N-CARBAMYLGLUTAMATE (CARBAGLU) IN THE TREATMENT OF HYPERAMMONEMIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 高氨血症与几种罕见的遗传性疾病相关，通常会导致智力低下、发育障碍和死亡。这项研究的总体目标是观察孤儿药物N-氨基甲酰-L-谷氨酸盐(Carbaglu，简称NCLG)治疗罕见遗传性疾病高氨血症的短期疗效和安全性。这些遗传性疾病包括氨基甲酰磷酸合成酶I缺乏症、NAGS缺乏症、丙酸血症和甲基丙二酸血症。主要目标是： 1.以尿素[~(13)C]标记掺入法和血氨、尿素、谷氨酰胺水平作为替代指标，探讨NCLG治疗3天是否能改善或恢复CPSI缺乏症患者的尿失禁能力。2.探讨应用[~(13)C]掺入法治疗PA和MMA患者是否存在尿失禁现象，以及NCLG治疗3天能否改善或恢复全部或部分患者的尿失禁能力。3.从临床和实验室指标评估NCLG短期(3天)治疗上述患者的安全性。假说是，在这四种疾病中，通过将~(13)C]掺入尿素所证明的尿失禁能力都是缺乏的，NCLG治疗将改善或恢复受它们影响的患者的尿失禁。这项研究将在华盛顿特区国家儿童医学中心的综合临床研究中心(GCRC)和费城儿童医院进行。患有这四种疾病中任何一种的患者(年龄从1天到70岁)都有资格参加这项研究。他们都将在短期试验中使用替代标记物(将[13C]标记从醋酸钠掺入尿素，以及血浆氨、尿素和谷氨酰胺水平)在NCLG治疗前和治疗后立即进行测试。患者还将使用临床和实验室参数评估NCLG的短期安全性。这项研究的结果将提供重要的疗效数据，这将有助于将Carbaglu)推向美国市场，以造福于在此试验中被发现对NCLG有反应的任何这些孤儿疾病的患者。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyperammonemia associated with several rare inherited disorders frequently causes mental retardation, developmental disabilities and death. The overall goal of this study is to investigate the short-term efficacy and safety of the orphan drug, N-Carbamyl-L-glutamate (Carbaglu , abbreviated as NCLG), for the treatment of hyperammonemia in rare inherited disorders: carbamyl phosphate synthetase I (CPSI) deficiency, NAGS deficiency, propionic acidemia (PA) and methylmalonic acidemia (MMA). The primary aims are: 1. To investigate whether 3-day treatment with NCLG can improve or restore ureagenesis capacity in patients with CPSI deficiency using as surrogate markers: [13C] label incorporation into urea and plasma levels of ammonia, urea and glutamine. 2. To investigate whether ureagenesis capacity is deficient in patients with PA and MMA using [13C] incorporation into urea and whether 3-day treatment with NCLG can improve or restore ureagenesis capacity in all or some of these patients. 3. To evaluate the safety of short-term (3-day) treatment with NCLG in the above patients using clinical and laboratory parameters. The hypothesis is that ureagenesis capacity as evidenced by [13C] incorporation into urea is deficient in each of these four disorders and that treatment with NCLG will improve or restore ureagenesis in patients affected by them. The study will be conducted in the General Clinical Research Centers (GCRC) of the Children's National Medical Center, Washington, D.C. and the Children's Hospital of Philadelphia. Patients (1 day to 70 years of age) with any of the four disorders are eligible for the study. They will all be tested in a short-term trial using surrogate markers (incorporation of [13C] label from Na-acetate into urea, and plasma levels of ammonia, urea and glutamine) before and immediately following 3 days of treatment with NCLG. The patients will also be evaluated for short-term safety of NCLG using clinical and laboratory parameters. The results of this study will provide important efficacy data, which should help to bring Carbaglu ) to the US market for the benefit of patients with any of these orphan diseases found to be responsive to NCLG in this trial.