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）：该 STTR 提案的最终目标是开发一种快速、灵敏且特异的诊断测试，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。毒性是通过母体药物转化为反应性代谢物介导的，该代谢物以 APAP-蛋白质加合物的形式与蛋白质共价结合。由于毒性，APAP 蛋白加合物出现在血清中，是一种极好的毒性生物标志物。目前，急性 APAP 过量的诊断是通过在接受中毒剂量后 24 小时内测定血清中 APAP 水平，或通过血清中肝转氨酶升高并伴有中毒用药史来进行的。这种方法有许多局限性，并且肝转氨酶的升高是非特异性的。 Acetaminophen Toxicity Diagnostics, LLC 将测试以下假设：APAP-蛋白质加合物可以使用基于抗体的试纸测定法进行测定。这将通过以下具体目标来实现： 1)：开发快速原型试纸测定法，用于测定 APAP-蛋白质加合物。 2)：展示用于检测 APAP 过量受害者血清中 APAP 蛋白加合物的原型试纸测定的诊断灵敏度和特异性。试纸测定的结果将与使用已建立的带有电化学检测的高效液相色谱测定的 APAP 蛋白加合物的“平行”检查进行比较。开发一种灵敏、快速的 APAP 蛋白加合物检测方法将增强临床环境中 APAP 中毒的诊断，并有助于及早识别存在严重肝毒性风险的个体，从而降低发病率和死亡率。 公共卫生相关性：过量服用对乙酰氨基酚是当今美国急性肝衰竭的主要原因。 对乙酰氨基酚是许多用于治疗疼痛和发烧的非处方产品的主要成分。 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对服药过量 24 小时后到医疗中心就诊的患者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期。 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不明原因急性肝功能衰竭的患者，该项目将开发一种可在当地医院使用的对乙酰氨基酚蛋白加合物测量的快速临床测试实验室，并将通过改善对乙酰氨基酚的诊断和认识来影响患者的整体医疗护理，并将减少未来因对乙酰氨基酚中毒而导致的死亡。

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

Isoniazid hepatotoxicity: progress in understanding the immunologic component.

• DOI: 10.1002/hep.26707
• 发表时间: 2014-03
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: James, Laura;Roberts, Dean
• 通讯作者: Roberts, Dean