N-carbamylglutamate in the treatment of hyperammonemia

N-氨甲酰谷氨酸治疗高氨血症

基本信息

批准号：
7505006
负责人：
Mendel Tuchman
金额：
$ 34.34万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7505006
关键词：
Adult Amino Acids Amino-acid N-acetyltransferase Ammonia Benzoates Biochemical Biological Markers Blood Brain Brain Injuries Carbamyl Phosphate Cessation of life Clinical Condition Congenital Disorders Count Data Developmental Disabilities Dietary Proteins Disease Encephalopathies Etiology Failure Glutamates Glutamine Goals Hydrolysis Hyperammonemia Hyperinsulinism In Vitro Inborn Errors of Metabolism Inborn Genetic Diseases Inherited Investigation Laboratories Ligase Liver Liver Failure Liver Mitochondria Magnetic Resonance Spectroscopy Measures Metabolic Diseases Methods Modality N acetyl L glutamate N-carbamylglutamate Nervous System Trauma Oral Participant Patients Phenylbutyrates Physiological Plasma Range Refractory Renal function Research Personnel Residual state Resistance Safety Secondary to Site Study Section Surrogate Markers Symptoms Syndrome Synthase I Testing Therapeutic Agents Thinking Toxic effect Tracer Urea Valproic Acid acylating agent analog benzoate carbamoyl phosphate synthetase deficiency healthy volunteer improved in vivo ketotic hyperglycinemia methylmalonic aciduria mutant nitrogen metabolism novel phenylbutyrate response stable isotope treatment duration urea cycle volunteer

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this application is to determine the short-term efficacy of N-carbamyl-L-glutamate (NCG) for the treatment of five inborn errors of metabolism that cause hyperammonemia and consequent brain damage: N-acetylglutamate synthase (NAGS) deficiency, carbamyl phosphate synthetase I (CPSI) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA), as well as hyperinsulinism and hyperammonemia syndrome (HHS). Specific Aim 1 is to determine whether a three-day treatment with NCG improves or restores ureagenesis in patients with NAGS deficiency, CPSI deficiency, PA, MMA, and HHS as evidenced by 13C incorporation into urea, concentrations of plasma ammonia, urea, and amino acids as well as brain glutamine concentrations measured by magnetic resonance spectroscopy. The results in patients with each of the five inherited disorders will be compared to those obtained in healthy adult volunteers (normal controls). In addition, the results of patients with NAGS deficiency, who the investigators expect to respond best to NCG (positive controls), will be compared to the results from the other four disorders to gauge their degree of correction of ureagenesis in response to NCG. Specific Aim 2 is to evaluate the safety of short-term (three-day) treatment with NCG in the healthy volunteers and patients. Clinical and laboratory safety parameters will be evaluated in all participants, including idiosyncratic symptoms and changes in blood counts as well as liver and kidney functions. The investigators' hypothesis is that NCG will ameliorate deficient ureagenesis in these congenital disorders. Thus, this application will provide important efficacy data for a novel treatment of several rare congenital disorders that are associated with hyperammonemia that often is refractory. Successful conclusion of the study may also afford a rationale for the investigation of other diseases and conditions that are complicated by hyperammonemia, including liver failure of diverse etiology and treatment with valproic acid.

描述（由申请人提供）：本申请的总体目标是确定 N-氨甲酰-L-谷氨酸 (NCG) 治疗五种先天性代谢缺陷（导致高氨血症和随之而来的脑损伤）的短期疗效：N -乙酰谷氨酸合酶（NAGS）缺乏症、氨甲酰磷酸合成酶I（CPSI）缺乏症、丙酸血症（PA）、甲基丙二酸血症（MMA）以及高胰岛素血症和高氨血症综合征（HHS）。具体目标 1 是确定为期三天的 NCG 治疗是否改善或恢复 NAGS 缺乏、CPSI 缺乏、PA、MMA 和 HHS 患者的尿素生成，如 13C 掺入尿素、血浆氨浓度、尿素和氨基通过磁共振波谱法测量酸和脑谷氨酰胺浓度。患有五种遗传性疾病的患者的结果将与健康成年志愿者（正常对照）的结果进行比较。此外，研究人员预计 NAGS 缺乏症患者对 NCG（阳性对照）反应最好，他们的结果将与其他四种疾病的结果进行比较，以衡量他们对 NCG 反应的尿素生成校正程度。具体目标 2 是评估健康志愿者和患者短期（三天）NCG 治疗的安全性。将对所有参与者的临床和实验室安全参数进行评估，包括特殊症状和血细胞计数以及肝肾功能的变化。研究人员的假设是，NCG 将改善这些先天性疾病中尿素生成不足的情况。因此，该应用将为几种罕见先天性疾病的新治疗提供重要的疗效数据，这些先天性疾病与通常难以治疗的高氨血症相关。该研究的成功结论也可能为高氨血症并发的其他疾病和病症的研究提供依据，包括不同病因的肝功能衰竭和丙戊酸治疗。