Comparative Efficacy of Phenylbutyrate vs. Benzoate in Urea Cycle Disorders

描述(由申请人提供)：尿素循环障碍(UCD)患者肝脏解毒能力下降导致高氨血症，导致易怒、嗜睡、脑水肿、癫痫发作和昏迷，可能导致死亡。目前治疗代谢紊乱的临床实践依赖于限制饮食蛋白质和服用苯甲酸钠或苯丁酸钠，这两种药物可以引发氮处理的替代途径。目前还没有对这两种药物结合氨基酸、排氮和降低血氨的能力进行直接比较。尽管缺乏关于这些药物的比较疗效的数据，苯丁酸钠通常是首选，尽管其成本是苯甲酸钠的约350倍。 这项赠款申请结合了临床、临床前和示踪动力学研究，以调查和比较苯甲酸钠和苯丁酸钠在结合氮化合物和控制餐后血氨方面的能力。~(13)C标记药物类似物的使用将允许在接受慢性药物治疗的UCD受试者中测定这些药物的经典药代动力学和结合效率。此外，15N标记的膳食蛋白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。生成的数据将首次允许对这两种药物进行直接比较。由于这些药物的价格不同(苯甲酸盐~250美元，苯丁酸苯酯90,000美元/年，70公斤患者/年)，以及这些患者的生存期和预期寿命的延长，所获得的知识将对设计具有成本效益的UCD患者的代谢管理至关重要。如果发现两种药物之间没有太大差异，用苯甲酸钠部分或全部取代苯丁酸钠有可能在不影响护理质量的情况下降低代谢管理的成本。

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.