Biomarkers of adverse responses to acetaminophen in children and adolescents

儿童和青少年对乙酰氨基酚不良反应的生物标志物

• 批准号: 8252206
• 负责人: Laura P James
• 金额: $ 37.41万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252206
• 关键词: Acetaminophen; Acetylcysteine; Acute; Acute Liver Failure; Address; Adolescent; Adult; Antidotes; Binding; Biological Assay; Biological Markers; Categories; Characteristics; Child; Child health care; Childhood; Citric Acid Cycle; Clinical; Clinical Markers; Data; Data Analyses; Detection; Development; Dose; Drug Kinetics; Drug usage; Evaluation; Exposure to; Fever; Foundations; Future; Generations; Glutathione; Hepatic; Hepatotoxicity; High Pressure Liquid Chromatography; Hospitalized Child; Human Development; Imines; Immune Sera; Injury; Institutes; Knowledge; Lead; Liver; Mass Spectrum Analysis; Measurement; Measures; Metabolic Biotransformation; Methods; Molecular; Nomograms; One-Step dentin bonding system; Overdose; Oxidation-Reduction; Pain; Parents; Patients; Pharmaceutical Preparations; Population; Populations at Risk; Proteins; Proteomics; Rattus; Relative (related person); Research; Risk; Risk Assessment; Role; Safety; Sampling; Sampling Studies; Site; Specificity; Staging; Sulfhydryl Compounds; Terminology; Testing; Therapeutic; Time; To specify; Toxic effect; Toxicant exposure; Toxicity Tests; Transaminases; United States; Work; acetaminophen overdose; adduct; base; improved; indexing; metabolomics; p-Benzoquinones; para-benzoquinone; pediatric pharmacology; peripheral blood; response; sample collection

Acetaminophen (APAP) is the most common drug used for the treatment of pain and fever in the world today and is also the leading cause of acute liver failure in the United States. The initial stages of APAP toxicity have been well-characterized and involve the biotransformation of the parent drug to a chemically reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which binds covalently to cellular proteins. NAPQI is detoxified by binding to the cysteinyl thiol on hepatic glutathione (GSH). In toxic APAP exposures, GSH reserves are depleted, increasing the amount of NAPQI that binds to cysteinyl thiols on cellular proteins, producing a variety of APAP-protein adducts. The lead site for this proposal pioneered the measurement of total APAP-protein adducts (APAP-ADDUCTS) as clinical markers of APAP toxicity and tested this biomarker in children and adults with acute APAP overdose, APAP-related acute liver failure, and recently, in patients receiving recommended doses of APAP. In adults receiving recommended doses of APAP, low levels of APAP-ADDUCTS were detected and an association was found for higher APAP- ADDUCT levels and higher elevated transaminase values levels in these patients. Based on our recent data, the following hypotheseis will be tested;. In children and adolescents with APAP exposures, (1) APAP-ADDUCTS will be detected in hospitalized children receiving therapeutic exposures, (2) unique and specific APAP adduct proteins exist and differ as a function of the magnitude of APAP exposure and, (3) unique protein adducts will correspond with established measures and co- variates of APAP toxicity. Using state-of-the-art, adduct-focused proteomic approaches, the following proposal will identify and evaluateexamine specific "second generation" biomarkers of APAP toxicity in children/adolescents receiving therapeutic doses of APAP and in children/adolescents that have received overdoses of APAP. Pediatric academic centers participating in the Network of Pediatric Pharmacology Research Units (PPRU; National Institutes of Child Health and Human Development) will assist with clinical sample collection and analytical and pharmacokinetic data analysis. Identification of specific APAP protein adducts and examination of these specific adducts relative to newly described metabolomic markers of APAP toxicity and established indices of liver toxicity will lay the foundation for improved future assessments of risk and safety for APAP in children and adolescents.

对乙酰氨基酚 (APAP) 是世界上最常用的治疗疼痛和发烧的药物 今天，也是美国急性肝衰竭的主要原因。 APAP的初始阶段 毒性已得到充分表征，涉及母体药物生物转化为化学物质 反应性代谢物 N-乙酰基-对苯醌亚胺 (NAPQI)，与细胞蛋白质共价结合。 NAPQI 通过与肝谷胱甘肽 (GSH) 上的半胱氨酰硫醇结合而解毒。有毒 APAP 中 暴露后，GSH 储备耗尽，增加了与半胱氨酰硫醇结合的 NAPQI 量 细胞蛋白，产生多种 APAP 蛋白加合物。该提案的主要网站开创了 测量总 APAP-蛋白加合物 (APAP-ADDUCTS) 作为 APAP 毒性的临床标志物 在患有急性 APAP 过量、APAP 相关急性肝功能衰竭的儿童和成人中测试了该生物标志物， 最近，在接受推荐剂量的 APAP 的患者中。接受推荐剂量的成人 的 APAP 中，检测到低水平的 APAP-ADDUCTS，并且发现与较高的 APAP-ADDUCTS 存在关联。 这些患者的 ADDUCT 水平和较高的转氨酶值水平。根据我们最近 数据，将检验以下假设；在接触 APAP 的儿童和青少年中，(1) APAP-ADDUCTS 将在接受治疗暴露的住院儿童中检测到，(2) 存在独特且特异的 APAP 加合物蛋白，并且其不同之处在于 APAP 大小的函数 暴露，（3）独特的蛋白质加合物将符合既定的措施和共同 APAP 毒性的变化。使用最先进的、以加合物为重点的蛋白质组学方法，以下 该提案将识别和评估检查 APAP 毒性的特定“第二代”生物标志物 接受治疗剂量的 APAP 的儿童/青少年以及接受过治疗剂量的儿童/青少年 APAP 过量。参与儿科药理学网络的儿科学术中心 研究单位（PPRU；国家儿童健康和人类发展研究所）将协助临床 样品收集以及分析和药代动力学数据分析。特定 APAP 蛋白的鉴定 加合物和这些特定加合物相对于新描述的代谢组标记物的检查 APAP 毒性和已建立的肝毒性指标将为改善未来奠定基础 儿童和青少年 APAP 的风险和安全性评估。