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Drug-induced hepatotoxicity

Yu Zhang, Xiantao Jiang, Junjie Zhang, Han Zhang, Yingchun Li
Determination of hepatotoxic drugs is critical for both clinical diagnosis and quantity control of their pharmaceutical formulations. In this work, a facile and sensitive sensor based on MXene modified screen-printed electrode (MXene/SPE) has been developed for detection of acetaminophen (ACOP) and isoniazid (INZ), which are two commonly used drugs but might induce liver damage in certain circumstances. MXene showed excellent electrocatalytic activity toward the oxidation of ACOP and INZ compared with bare SPE in 0...
January 29, 2019: Biosensors & Bioelectronics
Michael D Aleo, Jiri Aubrecht, Paul D Bonin, Deborah A Burt, Jennifer Colangelo, Lina Luo, Shelli Schomaker, Rachel Swiss, Simon Kirby, Greg C Rigdon, Pinky Dua
During a randomized Phase 1 clinical trial the drug candidate, PF-04895162 (ICA-105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2-weeks (NCT01691274). This was unexpected since studies in rats (<6 months) and cynomolgus monkeys (<9 months) treated up to 100 mg/kg/day did not identify the liver as a target organ. Mechanistic studies showed PF-04895162 had low cytotoxic potential in human hepatocytes, but inhibited liver mitochondrial function and bile salt export protein (BSEP) transport...
February 2019: Pharmacology Research & Perspectives
Yu Wang, Xi Xiang, Wei-Wei Huang, Andrew J Sandford, Shou-Quan Wu, Miao-Miao Zhang, Ming-Gui Wang, Guo Chen, Jian-Qing He
A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population...
February 18, 2019: Scientific Reports
P Moshaie-Nezhad, F Faed Maleki, S M Hosseini, M Yahyapour, M Iman, A Khamesipour
Exposure to high doses of acetaminophen is the most common cause of drug induced liver injury. We investigated the protective effects of Hedera helix extract against acetaminophen induced oxidative stress and hepatotoxicity using a mouse model. We used two control groups: group A was given 0.9% NaCl, group B was an acetaminophen control that was given a single injection of 600 mg/kg acetaminophen. T1-T4 groups were pretreated orally with different doses of H. helix extract. The mice were sacrificed and blood samples were collected to estimate the levels of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) and total bilirubin...
February 19, 2019: Biotechnic & Histochemistry: Official Publication of the Biological Stain Commission
Emilia Urrutia-Maldonado, Ana Abril-Molina, María Alés-Palmer, Jose María Gómez-Luque, Paloma Muñoz de Rueda, Esther Ocete-Hita
INTRODUCTION: Drug-induced liver injury due to chemotherapy is an important cause of morbidity in cancer patients, although its clinical manifestations are poorly understood. OBJECTIVE: The objective of the present study was to determine the characteristics (forms of presentation, severity, and type of injury) of hepatotoxicity due to chemotherapy in children treated for cancer. PATIENTS AND METHOD: A total of 22 oncological patients were included in the study, after ruling out other causes of increased transaminases (infectious, metabolic, autoimmune, or hereditary), according to the CIOMS causality scale, it is concluded that it was a possible, probable or definite episode of hepatic injury by drugs...
February 15, 2019: Anales de Pediatría: Publicación Oficial de la Asociación Española de Pediatría (A.E.P.)
Miaomiao Yang, Haiping Zhang, Bilin Tao, Hongqiu Pan, Lihuan Lu, Honggang Yi, Shaowen Tang
WHAT IS KNOWN AND OBJECTIVE: Reactive metabolites from anti-tuberculosis (anti-TB) drugs can result in abnormal accumulation of reactive oxygen species (ROS), which plays an important role in anti-TB drug-induced liver injury (ATLI). Liver cells could keep the production of ROS in balance by antioxidant activities. The heme oxygenase 1, encoded by the HMOX1 gene and NADH:quinone oxidoreductase 1, encoded by the NQO1 gene are crucial mediators of cellular defense against ROS. The present study aimed to investigate the associations between HMOX1 and NQO1 polymorphisms and ATLI in Chinese anti-TB treatment population...
