N-carbamylglutamate in the treatment of hyperammonemia

摘要 我们的总体目标是确定N-氨基甲酰-L-谷氨酸的短期疗效 (NCG)用于治疗引起高氨血症的五种先天性代谢错误 以及随之而来的脑损伤：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)， 甲基丙二酸血症与高胰岛素血症和高氨血症综合征 (HHS)。 我们的具体目标是： 1.确定用NCG治疗3天是否改善或恢复尿失禁。 ~(13)C证实的NAGS缺乏、CPSI缺乏、PA、MMA和HHS患者 加入尿素后，血氨、尿素和氨基酸浓度以及 磁共振光谱学测定脑谷氨酰胺浓度。这个 将这五种遗传性疾病患者的结果分别与 取自健康成年志愿者(正常对照)。此外，患者的结果 患有NAGS缺乏症的人，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，以衡量他们的矫正程度 尿失禁对NCG的反应。 2.评价健康人群短期(3天)服用NCG的安全性 志愿者和病人。临床和实验室安全参数将进行全面评估 参与者，包括特殊症状和血细胞计数和肝脏和 肾功能。 我们的假设是，NCG将改善这些先天性尿失禁患者 精神错乱。这一建议将为新的治疗方法提供重要的疗效数据。 几种罕见的先天性疾病，与高氨血症有关，通常是 耐火材料。这项研究的成功结束也可能为 对其他因以下原因而复杂化的疾病和情况进行调查 高氨血症，包括各种病因的肝功能衰竭和丙戊酸治疗 酸。Carbaglu Grant叙事 血液中氨的水平升高会导致大脑损伤，发育 残疾，这可能是致命的。N-乙酰谷氨酸(NAG)是肝脏中的一种小分子 这对于尿素循环是至关重要的，将血氨水平保持在 对大脑有毒性。我们有理由相信N-氨基甲酸酯(Carbaglu)，一种 一种与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的效果来降低患者的血氨水平 遗传性代谢疾病。该项目将调查Carbaglu是否可以改进 5种不同遗传性疾病高氨血症患者的尿素循环 级别。如果结果证实了我们的假设，这些患者可以用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 脑部受损。

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.