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https://www.readbyqxmd.com/read/28099803/deep-learning-to-predict-the-formation-of-quinone-species-in-drug-metabolism
#1
Tyler B Hughes, S Joshua Swamidass
Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are of- ten highly reactive, and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cy- tochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins...
January 18, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28097095/limited-knowledge-of-acetaminophen-in-patients-with-liver-disease
#2
Sammy Saab, Peter G Konyn, Matthew R Viramontes, Melissa A Jimenez, Jonathan F Grotts, Wally Hamidzadah, Veronica P Dang, Negin L Esmailzadeh, Gina Choi, Francisco A Durazo, Mohamed M El-Kabany, Steven-Huy B Han, Myron J Tong
Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease...
December 28, 2016: Journal of Clinical and Translational Hepatology
https://www.readbyqxmd.com/read/28088388/activation-of-gr-but-not-pxr-by-dexamethasone-attenuated-acetaminophen-hepatotoxicities-via-fgf21-induction
#3
Saurabh G Vispute, Pengli Bu, Yuan Le, Xingguo Cheng
Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity...
January 11, 2017: Toxicology
https://www.readbyqxmd.com/read/28086854/in-vitro-assessment-of-hepatoprotective-agents-against-damage-induced-by-acetaminophen-and-ccl4
#4
Liliana Torres González, Noemí Waksman Minsky, Linda Elsa Muñoz Espinosa, Ricardo Salazar Aranda, Jonathan Pérez Meseguer, Paula Cordero Pérez
BACKGROUND: In vitro bioassays are important in the evaluation of plants with possible hepatoprotective effects. The aims of this study were to evaluate the pretreatment of HepG2 cells with hepatoprotective agents against the damage induced by carbon tetrachloride (CCl4) and paracetamol (APAP). METHODS: Antioxidative activity was measured using an assay to measure 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging. The in vitro hepatotoxicity of CCl4 and APAP, and the cytotoxic and hepatoprotective properties of silymarin (SLM), silybinin (SLB), and silyphos (SLP) were evaluated by measuring cell viability; activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH); total antioxidant capacity (TAOxC); and reduced glutathione (GSH), superoxide dismutase (SOD), and lipid peroxidation (malondialdehyde (MDA) levels)...
January 13, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28072811/evaluation-of-the-ototoxicity-potential-of-once-daily-single-entity-hydrocodone-in-patients-with-chronic-pain-results-of-two-phase-3-clinical-studies
#5
Kathleen Campbell, J Walter Kutz, Angela Shoup, Warren Wen, Shau Yu Lynch, Ellie He, Steven R Ripa
BACKGROUND: Use/misuse of the opioid combination hydrocodone-acetaminophen has been associated with permanent hearing loss. Although reports have been rare, this potential effect can have significant detrimental effect on patients' overall quality of life. To date, the ototoxic effect of hydrocodone alone has not been systematically investigated. OBJECTIVE: In this report, we aimed to evaluate the potential ototoxicity of a novel, single-entity, once-daily, extended-release hydrocodone tablet (Hysingla® ER; HYD)...
January 2017: Pain Physician
https://www.readbyqxmd.com/read/28070111/a-monkey-model-of-acetaminophen-induced-hepatotoxicity-phenotypic-similarity-to-human
#6
Satoshi Tamai, Takuma Iguchi, Noriyo Niino, Kei Mikamoto, Ken Sakurai, Ayako Sayama, Hitomi Shimoda, Wataru Takasaki, Kazuhiko Mori
Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28068511/inhibition-of-glycogen-synthase-kinase-3-accelerated-liver-regeneration-after-acetaminophen-induced-hepatotoxicity-in-mice
#7
Bharat Bhushan, Samikshya Poudel, Michael W Manley, Nairita Roy, Udayan Apte
Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. Timely initiation of compensatory liver regeneration after APAP hepatotoxicity is critical for final recovery, but the mechanisms of liver regeneration after APAP-induced ALF have not been extensively explored yet. Previous studies from our laboratory have demonstrated that activation of β-catenin signaling after APAP overdose is associated with timely liver regeneration. Herein, we investigated the role of glycogen synthase kinase 3 (GSK3) in liver regeneration after APAP hepatotoxicity using a pharmacological inhibition strategy in mice...
January 6, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28045783/quantitative-method-for-simultaneous-analysis-of-acetaminophen-and-six-metabolites
#8
Laureen A Lammers, Roos Achterbergh, Marcel C M Pistorius, Johannes A Romijn, Ron A A Mathôt
BACKGROUND: Hepatotoxicity after ingestion of high-dose acetaminophen (N-acetyl-para-aminophenol, APAP) is caused by the metabolites of the drug. To gain more insight in factors influencing susceptibility to APAP hepatotoxicity, quantification of APAP and metabolites is important. A few methods have been developed to simultaneously quantify APAP and its most important metabolites. However, these methods require a comprehensive sample preparation and long run times. The aim of this study was to develop and validate a simplified, but sensitive, method for the simultaneous quantification of acetaminophen, the main metabolites acetaminophen-glucuronide and acetaminophen-sulfate, and four Cytochrome P450-mediated metabolites by using liquid chromatography with mass spectrometric detection (LC-MS/MS)...
