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