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Acetaminophen overdose

Anup Ramachandran, Hartmut Jaeschke
Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity...
March 8, 2019: Seminars in Liver Disease
Hongli Guo, Jieyu Sun, Deyi Li, Yahui Hu, Xiaowen Yu, Hu Hua, Xia Jing, Feng Chen, Zhanjun Jia, Jing Xu
Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines...
February 25, 2019: Biomedicine & Pharmacotherapy
Timothy Vo, Caroline Ledbetter, Matthew Zuckerman
OBJECTIVES: Advances in technology have brought with them innovations in delivery of medical educational content; for example, audio and video podcasts, flipped classroom learning, and e-books. These new modalities may be useful for delivery of content asynchronously, as an adjunct to traditional lecture-based and bedside clinical teaching. Here, we measured the differences in knowledge acquisition between medical students using a video-based content delivery method and students using a traditional method of asynchronous content delivery (a textbook chapter)...
February 26, 2019: Clinical Toxicology
Xuhua Ge, Hu Hua, Peipei Wang, Jiaqi Liu, Yue Zhang, Guixia Ding, Chunhua Zhu, Songming Huang, Zhanjun Jia, Aihua Zhang
Acetaminophen (APAP) is widely used as an antipyretic analgesic in clinic. However, overdose-related severe liver injury is a major concern of this drug. Recently, accumulating evidence indicated an important role of mitochondrial abnormality in the pathogenesis of APAP hepatoxicity. Thus, the present investigation was undertaken to evaluate the effect of mitochondrial complex I inhibition by rotenone on APAP hepatoxicity. In this study, male BALB/c mice were pretreated with 250 ppm of rotenone in food for 3 days, then the animals were intraperitoneally injected with 300 mg/kg APAP...
2019: American Journal of Translational Research
Robert G Hendrickson
While the traditional intravenous N-acetylcysteine (NAC) dosing regimen works well for the vast majority of acetaminophen overdoses, there may be cases of massive overdose where additional NAC may be necessary. Recent evidence suggests that patients with acetaminophen concentrations above the "300-line" develop hepatotoxicity at a higher rate than those below the 300-line, suggesting that an increase of dose may be beneficial at this cut-off. Additional clinical data suggest a further increase in doses at the 450-line and 600-lines...
February 19, 2019: Clinical Toxicology
Vera S Donnenberg, Philip Chaikin, Maja Mandic, Bernd Meibohm, John van den Anker, Erin Rhinehart, Anne N Nafziger, James F Burris
Although the medical profession strives for safe prescribing, most medications are unique challenges even when prescribed by an experienced provider. In this article we discuss the pitfalls associated with drug interactions between commonly used antibiotics and anticoagulants, the complexities associated with the administration of novel reversible anticoagulants, the often-overlooked severe adverse drug reactions from commonly used classes of medications such as corticosteroids, the nuances of managing an acetaminophen overdose, and uncommon yet serious adverse events associated with the use of contraceptive hormone drugs...
February 15, 2019: Journal of Clinical Pharmacology
R G Ahmed
OBJECTIVE: The objective of the study was to examine the impact of neonatal acetaminophen (APAP; paracetamol) administrations on the thyroid-liver axis in male Wistar rats. METHODS: APAP (100 or 350 mg/kg) was orally administered to neonates from postnatal day (PND) 20 to 40. RESULTS: Both APAP doses elicited a substantial increase in serum TSH, albumin, AST, ALT, and ALP values, and a profound decrease in serum FT4 and FT3 values at PND 40 relative to those in the control group...
February 12, 2019: Endocrine, Metabolic & Immune Disorders Drug Targets
Congjian Shi, Weiju Xue, Bowen Han, Fengli Yang, Yaping Yin, Chengmu Hu
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease which affects millions of people worldwide. Acetaminophen (APAP) overdose is the leading cause of acute liver failure. In this study, APAP (50, 100, 200mg/kg) were employed on mice fed with a high-fat diet, and APAP (2, 4, 8mM) were cultured with L02 cells in the presence of alcohol and oleic acid. APAP treatment significantly aggravated hepatic lipid accumulation, increased the serum levels of triglyceride (TG), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and increased hepatic lipid accumulation in H&E and Oil red O staining results...
February 9, 2019: European Journal of Pharmacology
Katherine Shortt, Daniel P Heruth, NiNi Zhang, Weibin Wu, Shipra Singh, Ding-You Li, Li Qin Zhang, Gerald J Wyckoff, Lei S Qi, Craig A Friesen, Shui Qing Ye
Acetaminophen (APAP) is a commonly used analgesic responsible for more than half of acute liver failure cases. Identification of previously unknown genetic risk factors would provide mechanistic insights and novel therapeutic targets for APAP-induced liver injury. This study used a genome-wide CRISPR-Cas9 screen to evaluate genes that are protective against, or cause susceptibility to, APAP-induced liver injury. HuH7 human hepatocellular carcinoma cells containing CRISPR-Cas9 gene knockouts were treated with 15 mM APAP for 30 minutes to 4 days...