December 30, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28034981/a-preliminary-examination-of-the-comparative-efficacy-of-intravenous-vs-oral-acetaminophen-in-the-treatment-of-perioperative-pain
#9
Anthony Plunkett, Chelsey Haley, Amy McCoart, Thomas Beltran, Krista Beth Highland, Cristobal Berry-Caban, Sherry Lamberth, Michael Bartoszek
: OBJECTIVE : The management of postoperative pain is a major health care issue. While the cost of intravenous acetaminophen (IVA) is significantly greater than its oral acetaminophen (OA) counterpart, less is known regarding comparative effectiveness of these routes. The purpose of this study was to determine whether perioperative IVA is equivalent in reducing postoperative pain compared with perioperative OA for laparoscopic cholecystectomy (LapChole). DESIGN:  Double-blinded, prospective, randomized placebo-controlled trial...
December 29, 2016: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/28031152/lycopene-pretreatment-improves-hepatotoxicity-induced-by-acetaminophen-in-c57bl-6-mice
#10
Ana Carla Balthar Bandeira, Rafaella Cecília da Silva, Joamyr Victor Rossoni, Vivian Paulino Figueiredo, André Talvani, Silvia Dantas Cangussú, Frank Silva Bezerra, Daniela Caldeira Costa
Acetaminophen (APAP) is an antipyretic and analgesic drug that, in high doses, leads to severe liver injury and potentially death. Oxidative stress is an important event in APAP overdose. Researchers are looking for natural antioxidants with the potential to mitigate the harmful effects of reactive oxygen species in different models. Lycopene has been widely studied for its antioxidant properties. The aim of this study was to evaluate the antioxidant potential of lycopene pretreatment in APAP-induced liver injury in C57BL/6 mice...
December 18, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28025693/laparoscopic-versus-open-inguinal-hernia-repair-in-children-%C3%A2-3-a-randomized-controlled-trial
#11
Colin D Gause, Maria G Sacco Casamassima, Jingyan Yang, Grace Hsiung, Daniel Rhee, Jose H Salazar, Dominic Papandria, Howard I Pryor, Dylan Stewart, Jeffrey Lukish, Paul Colombani, Nicole M Chandler, Emilie Johnson, Fizan Abdullah
PURPOSE: Laparoscopy is being increasingly applied to pediatric inguinal hernia repair. In younger children, however, open repair remains preferred due to concerns related to anesthesia and technical challenges. We sought to assess outcomes after laparoscopic and open inguinal hernia repair in children less than or equal to 3 years. METHODS: A prospective, single-blind, parallel group randomized controlled trial was conducted at three clinical sites. Children ≤3 years of age with reducible unilateral or bilateral inguinal hernias were randomized to laparoscopic herniorrhaphy (LH) or open herniorrhaphy (OH)...
December 26, 2016: Pediatric Surgery International
https://www.readbyqxmd.com/read/28007501/synergistic-attenuation-of-chronic-pain-using-mu-opioid-and-cannabinoid-receptor-2-agonists
#12
Shaness A Grenald, Madison A Young, Yue Wang, Michael H Ossipov, Mohab M Ibrahim, Tally M Largent-Milnes, Todd W Vanderah
The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability...
December 20, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/28006746/acetaminophen-induced-hepatotoxicity-preventive-effect-of-trans-anethole
#13
Bruno Ambrósio da Rocha, Alessandra M Versuti Ritter, Franciele Queiroz Ames, Odinei Hess Gonçalves, Fernanda Vitória Leimann, Lívia Bracht, Maria Raquel Marçal Natali, Roberto Kenji Nakamura Cuman, Ciomar Ap Bersani-Amado
The hepatotoxicity induced by APAP is caused by the excessive production of N-acetyl-para-benzoquinone imine (NAPQI), which, when reacting with hepatic proteins proved to cause irreversible lesions. Associated with this process, an intense inflammatory process is also evidenced, characterized by the increased cell influx and production/release of inflammatory mediators. Trans anethole, an aromatic compounds has been showed anti-inflammatory efficacy by inhibit the cellular recruitment and synthesis/releases of many proinflammatory mediators such as prostaglandin (PGE2), cytokines (TNF, IL-1) and nitrico oxide (NO)...
December 19, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28002875/outcomes-from-massive-paracetamol-overdose-a-retrospective-observational-study
#14
Daniel J B Marks, Paul I Dargan, John R H Archer, Charlotte L Davies, Alison M Dines, David M Wood, Shaun L Greene
AIM: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardised, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAPpl ) and treatment nomogram thresholds at those time points (APAPt ) provides a useful assessment tool...
