Center for Clinical Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA.
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA.
Crit Care Med. 2018 Sep;46(9):1471-1479. doi: 10.1097/CCM.0000000000003203.
To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment.
Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009).
Thirty-six-bed PICU in a university-affiliated children's hospital.
Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects.
Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube.
The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation.
This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.
运用基于代谢组学的途径和网络分析方法，评估儿童严重创伤性脑损伤后脑脊液代谢组学的变化，并评估丙磺舒联合 N-乙酰半胱氨酸治疗相对于安慰剂治疗对谷胱甘肽相关途径和其他途径及网络的影响。
对一项已完成的丙磺舒联合 N-乙酰半胱氨酸治疗严重创伤性脑损伤的多中心、随机、安慰剂对照临床试验（注册号：NCT01322009）中获得的脑脊液进行分析。
一所大学附属儿童医院的 36 张病床的儿科重症监护病房（PICU）。
12 例年龄 2-18 岁的严重创伤性脑损伤患儿和 5 例年龄匹配的对照患儿。
丙磺舒（25mg/kg）和 N-乙酰半胱氨酸（140mg/kg）或安慰剂通过鼻胃管给予。
在药物或安慰剂治疗后 24 小时及对照组中，对创伤性脑损伤患者的脑脊液代谢组学进行分析。采用 XCMS-online 进行特征检测、保留时间、对齐、注释和主成分分析及统计分析。采用“mummichog”软件进行途径和网络分析。双组分主成分分析显示，每组均聚类，具有明显的代谢组学特征。确定了几个可能与创伤性脑损伤有机制关联的新途径。代谢组学与途径/网络分析相结合，显示丙磺舒联合 N-乙酰半胱氨酸治疗组患者脑脊液中有 7 个谷胱甘肽中心途径和 2 个网络富集，而安慰剂治疗组患者则无。还确定了几个包含丙磺舒抑制转运体已知底物的其他途径/网络，提供了额外的机制验证。
本概念验证神经药代代谢组学评估揭示了已知和以前未识别的代谢途径的改变，并支持丙磺舒联合 N-乙酰半胱氨酸治疗儿童严重创伤性脑损伤的治疗靶点。