February 4, 2019: Scientific Reports
Saleh G Algfeley, Salim S Al-Rejaie, Mahmoud N Nagi
An overdose of acetaminophen (APAP) causes liver injury in experimental animals and humans. The activation step (formation of reactive metabolite, N-acetyl-p-benzoquinone imine by cytochrome P450 system) and the consequent downstream pathway of oxidative stress, nitrosative stress, and inflammation play an important role in APAP-induced hepatotoxicity. Formulation of APAP with an inhibitor of the activation step would be ideal to prevent accidental and intentional APAP toxicity. Dimethyl sulfoxide (DMSO) is a common colorless, inexpensive solvent, and considered safe in human...
January 30, 2019: Drug Development Research
Ryan C Kennedy, Andrew K Smith, Glen E P Ropella, Mitchell R McGill, Hartmut Jaeschke, C Anthony Hunt
Acetaminophen (APAP) induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multi-attribute explanation for how and why early necrosis occurs close to the central vein (CV)...
January 29, 2019: Toxicological Sciences: An Official Journal of the Society of Toxicology
Adam Mutsaers, Jason P Green, Marco L A Sivilotti, Mark C Yarema, Dylan Tucker, David W Johnson, Daniel A Spyker, Barry H Rumack
CONTEXT: The Rumack-Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. "Line-crossing" between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold. METHODS AND MATERIALS: The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980-2005) following APAP poisoning...
January 28, 2019: Clinical Toxicology
Christopher Hoyte, Richard C Dart
No abstract text is available yet for this article.
January 28, 2019: Clinical Toxicology
Melissa M Clemens, Stefanie Kennon-McGill, Udayan Apte, Laura P James, Brian N Finck, Mitchell R McGill
Repair mechanisms after acetaminophen (APAP) hepatotoxicity are poorly understood. We recently discovered that phosphatidic acid (PA) increases in mice and humans after APAP overdose, and is critical for liver regeneration. Here, we hypothesized that PA inhibits glycogen synthase kinase-3β (GSK3β), a component of canonical Wnt/β-catenin signaling, after APAP overdose. To test that, we treated mice with 300 mg/kg APAP at 0 h followed by vehicle or 20 mg/kg of the glycerol 3-phosphate acyltransferase inhibitor FSG67 at 3, 24 and 48 h...
January 14, 2019: Food and Chemical Toxicology
Bharat Bhushan, Udayan Apte
Acetaminophen (N-acetyl-para-aminophenol; APAP) overdose is the most common cause of acute liver failure in the Western world, with limited treatment opportunities. For years, research on APAP overdose has been focused on investigating the mechanisms of hepatotoxicity, with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a crucial determinant of the final outcome...
January 14, 2019: American Journal of Pathology
Hongming Lv, Lihua Hong, Ye Tian, Changjiu Yin, Chao Zhu, Haihua Feng
BACKGROUND: Acetaminophen (APAP) overdose-induced acute liver failure (ALF) is mainly resulted from uncontrolled oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a key antioxidant transcription factor, is essential for alleviating APAP-induced hepatotoxicity. Corilagin (Cori) is a natural polyphenol compound that possesses effective antioxidant activity; however, the protective effect of Cori on APAP-induced hepatotoxicity is still unknown. The current study aimed to explore whether Cori could mitigate hepatotoxicity caused by APAP and the underlying molecular mechanisms of action...
January 10, 2019: Cell Communication and Signaling: CCS
James Dear
BACKGROUND: Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose...
January 8, 2019: Trials
Huachao Li, Yueming Chen, Jiahao Zhang, Xiangcui Chen, Zheng Li, Bing Liu, Luyong Zhang
Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice...
December 29, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Stef De Lombaerde, Lindsey Devisscher, Jeroen Verhoeven, Sara Neyt, Hans Van Vlierberghe, Christian Vanhove, Filip De Vos
Recently, our research group reported on the development of 3β-[18 F]Fluorocholic acid (3β-[18 F]FCA), a 18 F labeled bile acid to detect drug interference with the bile acid transporters (drug-induced cholestasis). It was hypothesized that 3β-[18 F]FCA could also be used as a non-invasive tool to monitor (regional) liver function in vivo in different liver diseases through altered expression of bile acid transporters. METHODS: Hepatobiliary transport of 3β-[18 F]FCA was evaluated in four murine liver disease models...
December 8, 2018: Nuclear Medicine and Biology
Dongshi Chen, Hong-Min Ni, Lei Wang, Xiaowen Ma, Jian Yu, Wen-Xing Ding, Lin Zhang
Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury. However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family member, was markedly induced by APAP in the mouse livers and in isolated human and mouse hepatocytes...
December 14, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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