February 18, 2019: Journal of Clinical Pharmacy and Therapeutics
Mubshara Saadia, Muhammad Sher, Sajid Bashir, Mian Anjum Murtaza, Amin Shah, Mahmood Ahmad Khan
Synthetic drugs are associated with adverse side-effects and rapid increase in resistance to most of them inspires to evaluate plants for their therapeutic values. We have been aimed to suggest the medicinal use of Nigella sativa seed aqueous extract to minimize the severity of liver damage via its antioxidant properties and its role in maintenance of cell ion-homeostasis. Annoyances in serum levels of some antioxidants and trace metals in human hepatitis C infected patients were compared with that from acetaminophen-induced hepatotoxic rabbits...
January 2019: Pakistan Journal of Pharmaceutical Sciences
Paul Watkins
The DILI-sim Initiative is a public-private partnership involving scientists from industry, academia and the FDA. The Initiative uses Quantitative Systems Toxicology (QST) to build and refine a model (DILIsym® ) capable of understanding and predicting liver safety liabilities in new drug candidates and to optimize interpretation of liver safety biomarkers used in clinical studies. Insights gained to date include the observation that most dose-dependent hepatoxicity can be accounted for by combinations of just three mechanisms (oxidative stress, interference with mitochondrial respiration, and alterations in bile acid homeostasis) and the importance of non-competitive inhibition of bile acid transporters...
February 14, 2019: Clinical and Translational Science
Bridget Bishop, Nicholas Hannah, Adam Doyle, Francesco Amico, Brad Hockey, David Moore, Siddharth Sood, Alexandra Gorelik, Danny Liew, Dolores Njoku, Amanda Nicoll
BACKGROUND: Volatile anaesthetics are known to cause drug-induced liver injury, a hepatotoxic reaction characterised by antibodies to trifluoroacetylated lipid and protein adducts and cytochrome p450 2E1. The incidence of volatile anaesthetic drug-induced liver injury from older agents has been described, but modern agents have not been prospectively studied. AIM: To determine prospectively the incidence of volatile anaesthetic drug-induced liver injury from sevoflurane and desflurane...
February 13, 2019: Alimentary Pharmacology & Therapeutics
Carolyn K J Young, Matthew J Young
HepaRG is a proliferative human hepatoma-derived cell line that can be differentiated into hepatocyte-like and biliary-like cells. Differentiated HepaRG cultures maintain key hepatic functions including drug transporters and xenobiotic-metabolizing enzymes. To gain insight into proliferative and differentiated HepaRG metabolism we profiled various bioenergetic parameters and investigated cell culture levels of adenosine triphosphate (ATP), lactate, and lactate dehydrogenase (LDH) activity. Compared to differentiated-derived HepaRG, cells from proliferative cultures had increased basal and ATP-linked respiration and decreased maximal and spare respiratory capacities...
February 12, 2019: Cell Cycle
Hongqiu Pan, Miaomiao Yang, Lihuan Lu, Bilin Tao, Xiaomin He, Hongbo Chen, Honggang Yi, Shaowen Tang
OBJECTIVE: Antituberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism has not been elucidated thoroughly to date. A recent genome-wide association study reported that seven single-nucleotide polymorphisms (SNPs) in the family with sequence similarity 65, member B gene (FAM65B), ATP/GTP-binding protein-like 4 gene (AGBL4), and cut-like homeobox 2 gene (CUX2) were associated strongly with ATDH in Ethiopian patients. We validated this relationship in a Chinese Han anti-TB treatment population...
February 1, 2019: Pharmacogenetics and Genomics
Yingkun Liu, Congyong Sun, Wenjing Li, Michael Adu-Frimpong, Qilong Wang, Jiangnan Yu, Ximing Xu
In this study, syringic acid-loaded TPGS liposome (SA-TPGS-Ls) was successfully prepared to improve oral bioavailability of syringic acid (SA). SA is a natural and notable antioxidant activity compound with its limited bioavailability ascribable to its poor aqueous solubility and fast elimination. Recently, TPGS has become a perfect molecular biomaterial in developing several carrier systems with sustained, controlled, and targeted the drug delivery. SA-TPGS-Ls was prepared via thin-film dispersion method and characterized in terms of particle size, stability, morphology, and encapsulation efficiency (EE)...
February 4, 2019: AAPS PharmSciTech
Shuai Xu, Hong-Wen Liu, Xia Yin, Lin Yuan, Shuang-Yan Huan, Xiao-Bing Zhang
Carbon monoxide (CO) acts as an important gasotransmitter in delivering intramolecular and intermolecular signals to regulate a variety of physiological processes. This lipid-soluble gas can freely pass through the cell membrane and then diffuse to adjacent cells acting as a messenger. Although many fluorescent probes have been reported to detect intracellular CO, it is still a challenge to visualize the release behavior of endogenous CO. The main obstacle is the lack of a probe that can anchor onto the cell membrane while having the ability to image CO in real time...
