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-氨甲酰-L-谷氨酸的短期疗效 (NCG) 用于治疗导致高氨血症的五种先天性代谢缺陷 以及随之而来的脑损伤：N-乙酰谷氨酸合酶（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 （美国卫生与公众服务部）。 我们的具体目标是： 1. 确定 3 天的 NCG 治疗是否改善或恢复尿素生成 13C 证明患有 NAGS 缺乏、CPSI 缺乏、PA、MMA 和 HHS 的患者 掺入尿素、血浆氨浓度、尿素和氨基酸以及 通过磁共振波谱法测量脑谷氨酰胺浓度。这 患有五种遗传性疾病的患者的结果将与那些患有五种遗传性疾病的患者的结果进行比较 在健康成年志愿者（正常对照）中获得。此外，患者的结果 患有 NAGS 缺陷的人，我们预计对 NCG（阳性对照）反应最好的人将是 与其他四种疾病的结果进行比较，以衡量其纠正程度 响应 NCG 的尿素生成。 2. 评估健康人短期（3 天）NCG 治疗的安全性 志愿者和患者。临床和实验室安全参数将在所有方面进行评估 参与者，包括特殊症状以及血细胞计数和肝脏的变化 肾脏功能。 我们的假设是 NCG 将改善这些先天性尿素生成缺陷 失调。该提案将为一种新的治疗方法提供重要的疗效数据 几种与高氨血症相关的罕见先天性疾病，通常是 耐火。该研究的成功结论也可能为该研究提供理由 调查复杂的其他疾病和病症 高氨血症，包括不同病因的肝衰竭和丙戊酸治疗 酸。卡巴格鲁赠款叙述 血液中氨含量升高会导致脑损伤、发育障碍 残疾，并且可能是致命的。 N-乙酰谷氨酸（NAG）是肝脏中的一种小分子 这对于尿素循环至关重要，使血氨水平保持在低于正常水平的水平 对大脑有毒。我们有理由相信 N-氨甲酰谷氨酸 (Carbaglu) 与 NAG 非常相似的化学物质，但与 NAG 不同的是它不会在体内分解， 可以模仿 NAG 的效果，降低多种疾病患者的氨水平 遗传性代谢疾病。该项目将调查Carbaglu是否可以改进 与高氨相关的 5 种不同遗传病患者的尿素循环 水平。如果结果证实了我们的假设，这些患者可以接受 Carbaglu 治疗 使他们的氨水平保持在正常或接近正常水平，保护他们免受 脑损伤。