Acetaminophen (APAP) is the most commonly used drug for the treatment of pain and fever in the world today. In large doses, APAP causes acute liver failure and is the leading cause of acute liver failure in the US. The current laboratory test for the diagnosis of APAP toxicity, measurement of APAP levels in peripheral blood, is only effective in the first 24 hours of APAP overdose. Acetaminophen Toxicity Diagnostics (ATD), LLC has developed a rapid, point-of-care diagnostic assay (dipstick) for the measurement of APAP protein adducts. Adducts are sensitive and specific biomarkers of APAP hepatotoxicity that may be detected in peripheral blood 6 to 7 days after a toxic overdose of APAP. The dipstick detects APAP irreversibly bound to proteins (APAP protein adducts) by using antibodies specific for adducts in the detection system. The dipstick is reliable, accurate and provides rapid results.
In Specific Aim 1, the dipstick will be calibrated to detect levels of APAP protein adducts corresponding to severe liver toxicity and 2000 precision manufactured, research use dipsticks will be produced.
In Specific Aim 2, the dipsticks will be tested internally for stability, specificity, and diagnostic sensitivity using stored, frozen clinical samples.
In Specific Aim 3, six major hepatology centers will participate in a study to measure dipstick performance in patients with acute liver injury and acute liver failure. Successful completion of these aims will establish the clinical utility of the dipstick, an innovation that will enhance the diagnosis of APAP toxicity.

Public Health Relevance

Acetaminophen is the most widely used drug for the treatment of pain and fever around the world. Large doses of acetaminophen can cause acute liver failure and death. Diagnostic tests are needed for patients that have acetaminophen related liver injury. The current laboratory test only works in the first 24 hours after acetaminophen overdose. Acetaminophen Toxicity Diagnostics, LLC has developed a rapid dipstick test that measures biomarkers of acetaminophen liver injury. These biomarkers (known as acetaminophen protein adducts) can be measured in the blood samples of patients with acetaminophen related liver injury for 6 to 7 days after the overdose. This project will further develop the dipstick test so that it can be available to physicians in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
5R42DK079387-04
Application #
8303380
Study Section
Special Emphasis Panel (ZRG1-DKUS-E (10))
Program Officer
Densmore, Christine L
Project Start
2007-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$698,788
Indirect Cost
Name
Acetaminophen Toxicity Diagnostics, LLC
Department
Type
DUNS #
785893095
City
Little Rock
State
AR
Country
United States
Zip Code
72202
James, Laura P; Chiew, Angela; Abdel-Rahman, Susan M et al. (2013) Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations. Eur J Clin Pharmacol 69:851-7
James, Laura P; Gill, Prit; Simpson, Pippa (2013) Predicting risk in patients with acetaminophen overdose. Expert Rev Gastroenterol Hepatol 7:509-12