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Drug overdose liver failure

Rafael S Czepielewski, Natália Jaeger, Pedro E Marques, Maísa M Antunes, Maurício M Rigo, Débora M Alvarenga, Rafaela V Pereira, Rodrigo D da Silva, Tiago G Lopes, Vinícius D da Silva, Bárbara N Porto, Gustavo B Menezes, Cristina Bonorino
Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXCR2 ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration and mechanisms underlying this phenomenon...
March 10, 2017: European Journal of Immunology
Angelina Huseinovic, Jolanda S van Leeuwen, Tibor van Welsem, Iris Stulemeijer, Fred van Leeuwen, Nico P E Vermeulen, Jan M Kooter, J Chris Vos
Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed...
2017: PloS One
Jingyao Zhang, Simin Zhang, Jianbin Bi, Jingxian Gu, Yan Deng, Chang Liu
BACKGROUND: Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure...
January 31, 2017: International Immunopharmacology
Xiao Yang, Yibei Zhan, Qi Sun, Xi Xu, Yi Kong, Jianfa Zhang
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5'-monophsphate (5'-AMP). We demonstrated that co-administration of APAP and 5'-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function...
January 24, 2017: Oncotarget
Dev Katarey, Sumita Verma
Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paracetamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature because affected individuals represent only a small proportion of those treated with such drugs. In many cases, the mechanism for idiosyncrasy is immune-mediation and is often identified by genetic risk determined by human leukocyte antigen variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests...
December 2016: Clinical Medicine: Journal of the Royal College of Physicians of London
Benjamin L Woolbright, Hartmut Jaeschke
Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has recently occurred in the literature over whether there is a second phase of injury, mediated by inflammatory processes...
April 2017: Journal of Hepatology
Remon R Rofaeil, Maha Y Kamel, Walaa Y Abdelzaher
Acetaminophen (APAP) overdose is a common cause of acute liver failure, and beta-blockers are commonly used drugs in clinical practice. This study aimed to evaluate the effect of two different beta-blocker agents as nebivolol and atenolol against APAP-induced hepatotoxicity. Male Wistar rats were treated with APAP (2 g/kg/day, p.o.) to induce hepatotoxicity. Our results showed that nebivolol and atenolol reduced heart rate and blood pressure. Nebivolol (5 mg/kg/day, p.o.) for 14 days has a hepatoprotective effect shown by significant decrease in hepatic injury parameters (serum AST and ALT) with significant suppression of hepatic malondialdehyde (MDA) and nitric oxide (NO) which were elevated with APAP administration...
November 14, 2016: Fundamental & Clinical Pharmacology
M Mosedale, P B Watkins
Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis...
April 2017: Clinical Pharmacology and Therapeutics
Kuo Du, Anup Ramachandran, James L Weemhoff, Hemantkumar Chavan, Yuchao Xie, Partha Krishnamurthy, Hartmut Jaeschke
Overdose of acetaminophen (APAP) causes severe liver injury and even acute liver failure in both mice and human. A recent study by Kim et al. (2015, Metformin ameliorates acetaminophen hepatotoxicity via Gadd45β-dependent regulation of JNK signaling in mice. J. Hepatol. 63, 75-82) showed that metformin, a first-line drug to treat type 2 diabetes mellitus, protected against APAP hepatotoxicity in mice. However, its exact protective mechanism has not been well clarified. To investigate this, C57BL/6J mice were treated with 400 mg/kg APAP and 350 mg/kg metformin was given 0...
December 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Karen C Thomas, Diana G Wilkins, Steven C Curry, Todd C Grey, David M Andrenyak, Lawrence D McGill, Douglas E Rollins
Acetaminophen overdose is a leading cause of drug-induced liver failure in the United States. Acetaminophen-protein adducts have been suggested as a biomarker of hepatotoxicity. The purpose of this study was to determine whether protein-derived acetaminophen-protein adducts are quantifiable in postmortem samples. Heart blood, femoral blood, and liver tissue were collected at autopsy from 22 decedents suspected of opioid-acetaminophen overdose. Samples were assayed for protein-derived acetaminophen-protein adducts, acetaminophen, and selected opioids found in combination products containing acetaminophen...
September 2016: Journal of Forensic Sciences
(no author information available yet)
No abstract text is available yet for this article.
June 2016: Annals of Intensive Care
(no author information available yet)
In late 2015, the first-choice treatment for patients with chronic hepatitis C due to a genotype 1 virus (HCV-1) was the combination of ledipasvir (an NS5A protein inhibitor) + sofosbuvir (a nucleotide inhibitor of NS5B RNA polymerase), despite major uncertainties regarding its adverse effects. This combination is almost always virologically effective. Dasabuvir is a non-nucleoside inhibitor of the viral RNA polymerase NS5B. It is authorised in the EU for the treatment of patients with chronic hepatitis C due to HCV-1, usually combined with the fixed-dose combination (Viekirax) of ombitasvir (an HCV NS5A protein inhibitor) + paritaprevir (an HCV protease inhibitor) + ritonavir (to enhance paritaprevir bioavailability)...
