Unexpected Late Rise in Plasma Acetaminophen Concentrations with Change in Risk Stratification in Acute Acetaminophen Overdoses

Dougherty, Patrick P.; Klein‐Schwartz, Wendy

doi:10.1016/j.jemermed.2011.05.023

Cited by 19 publications

(12 citation statements)

References 11 publications

(17 reference statements)

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“…Because 5 mM of APAP caused submaximal effects, this concentration was selected for all subsequent experiments. Importantly, the highest plasma APAP concentrations found in patients after a hepatotoxic overdose are equivalent to similar concentrations (low millimolar) . Because plasma protein binding of APAP is negligible, the in vitro concentrations can thus be directly correlated with plasma concentrations.…”

Section: Resultsmentioning

confidence: 99%

Targeting mitochondria with methylene blue protects mice against acetaminophen‐induced liver injury

et al. 2014

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Acetaminophen (APAP) overdose is a frequent cause of drug-induced liver injury and the most frequent cause of acute liver failure in the Western world. Previous studies with mouse models have revealed that impairment of mitochondrial respiration is an early event in the pathogenesis, but the exact mechanisms have remained unclear, and therapeutic approaches to specifically target mitochondria have been insufficiently explored. Here, we found that the reactive oxidative metabolite of APAP, N-acetyl-p-benzoquinoneimine (NAPQI), caused the selective inhibition of mitochondrial complex II activity by >90% in both mouse hepatic mitochondria and yeast-derived complexes reconstituted into nanoscale model membranes, as well as the decrease of succinate-driven adenosine triphosphate (ATP) biosynthesis rates. Based on these findings, we hypothesized that methylene blue (MB), a mitochondria-permeant redox-active compound that can act as an alternative electron carrier, protects against APAP-induced hepatocyte injury. We found that MB (<3 mM) readily accepted electrons from NAPQI-altered, succinate-energized complex II and transferred them to cytochrome c, restoring ATP biosynthesis rates. In cultured mouse hepatocytes, MB prevented the mitochondrial permeability transition and loss of intracellular ATP without interfering with APAP bioactivation. In male C57BL/6J mice treated with APAP (450 mg/kg, intraperitoneally [IP]), MB (10 mg/kg, IP, administered 90 minutes post-APAP) protected against hepatotoxicity, whereas mice treated with APAP alone developed massive centrilobular necrosis and increased serum alanine aminotransferase activity. APAP treatment inhibited complex II activity ex vivo, but did not alter the protein expression levels of subunits SdhA or SdhC after 4 hours. Conclusion: MB can effectively protect mice against APAP-induced liver injury by bypassing the NAPQI-altered mitochondrial complex II, thus alleviating the cellular energy crisis. Because MB is a clinically used drug, its potential application after APAP overdose in patients should be further explored. (HEPATOLOGY 2015;61:326-336)

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Section: Resultsmentioning

confidence: 99%

Targeting mitochondria with methylene blue protects mice against acetaminophen‐induced liver injury

et al. 2014

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“…ALT is the most commonly used biochemical indicator of liver injury, but lacks specificity (Amacher 1998 ; Ozer et al 2008 ). Patient histories reporting ingestion of toxic does of APAP are known to be unreliable (Dougherty and Klein-Schwartz 2012 ; Polson et al 2008 ), and many patients are unaware of the inclusion of APAP in over-the-counter medications (Wolf et al 2012 ) and prescription pain medications. Elevation of APAP levels in peripheral blood within the first 24 h of the APAP overdose is used by practicing physicians to assess the risk of liver injury and the potential need for treatment with the antidote, N -acetylcysteine (NAC).…”

Section: Introductionmentioning

confidence: 99%

Translational biomarkers of acetaminophen-induced acute liver injury

et al. 2015

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Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

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“…This finding is unexpected, given that antihistamines slow gastrointestinal motility which could reduce APAP absorption rate. Case reports [16][17][18] and case series 8,19 describe delayed peak PACs following overdoses of APAP-diphenhydramine products. However, in a prospective, randomized study of simulated APAP overdose in human volunteers, coingested diphenhydramine had no significant effect on APAP absorption.…”

Section: Discussionmentioning

confidence: 99%

“…Individuals are stratified into low or high risk for developing acute hepatotoxicity based on measured plasma acetaminophen concentrations (PACs) between 4 and 24 hours since ingestion falling below or above the Rumack–Matthew nomogram, respectively, in order to make NAC administration decisions. While the nomogram has been a staple for the management of acute APAP overdose, it has been demonstrated that the nomogram fails to predict toxicity based on a single PAC in some patients . Failure of the nomogram with an isolated PAC may be attributable to ingestion of extended‐release or combination APAP products that alter the absorption characteristics of APAP and ultimately the individual's APAP concentration–time profile .…”

Section: Study Objectivementioning

confidence: 99%

“…While the nomogram has been a staple for the management of acute APAP overdose, it has been demonstrated that the nomogram fails to predict toxicity based on a single PAC in some patients. 8 Failure of the nomogram with an isolated PAC may be attributable to ingestion of extended-release or combination APAP products that alter the absorption characteristics of APAP and ultimately the individual's APAP concentration-time profile. 9 In addition, the nomogram cannot be extrapolated earlier than 4 hours since ingestion in order to make timely treatment decisions.…”

Section: Study Objectivementioning

confidence: 99%

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Bayesian Forecasting Tool to Predict the Need for Antidote in Acute Acetaminophen Overdose

et al. 2017

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Unexpected Late Rise in Plasma Acetaminophen Concentrations with Change in Risk Stratification in Acute Acetaminophen Overdoses

Cited by 19 publications

References 11 publications

Targeting mitochondria with methylene blue protects mice against acetaminophen‐induced liver injury

Targeting mitochondria with methylene blue protects mice against acetaminophen‐induced liver injury

Translational biomarkers of acetaminophen-induced acute liver injury

Bayesian Forecasting Tool to Predict the Need for Antidote in Acute Acetaminophen Overdose

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