N-carbamylglutamate in the treatment of hyperammonemia

描述（由申请人提供）：本申请的总体目标是确定N-氨甲酰基-L-谷氨酸盐（NCG）治疗引起高氨血症和随后脑损伤的五种先天性代谢缺陷的短期疗效：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（HHS）。 具体目标1是确定NCG治疗3天是否改善或恢复NAGS缺乏症、CPSI缺乏症、PA、MMA和HHS患者的尿素生成，如通过13 C掺入尿素、血浆氨、尿素和氨基酸浓度以及通过磁共振波谱测量的脑谷氨酰胺浓度所证明的。 将五种遗传性疾病患者的结果与健康成人志愿者（正常对照）的结果进行比较。 此外，将研究者预期对NCG反应最好的NAGS缺乏症患者（阳性对照）的结果与其他四种疾病的结果进行比较，以评估其对NCG反应的尿素生成纠正程度。 具体目标2是在健康志愿者和患者中评价NCG短期（3天）治疗的安全性。 将在所有受试者中评价临床和实验室安全性参数，包括特异质症状和血细胞计数以及肝肾功能的变化。 研究者的假设是NCG将改善这些先天性疾病中的尿素生成不足。 因此，本申请将为几种罕见先天性疾病的新治疗提供重要的疗效数据，这些疾病与通常难治性的高氨血症相关。 本研究的成功结论也可能为研究其他并发高氨血症的疾病和病症提供依据，包括不同病因的肝衰竭和丙戊酸治疗。

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.