Dipstick Assay for Detection of Acetaminophen Protein Adducts

用于检测对乙酰氨基酚蛋白加合物的试纸测定

• 批准号: 8013387
• 负责人: Laura P James
• 金额: $ 8.9万
• 依托单位: ACETAMINOPHEN TOXICITY DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013387
• 关键词: Acetaminophen; Acute; Acute Liver Failure; Affect; Alanine; Aminophenols; Antibodies; Arkansas; Aspartate Transaminase; Binding; Biological Assay; Biological Markers; Blood; Cessation of life; Chronic; Clinical; Clinical Trials; Cysteine; Cytolysis; Decision Making; Densitometry; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diagnostic tests; Dose; Early identification; End Point Assay; Epitopes; Evaluation; Exposure to; Fever; Funding; Future; Gestures; Goals; Gold; Great Britain; Hepatic; Hepatocyte; Hepatotoxicity; High Pressure Liquid Chromatography; Hospitals; Hour; Human; Imines; Individual; Ingestion; Injury; Label; Laboratories; Laboratory Research; Lateral; Lead; Liver; Measurement; Mediating; Medical; Medical center; Membrane; Morbidity - disease rate; Nomograms; Overdose; Pain; Parents; Patient Care; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phase; Poison Control Centers; Poisoning; Positioning Attribute; Preparation; Proteins; Recording of previous events; Relative (related person); Research Institute; Risk; Sampling; Sensitivity and Specificity; Serum; Small Business Technology Transfer Research; Telephone; Testing; Therapeutic; Time; Toxic effect; Toxicant exposure; Transaminases; United States; United States Food and Drug Administration; Validation; Visual; acetaminophen overdose; adduct; analytical method; base; clinical efficacy; commercialization; comparative; hospital laboratories; improved; mortality; nanoparticulate; p-Benzoquinones; para-benzoquinone; peripheral blood; point of care; prototype; public health relevance; research clinical testing; suicidal

DESCRIPTION (provided by applicant): The ultimate goal of this STTR proposal is to develop a rapid, sensitive, and specific diagnostic test that can identify acetaminophen (APAP) protein adducts in human sera. APAP toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain today. Toxicity is mediated by conversion of the parent drug to a reactive metabolite that covalently binds to protein as APAP-protein adducts. APAP-protein adducts appear in serum as a result of the toxicity and are an excellent biomarker of toxicity. The diagnosis of acute APAP overdose is currently made by determination of the APAP level in serum within 24 hours of receiving the toxic dose, or by elevation of hepatic transaminases in serum, accompanied by a history of toxic dosing. This approach has numerous limitations and the elevation of hepatic transaminases is nonspecific. Acetaminophen Toxicity Diagnostics, LLC will test the hypothesis is that APAP-protein adducts can be determined using an antibody-based dipstick assay. This will be accomplished through the following Specific Aims: 1): Develop a rapid prototype dipstick assay for determination of APAP-protein adducts. 2): Demonstrate the diagnostic sensitivity and specificity of the prototype dipstick assay for detection of APAP- protein adducts in the serum of APAP overdose victims. Results of the dipstick assay will be compared to "in parallel" examination of APAP protein adducts using an established high performance liquid chromatography assay with electrochemical detection. Development of a sensitive and rapid assay for APAP-protein adducts will enhance the diagnosis of APAP poisoning in clinical settings and lead to the earlier identification of individuals at risk for severe liver toxicity, thus reducing morbidity and mortality. PUBLIC HEALTH RELEVANCE: Overdoses of acetaminophen are a major cause of acute liver failure in the United States today. Acetaminophen is the major ingredient in many over- the - counter products sold for the treatment of pain and fever. Acetaminophen protein adducts are known blood markers of liver injury from acetaminophen. Measurement of acetaminophen protein adducts will help make the diagnosis of acetaminophen-related liver injury in patients that present to medical centers 24 hours after the overdose has occurred. This is a time period when the existing diagnostic test is not reliable. Also, measurement of acetaminophen protein adducts can be used in patients whose history of acetaminophen use is unclear or who have acute liver failure from unknown causes, This project will develop a rapid clinical test for measurement of acetaminophen protein adducts that can be used in local hospital laboratories and will affect the overall medical care of patients by improving the diagnosis and recognition of acetaminophen efforts and will reduce future deaths from acetaminophen toxicity.

描述（由申请人提供）：本STTR提案的最终目标是开发一种快速、灵敏和特异的诊断测试，可以识别人血清中的对乙酰氨基酚（APAP）蛋白加合物。APAP毒性是当今美国和英国急性肝衰竭（ALF）的最常见原因。毒性通过母体药物转化为与蛋白质共价结合的活性代谢产物（APAP-蛋白加合物）介导。APAP-蛋白加合物作为毒性的结果出现在血清中，并且是毒性的极好生物标志物。急性APAP过量的诊断目前是通过在接受毒性剂量后24小时内测定血清中的APAP水平，或通过血清中肝转氨酶升高，伴有毒性给药史来进行的。这种方法有许多局限性，肝转氨酶升高是非特异性的。对乙酰氨基酚毒性诊断有限责任公司将检验APAP-蛋白加合物可使用基于抗体的试纸测定法测定的假设。这将通过以下具体目标来实现：1）：开发用于测定APAP-蛋白加合物的快速原型试纸测定法。2）、证明原型试纸检测法用于检测APAP过量受害者血清中APAP-蛋白加合物的诊断灵敏度和特异性。将试纸条试验的结果与使用已建立的高效液相色谱法和电化学检测法对APAP蛋白加合物进行的“平行”检查进行比较。APAP-蛋白加合物的灵敏和快速检测的发展将提高APAP中毒的临床诊断，并导致早期识别的严修在严重的肝毒性的风险，从而降低发病率和死亡率。 公共卫生相关性：过量的对乙酰氨基酚是当今美国急性肝衰竭的主要原因。 醋氨酚是许多治疗疼痛和发烧的非处方药的主要成分。 对乙酰氨基酚蛋白加合物是已知的对乙酰氨基酚肝损伤的血液标志物。 对乙酰氨基酚蛋白加合物的测量将有助于在发生过量后24小时到医疗中心就诊的患者中诊断与对乙酰氨基酚相关的肝损伤。 这是现有诊断测试不可靠的时间段。 此外，对乙酰氨基酚蛋白加合物的测量可用于对乙酰氨基酚使用史不清楚或患有不明原因的急性肝衰竭的患者，该项目将开发一种用于测量对乙酰氨基酚蛋白加合物的快速临床测试，可用于当地医院实验室，并将通过改善对乙酰氨基酚的诊断和识别努力来影响患者的整体医疗护理，并将减少对乙酰氨基酚中毒导致的死亡

项目成果

Acute liver failure after recommended doses of acetaminophen in patients with myopathies.

肌病患者服用推荐剂量的对乙酰氨基酚后出现急性肝功能衰竭。

• DOI: 10.1097/ccm.0b013e318206cc8f
• 发表时间: 2011
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Ceelie,Ilse;James,LauraP;Gijsen,Violette;Mathot,RonAA;Ito,Shinya;Tesselaar,CoranneD;Tibboel,Dick;Koren,Gideon;deWildt,SaskiaN
• 通讯作者: deWildt,SaskiaN