N-carbamylglutamate in the treatment of hyperammonemia

N-氨甲酰谷氨酸治疗高氨血症

• 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
• 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

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错误的短期疗效，这些代谢错误导致高氨血症和随之而来的脑损伤：n -乙酰谷氨酸合成酶（NAGS）缺乏、氨甲酰磷酸合成酶I （CPSI）缺乏、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）。