May 2016: Prescrire International
Irena Kasmi, Sashenka Sallabanda, Gentian Kasmi
BACKGROUND: Acetaminophen is a drug widely used in children because of its safety and efficacy. Although the risk of its toxicity is lower in children such reactions occur in pediatric patients from intentional overdoses and less frequently attributable to unintended inappropriate dosing. The aim of reporting this case is to attract the attention to the risk of the acetaminophen toxicity when administered in high doses. CASE PRESENTATION: We report here a 5 year old girl who developed fulminate liver failure with renal impairment and acute pancreatitis, as a result of acetaminophen toxicity caused from unintentional repeated supratherapeutic ingestion, with a total administered dose of 4800 mg in three consecutive days, 1600 mg/day, approximately 90 mg/kg/day...
September 15, 2015: Open Access Macedonian Journal of Medical Sciences
Anne-Elise Severin, Nadine Petitpain, Julien Scala-Bertola, Clotilde Latarche, Melissa Yelehe-Okouma, Paolo Di Patrizio, Pierre Gillet
Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage...
June 2016: Thérapie
Christoph Thiel, Henrik Cordes, Isabel Conde, José Vicente Castell, Lars Mathias Blank, Lars Kuepfer
Understanding central mechanisms underlying drug-induced toxicity plays a crucial role in drug development and drug safety. However, a translation of cellular in vitro findings to an actual in vivo context remains challenging. Here, physiologically based pharmacokinetic (PBPK) modeling was used for in vivo contextualization of in vitro toxicity data (PICD) to quantitatively predict in vivo drug response over time by integrating multiple levels of biological organization. Explicitly, in vitro toxicity data at the cellular level were integrated into whole-body PBPK models at the organism level by coupling in vitro drug exposure with in vivo drug concentration-time profiles simulated in the extracellular environment within the organ...
February 2017: Archives of Toxicology
Yi Ding, Qing Li, Yuan Xu, Yuning Chen, Yue Deng, Feng Zhi, Ke Qian
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. The purpose of this study was to investigate whether paeonol protected against APAP-induced hepatotoxicity. Mice treated with paeonol (25, 50, 100 mg/kg) received 400 mg/kg acetaminophen intraperitoneally (i.p.) and hepatotoxicity was assessed. Pre-treatment with paeonol for 6 and 24 h ameliorated APAP-induced hepatic necrosis and significantly reduced the serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels in a dose-dependent manner...
2016: PloS One
David G Cairney, Hannah K S Beckwith, Khalid Al-Hourani, Michael Eddleston, D Nicholas Bateman, James W Dear
CONTEXT: Paracetamol (acetaminophen) overdose is a common reason for emergency hospital admission in the UK and the leading cause of acute liver failure in the Western world. Currently, the antidote acetylcysteine (NAC) is administered at a dose determined only by body weight without regard for the body burden of paracetamol. OBJECTIVE: To determine whether higher plasma paracetamol concentrations are associated with increased risk of liver injury despite prompt treatment with intravenous NAC...
June 2016: Clinical Toxicology
Dagmara Szkolnicka, Baltasar Lucendo-Villarin, Joanna K Moore, Kenneth J Simpson, Stuart J Forbes, David C Hay
UNLABELLED: The liver performs multiple functions within the human body. It is composed of numerous cell types, which play important roles in organ physiology. Our study centers on the major metabolic cell type of the liver, the hepatocyte, and its susceptibility to damage during drug overdose. In these studies, hepatocytes were generated from a renewable and genetically defined resource. In vitro-derived hepatocytes were extensively profiled and exposed to varying levels of paracetamol and plasma isolated from liver-failure patients, with a view to identifying noncoding microRNAs that could reduce drug- or serum-induced hepatotoxicity...
June 2016: Stem Cells Translational Medicine
J Le Vaillant, L Pellerin, J Brouard, D Nimal-Cuvillon
AIM: Biological complications in adolescents' self-poisoning are not currently evaluated. The aim of this study was to describe the toxicological characteristics of suicide attempts, the ingested substances, and their complications to better prevent the risks associated with deliberate self-poisoning. MATERIALS AND METHODS: This was a descriptive, prospective, single-center study. It took place in the pediatric emergency, hospitalization, and intensive care unit of the Caen University Hospital...
May 2016: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
Wei Zheng, Zhiyong Zhang, Sushun Liu, Jianbin Bi, Jingyao Zhang, Lixue Du, Xiaoming Ding, Chang Liu
Acetaminophen (APAP) overdose is a major cause of drug acute liver failure. Studies have shown that remote ischemic pre- and post-conditioning (R-IPC and R-IPOST) can protect the liver against ischemia-reperfusion (I/R) and LPS induced injuries. The aim of this study was to investigate the effect of R-IPC and R-IPOST on APAP-induced hepatotoxicity in mice. Mice were randomized (n = 6 per group) to seven major groups that were treated as follows: (1) the normal control group; (2) the sham operated group; (3) the APAP group; (4) R-IPC + APAP group; (5) R-IPC + APAP + ZnPP group; (6) R-IPOST + APAP group; and (7) R-IPOST + APAP + ZnPP group...
March 17, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
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