N-carbamylglutamate in the treatment of hyperammonemia

N-氨甲酰谷氨酸治疗高氨血症

• 批准号: 7848468
• 负责人: Mendel Tuchman
• 金额: $ 1.07万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848468
• 关键词: Adult; Amino Acids; Ammonia; Benzoates; Biochemical; Biological Markers; Blood; Brain; Brain Injuries; Carbamyl Phosphate; Cessation of life; Chemicals; Clinical; Congenital Disorders; Data; Developmental Disabilities; Dietary Proteins; Disease; Encephalopathies; Etiology; Failure; Glutamates; Glutamine; Goals; Grant; Hereditary Disease; 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; Refractory; Renal function; Residual state; Resistance; Safety; Secondary to; Site; Study Section; Surrogate Markers; Symptoms; Syndrome; Synthase I; Testing; Therapeutic Agents; Toxic effect; Tracer; Urea; Valproic Acid; abstracting; acylating agent; analog; carbamoyl phosphate synthetase deficiency; effective therapy; healthy volunteer; improved; in vivo; ketotic hyperglycinemia; methylmalonic aciduria; mutant; nitrogen metabolism; novel; response; small molecule; stable isotope; treatment duration; urea cycle; volunteer

Abstract Our overall goal 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) and hyperinsulinism and hyperammonemia syndrome (HHS). Our specific aims are: 1. To determine whether a 3-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 and 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 we 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. 2. To evaluate the safety of short-term (3-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 and liver and kidney functions. Our hypothesis is that NCG will ameliorate deficient ureagenesis in these congenital disorders. This proposal 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 also may 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. Carbaglu grant narrative Elevated ammonia levels in the blood can cause brain damage, developmental disabilities and it 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 have reason to believe 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 urea cycle in patients with 5 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.

抽象的 我们的总体目标是确定N-甲基-L-谷氨酸的短期疗效 （NCG）用于治疗五个导致高氨血症的新陈代谢的五个天生错误 随之而来的脑损伤：N-乙酰谷氨酸合酶（NAGS）缺乏， 氨基甲酰磷酸合成酶I（CPSI）缺乏症，丙酸血症（PA），，， 甲基丙二酸酸血症（MMA）和高胰岛素和高症综合征 （HHS）。 我们的具体目的是： 1。确定3天的NCG治疗是否可以改善或恢复尿素作用 13C证明，患有NAG缺乏，CPSI缺乏症，PA，MMA和HHS患者 掺入尿素，血浆氨，尿素和氨基酸的浓度以及 通过磁共振光谱测量的脑谷氨酰胺浓度。这 将五个遗传性疾病中每一种患者与那些患者进行比较 在健康的成年志愿者中获得（正常对照）。另外，患者的结果 我们希望他对NCG（肯定对照）做出最佳反应的NAG缺乏症将是 与其他四种疾病的结果相比，以衡量其校正程度 尿素发生响应NCG。 2。评估健康中NCG短期治疗的安全性 志愿者和患者。将评估临床和实验室安全参数 参与者，包括特殊症状以及血液计数和肝脏的变化以及 肾功能。 我们的假设是，NCG将在这些先天性中改善尿素不足 疾病。该建议将为新的治疗方法提供重要的功效数据 与高症相关的几种罕见的先天性疾病通常是 耐火。这项研究的成功结论也可能给人以理由 对其他疾病和疾病的调查很复杂 高症血症，包括病因多样的肝衰竭和valproic治疗 酸。 Carbaglu Grant的叙述 血液中氨水水平升高会导致脑损伤，发育 残疾，可能是致命的。 N-乙酰谷氨酸（NAG）是肝脏中的小分子 这对于尿素周期至关重要，使血液氨水水平低于 对大脑有毒。我们有理由相信N-甲基谷氨酸（Carbaglu），一个 与NAG非常相似的化学物质，但与NAG不同，体内没有分解， 是否可以模仿NAG的影响，以降低许多患者的氨水 继承的代谢疾病。该项目将调查Carbaglu是否可以改善 与高氨相关的5种不同遗传疾病患者的尿素周期 水平。如果结果证实了我们的假设，则可以用Carbaglu治疗这些患者 要使氨水保持正常或接近正常水平，请保护它们免受 脑损伤。