Comparative Efficacy of Phenylbutyrate vs. Benzoate in Urea Cycle Disorders

描述（由申请方提供）：尿素循环障碍（UCD）患者的肝脏氨解毒能力降低，导致高氨血症，导致易激惹、嗜睡、脑水肿、癫痫发作和昏迷，可导致死亡。目前的临床实践代谢管理的障碍取决于饮食蛋白质的限制和苯甲酸钠或苯丁酸钠，药物，引发替代途径的氮处置的管理。 尚未直接比较这两种药物结合氨基酸、排泄氮和降低血浆氨的能力。尽管缺乏关于这些药物的比较疗效的数据，但苯丁酸钠通常是首选，尽管其成本比苯甲酸钠高约350倍。 该授权申请结合了临床，临床前和示踪动力学研究，以研究比较苯甲酸钠和苯丁酸钠结合含氮化合物和控制餐后血浆氨的能力。利用13 C标记的药物类似物将允许确定这些药物在接受慢性药物治疗的UCD受试者中的经典药代动力学和偶联效率。此外，15 N标记的膳食蛋白质将使我们能够确定这两种药物结合和排泄的氮（内源性或膳食）的来源。 所产生的数据将首次允许对两种药物进行直接比较。由于这些药物的成本差异（苯甲酸盐约250美元，苯丁酸盐90，000美元，70公斤患者/年）以及这些患者的生存率和预期寿命的增加，所获得的知识对于设计具有成本效益的UCD患者代谢管理至关重要。如果两种药物之间没有发现大的差异，苯甲酸钠部分或全部取代苯丁酸钠有可能降低代谢管理的成本，而不影响护理质量。

DESCRIPTION (provided by applicant): The reduction in the hepatic capacity to detoxify ammonia in Urea Cycle Disorders (UCD) patients results in hyperammonemia that causes irritability, lethargy, cerebral edema, seizures and coma that can lead to death. Current clinical practice for the metabolic management of the disorders depends on dietary protein restriction and the administration of sodium benzoate or sodium phenylbutyrate, drugs that elicit alternative pathways for nitrogen disposal. There has been no direct comparison of the ability of these two drugs to conjugate amino acids, excrete nitrogen and reduce plasma ammonia. Despite the lack of data regarding the comparative efficacy of these drugs, sodium phenylbutyrate is usually the preferred option despite the fact that its cost is ~350 fold greater than that of sodium benzoate. This grant application combines clinical, preclinical and tracer kinetics studies to investigate an compare sodium benzoate and sodium phenylbutyrate in their abilities to conjugate nitrogenous compounds and control plasma ammonia after a meal. The utilization of 13C labeled drug analogues will allow for the determination of classical pharmacokinetics and conjugation efficiency of these drugs in UCD subjects undergoing chronic drug therapy. In addition, 15N labeled dietary protein will allow us to establish the source of the nitrogen (endogenous or dietary) conjugated and excreted by these two drugs. The data generated will, for the first time, allow a direct comparison between the two drugs. Due to differences in the cost of these drugs (benzoate ~$250, phenylbutyrate $90,000 for a 70 kg patient/year) and the increased survival and longer life expectancy of these patients, the knowledge gained will be crucial to devise cost effective metabolic management of patients with UCD. If no large differences between the two drugs are found, the partial or total replacement of sodium phenylbutyrate with sodium benzoate has the potential to reduce the cost of metabolic management without compromising the quality of care.