January 7, 2019: Chemical Science
Huifang Li, Yan Liu, Junru Li, Yunzhi Liu, Lijun Dong, Yue Yin, Yu Yu, Jia Zhou, Liyun Zhang, Xiao Lu, Zhengliang Chen, Daming Zuo
Mannan-binding lectin (MBL) acts as a soluble pattern recognition molecule in the innate immune system, which is primarily produced by the liver. MBL deficiency occurs with high frequency in the population and is reported to be associated with susceptibility to several liver diseases. In the present study, we investigated the pathophysiological role of MBL in acetaminophen (APAP)-induced hepatotoxicity. After APAP treatment, MBL-deficient (MBL-/- ) mice had significantly higher mortality and aggravated hepatic necrosis as well as elevated serum lactate dehydrogenase and alanine aminotransferase levels compared to control mice...
February 1, 2019: European Journal of Immunology
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
Mohamed G Ewees, Tamer M Abdelghany, Abdel-Aziz H Abdel-Aziz, Mohamed S Abdelbakky
Methotrexate (MTX) is a widely used drug for treatment of many malignant, rheumatic, and autoimmune diseases. However, hepatotoxicity remains one of the most serious side effects of MTX. The extrinsic coagulation pathway is activated after tissue injury through the release of tissue factor (TF) which activates a cascade of clotting factors including prothrombin and fibrinogen. Liver sinusoidal endothelial cells express endothelial nitric oxide synthase (eNOS) as a source for nitric oxide (NO) that serves as vasodilator and antithrombotic factor...
January 28, 2019: Naunyn-Schmiedeberg's Archives of Pharmacology
Farimah Beheshti, Mahmoud Hosseini, Mehdi Taheri Sarvtin, Ali Kamali, Akbar Anaeigoudari
Lipopolysaccharide (LPS) as the major component of the outer membrane of Gram-negative bacteria activates macrophages to produce a high level of pro-inflammatory cytokines which is considered as a cause of liver dysfunction. Overproduction of nitric oxide (NO) has been suggested to have a role in hepatic injury. The aim of the present study was to explore the protective effects of aminoguanidine (AG) as inducible nitric oxide synthase (iNOS) inhibitor against LPS -induced liver dysfunction in rat. The animals were divided into five groups: (1) control (2) LPS (3) LPS-AG50, (4) LPS-AG100 and (5) LPS-AG150...
January 29, 2019: Drug and Chemical Toxicology
Joseph J Jennings, Rohan Mandaliya, Ahmad Nakshabandi, James H Lewis
Immune checkpoint inhibitors (ICIs) block cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) receptors that control antitumor activities of lymphocytes. While highly efficacious, these drugs have been associated with several immune-related adverse events (irAEs) due to the disruption of self-tolerance. Immune-mediated hepatitis (IMH) usually presents as mild elevations of liver enzymes though it can rarely be associated with life-threatening hepatic injury...
January 24, 2019: Expert Opinion on Drug Metabolism & Toxicology
Jeongyoon Kwon, Seungyeon Kim, Hyejin Yoo, Euni Lee
OBJECTIVE: This study aimed to evaluate the risk for hepatotoxicity with nimesulide, a non-steroidal anti-inflammatory drug (NSAID) available in Republic of Korea but withdrawn from the market in several countries. METHODS: A systematic review and meta-analysis were conducted of studies retrieved from PubMed, EMBASE, Cochrane, the Research Information Sharing Service and up to September 2017. All studies reporting nimesulide-associated hepatotoxicity in patients as compared with the unexposed or the exposed to other NSAIDs were included...
2019: PloS One
Dian Kang, Yuhao Shao, Zhangpei Zhu, Xiaoxi Yin, Boyu Shen, Chong Chen, Yangfan Xu, Jiajia Shen, Haofeng Li, Xinuo Li, Lin Xie, Guangji Wang, Yan Liang
BACKGROUND: Herbal medicines (HMs) have been proven to be productive sources of leads for the development of drugs. To date approximately 150 lignans have been identified from Schisandra sphenanthera. Hepatoprotective activity is a well-known characteristic of schisandra lignans, yet the authentic types of active lignans are still not well known. PURPOSE: The present study aimed to develop a reliable and efficient strategy for identifying the hepatoprotective ingredients of schisandra lignan extract (SLE)...
September 5, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
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