Glycerol phenylbutyrate treatment in children with urea cycle disorders: Pooled analysis of short and long-term ammonia control and outcomes
Glycerol phenylbutyrate treatment in children with urea cycle disorders: Pooled analysis of short and long-term ammonia control and outcomes
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DOI：
10.1016/j.ymgme.2014.02.007
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发表时间：
2014-05-01
影响因子：
3.8
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Berry, Susan A.;Lichter-Konecki, Uta;Lee, Brendan
目的：评估苯丁酸甘油酯 (GPB) 治疗尿素循环障碍 (UCD) 儿科患者的效果。研究设计：在两项短期、开放标签交叉研究中，对 2 个月至 17 岁的 UCD 患者 (n = 26) 使用 GPB 和苯丁酸钠 (NaPBA) 进行治疗，比较了等效稳态期间的 24 小时氨暴露 (AUC(0-24)) 和谷氨酰胺水平GPB 和苯丁酸钠 (NaPBA) 的剂量。这 26 名患者加上另外 23 名患者也在三项为期 12 个月的开放标签扩展研究之一中接受了 GPB，该研究评估了长期氨控制、高氨血症 (HA) 危机、氨基酸水平和患者生长。 结果：在每项单独的交叉研究中，GPB 的平均氨暴露不劣于 NaPBA。在汇总分析中，GPB 显着低于 NaPBA（平均 [SD] AUC(0-24)：627 [302] vs. 872 [516] mu mol/L；p = 0.008），异常值显着减少（GPB 为 15%，NaPBA 为 35%；p = 0.02）。在 GPB 给药的 12 个月内，平均氨水平保持在正常范围内，并且与入组前 12 个月相比，经历 HA 危机的患者比例较小（24.5% vs. 42.9%）较少（17 vs. 38）。短期给药期间，GPB 的谷氨酰胺水平往往低于 NaPBA（平均 [SD]：660.8 [164.4] vs. 710.0 [158.7] mu mol/L；p = 0.114），并且在 GPB 给药的 12 个月期间，平均谷氨酰胺和支链氨基酸以及其他必需氨基酸水平保持在正常范围内。基线时平均身高和体重 Z 分数在正常范围内，并且在 GPB 治疗期间没有显着变化。结论：GPB 给药与 24 小时氨暴露相关，在个别研究中，该值不劣于 NaPBA 给药期间，并且在汇总分析中显着较低。与入组前 12 个月相比，长期 GPB 给药与正常水平的谷氨酰胺和必需氨基酸（包括支链氨基酸）、适龄生长和较少的 HA 危机相关。 (C) 2014 Elsevier Inc. 保留所有权利。
Objective: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs).Study design: UCD patients (n = 26) ages 2 months through 17 years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC(0-24)) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth.Results: Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC(0-24): 627 [302] vs. 872 [516] mu mol/L; p = 0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p = 0.02). Mean ammonia levels remained within the normal range during 12 months of GPB dosing and, when compared with the 12 months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] mu mol/L; p = 0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12 months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12 months of GPB treatment.Conclusions: Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12 month period preceding enrollment. (C) 2014 Elsevier Inc. All rights reserved.