N-carbamylglutamate in the treatment of hyperammonemia

描述(申请人提供)：本申请的总体目标是确定N-氨基甲酰-L-谷氨酸(NCG)治疗五种导致高氨血症和继发性脑损伤的先天性代谢错误的短期疗效：N-乙酰谷氨酸合成酶(NAGS)缺乏、氨基甲酰磷酸合成酶I(CPSI)缺乏、丙酸血症(PA)、甲基丙二酸血症(MMA)以及高胰岛素和高氨血症综合征(HHS)。 具体目的1是确定三天的NCG治疗是否改善或恢复NAGS缺乏、CPSI缺乏、PA、MMA和HHS患者的尿失禁，这一点通过13C掺入尿素、血浆氨、尿素和氨基酸浓度以及磁共振波谱测量的脑谷氨酰胺浓度来证实。这五种遗传性疾病患者的结果将与健康成年志愿者(正常对照组)的结果进行比较。此外，研究人员预计对NCG(阳性对照)反应最好的NAGS缺乏症患者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反应的尿失禁纠正程度。具体目的2是评估NCG短期(三天)治疗健康志愿者和患者的安全性。临床和实验室安全参数将在所有参与者中进行评估，包括特殊症状和血细胞计数以及肝和肾功能的变化。 研究人员的假设是，NCG将改善这些先天性疾病中缺陷的尿失禁。因此，这一应用将为几种罕见的先天性疾病的新治疗提供重要的疗效数据，这些疾病与通常难以治愈的高氨血症有关。这项研究的成功结束也可能为研究高氨血症并发的其他疾病和状况提供理论基础，包括各种病因的肝功能衰竭和丙戊酸治疗。

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.