December 21, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27995203/barofuse-a-novel-pressure-driven-adjustable-throughput-perfusion-system-for-tissue-maintenance-and-assessment
#15
Austin Rountree, Amit Karkamkar, Gamal Khalil, Albert Folch, Daniel L Cook, Ian R Sweet
OBJECTIVES: Microfluidic perfusion systems are used for assessing cell and tissue function while assuring cellular viability. Low perfusate flow rates, desired both for conserving reagents and for extending the number of channels and duration of experiments, conventionally depend on peristaltic pumps to maintain flow yet such pumps are unwieldy and scale poorly for high-throughput applications requiring 16 or more channels. The goal of the study was to develop a scalable multichannel microfluidics system capable of maintaining and assessing kinetic responses of small amounts of tissue to drugs or changes in test conditions...
December 2016: Heliyon
https://www.readbyqxmd.com/read/27984590/competing-mechanistic-hypotheses-of-acetaminophen-induced-hepatotoxicity-challenged-by-virtual-experiments
#16
Andrew K Smith, Brenden K Petersen, Glen E P Ropella, Ryan C Kennedy, Neil Kaplowitz, Murad Ookhtens, C Anthony Hunt
Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon...
December 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27977844/paracetamol-acetaminophen-or-non-steroidal-anti-inflammatory-drugs-alone-or-combined-for-pain-relief-in-acute-otitis-media-in-children
#17
REVIEW
Alies Sjoukes, Roderick P Venekamp, Alma C van de Pol, Alastair D Hay, Paul Little, Anne Gm Schilder, Roger Amj Damoiseaux
BACKGROUND: Acute otitis media (AOM) is one of the most common childhood infectious diseases and a significant reason for antibiotic prescriptions in children worldwide. Pain from middle ear infection and pressure behind the eardrum is the key symptom of AOM. Ear pain is central to children's and parents' experience of the illness. Because antibiotics provide only marginal benefits, analgesic treatment including paracetamol (acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs) is regarded as the cornerstone of AOM management in children...
15, 2016: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/27960556/acetaminophen-toxicity-in-rat-and-mouse-hepatocytes-in-vitro
#18
Otto Kučera, René Endlicher, David Rychtrmoc, Halka Lotková, Ondřej Sobotka, Zuzana Červinková
CONTEXT: Acetaminophen (APAP) hepatotoxicity is often studied in primary cultures of hepatocytes of various species, but there are only few works comparing interspecies differences in susceptibility of hepatocytes to APAP in vitro. OBJECTIVES: The aim of our work was to compare hepatotoxicity of APAP in rat and mouse hepatocytes in primary cultures. MATERIALS AND METHODS: Hepatocytes isolated from male Wistar rats and C57Bl/6J mice were exposed to APAP for up to 24 h...
December 14, 2016: Drug and Chemical Toxicology
https://www.readbyqxmd.com/read/27959299/drug-induced-liver-injury
#19
Leslie A Hamilton, Angela Collins-Yoder, Rachel E Collins
Drug-induced liver injury (DILI) can result from both idiosyncratic and intrinsic mechanisms. This article discusses the clinical impact of DILI from a broad range of medications as well as herbal and dietary supplements. Risk factors for idiosyncratic DILI (IDILI) are the result of multiple host, environmental, and compound factors. Some triggers of IDILI often seen in critical care include antibiotics, antiepileptic medications, statins, novel anticoagulants, proton pump inhibitors, inhaled anesthetics, nonsteroidal anti-inflammatory agents, methotrexate, sulfasalazine, and azathioprine...
October 2016: AACN Advanced Critical Care
https://www.readbyqxmd.com/read/27943118/hospitalization-costs-for-patients-undergoing-orthopedic-surgery-treated-with-intravenous-acetaminophen-iv-apap-plus-other-iv-analgesics-or-iv-opioid-monotherapy-for-postoperative-pain
#20
Brett A Maiese, An T Pham, Manasee V Shah, Michael T Eaddy, Orsolya E Lunacsek, George J Wan
INTRODUCTION: To assess the impact on hospitalization costs of multimodal analgesia (MMA), including intravenous acetaminophen (IV-APAP), versus IV opioid monotherapy for postoperative pain management in patients undergoing orthopedic surgery. METHODS: Utilizing the Truven Health MarketScan(®) Hospital Drug Database (HDD), patients undergoing total knee arthroplasty (TKA), total hip arthroplasty (THA), or surgical repair of hip fracture between 1/1/2011 and 8/31/2014 were separated into postoperative pain management groups: MMA with IV-APAP plus other IV analgesics (IV-APAP group) or an IV opioid monotherapy group...
December 10, 2016: Advances in Therapy
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