄的特定神经发育仪器评估神经认知的发展。 AIM 2的主要结果包括NCG对高氨血症及其临床症状及其住院时间的影响。目标3的结果是评估NCG对尿素发生率的短期影响与长期对NCG的临床反应与AIM 1和2确定的急性临床环境之间的相关性。我们的假设是NCG将改善这些疾病中的临床结果。这些研究旨在为NCG功效和安全性提供科学证据，这些证据可用于扩大该药物的指示，从而获得FDA批准。 公共卫生相关性：血液中升高的氨水平会造成严重的脑损伤，发育障碍，可能是致命的。 N-乙酰谷氨酸（NAG）是肝脏中的一个小分子，对尿素周期至关重要，使血液氨水水平低于对大脑有毒的水平。现在，我们有强有力的初步证据表明，N-甲酰基谷氨酸（Carbaglu）是一种与NAG非常相似的化学物质，但与NAG不同，体内并未分解，可以模仿NAG降低患者患者氨水水平的效果。该项目将调查卡尔巴卢是否可以改善临床结果，并减少或防止四种与高氨水平相关的遗传疾病患者的氨损伤。如果结果证实了我们的假设，则可以将这些患者用Carbaglu治疗，以使其氨水保持正常或接近正常水平，从而保护他们免受脑损伤。