Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.
Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.
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DOI：
10.1016/j.ymgme.2013.09.017
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发表时间：
2013-12
影响因子：
3.8
通讯作者：
Scharschmidt, B. F.
中科院分区：
文献类型：
--
作者：
Mokhtarani, M.;Diaz, G. A.;Rhead, W.;Berry, S. A.;Lichter-Konecki, U.;Feigenbaum, A.;Schulze, A.;Longo, N.;Bartley, J.;Berquist, W.;Gallagher, R.;Smith, W.;McCandless, S. E.;Harding, C.;Rockey, D. C.;Vierling, J. M.;Mantry, P.;Ghabril, M.;Brown, R. S., Jr.;Dickinson, K.;Moors, T.;Norris, C.;Coakley, D.;Milikien, D. A.;Nagamani, S. C.;LeMons, C.;Lee, B.;Scharschmidt, B. F.
苯乙酸（PAA）是苯丁酸钠（NaPBA）和苯丁酸甘油酯（GPB，HPN-100）的活性部分，两者均获批用于治疗尿素循环障碍（UCD）-以高氨血症为特征的罕见遗传性疾病。PAA在肝脏中与谷氨酰胺结合形成苯乙酰谷氨酰胺（PAGN），经尿液排泄。据报告，PAA血浆水平≥500 μg/dL与接受PAA静脉给药的癌症患者的可逆性神经系统不良事件（AE）相关。因此，我们研究了接受这些PAA前体药物治疗的患者中PAA水平与神经系统AE之间的关系，以及确定最有可能发生高PAA水平患者的方法。在4683份连续采集的血液样本中检查了神经系统AE、PAA水平和血浆PAA/PAGN比值之间的关系：[1]健康成人[2]、年龄≥2个月的UCD患者和[3]肝硬化和肝性脑病（HE）患者。分析了PAA与PAGN的血浆比值在识别具有高PAA值风险的患者中的效用。4683份样品中只有0.2%（11份）超过500 μ g/ml。在UCD或HE患者中，神经系统AE与PAA水平之间无相关性，但在健康成人中观察到与PAA水平相关的一过性AE，包括头痛和恶心。不考虑人群，在PAA水平和血浆PAA：PAGN比率之间观察到曲线关系，并且在随机抽血中比率> 2.5（均以μg/mL计）鉴定处于PAA水平> 500 μg/ml的风险中的患者。健康成人中PAA水平与可逆性AE之间存在相关性，但UCD或HE患者中不存在相关性，这可能反映了人群之间的内在差异和/或持续给药的代谢适应性。血浆PAA：PAGN比率是PAA代谢速率的功能性量度，并且代表有用的给药生物标志物。
Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100), both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients ≥2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. Only 0.2% (11) of 4683 samples exceeded 500 ug/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio > 2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels > 500 μg/ml. The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.
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影响因子：
2.9
作者：
PISCITELLI, SC;THIBAULT, A;MYERS, CE
通讯作者：
MYERS, CE
影响因子：
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作者：
LIANG, KY;ZEGER, SL
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作者：
COLLINS, AF;PEARSON, HA;DOVER, GJ
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影响因子：
3.8
作者：
Lichter-Konecki U;Diaz GA;Merritt JL 2nd;Feigenbaum A;Jomphe C;Marier JF;Beliveau M;Mauney J;Dickinson K;Martinez A;Mokhtarani M;Scharschmidt B;Rhead W
通讯作者：
Rhead W