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.

R41DK079387

2008-04-01

2011-03-31