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.

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），甲基化酸血症（MMA）以及高胰岛素和高症综合征（HHS）。 具体目的1是确定NAG缺乏，CPSI缺乏症，PA，MMA和HHS患者的三天治疗是否可以改善或恢复尿素发生，这证明了13C掺入尿素中的浓度，血浆氨氨基，尿素，尿素和氨基酸和氨基酸以及脑粘液胶质浓度的浓度通过磁性的磁性谱图。 将五个遗传性疾病中每种患者的结果与健康的成年志愿者（正常对照）中获得的结果进行比较。 此外，研究人员期望对NCG做出最佳反应（阳性对照）的患者的结果将与其他四种疾病的结果进行比较，以评估其对NCG响应的尿素发生的程度。 具体目的2是评估健康志愿者和患者中NCG短期（三天）治疗的安全性。 将在所有参与者中评估临床和实验室安全参数，包括特殊症状以及血液计数的变化以及肝脏和肾功能。 研究者的假设是NCG将在这些先天性疾病中改善尿素不足。 因此，该应用将提供重要的功效数据，以对几种与高症相关的几种罕见先天性疾病进行新的治疗，这些疾病通常是难治性的。 这项研究的成功结论还可以为研究其他疾病和疾病的研究提供了理由，这些疾病和疾病因高氨血症而复杂化，包括多种病因学和丙戊酸治疗的肝脏衰竭。