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hepatotoxic drugs

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https://www.readbyqxmd.com/read/28646254/cytoprotective-effects-of-diallyl-trisulfide-against-valproate-induced-hepatotoxicity-new-anticonvulsant-strategy
#1
Ahmed A Shaaban, Dina S El-Agamy
Sodium valproate (VP) is an important antiepileptic drug, although it can produce deleterious hepatotoxic reactions. Diallyl trisulfide (DATS) is the principle component of garlic oil that possesses antioxidant properties. This study explored the potential hepatoprotective activity of DATS against VP-induced hepatic damage and its underlying mechanisms. In addition, the study assessed the effect of DATS on VP antiepileptic activity. Rats were given DATS once daily at two different doses along with VP for 2 weeks...
June 23, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28645576/mechanisms-of-hepatocellular-toxicity-associated-with-new-psychoactive-synthetic-cathinones
#2
Dino Luethi, Matthias E Liechti, Stephan Krähenbühl
Synthetic cathinones are a new class of psychostimulant substances. Rarely, they can cause liver injury but associated mechanisms are not completely elucidated. In order to increase our knowledge about mechanisms of hepatotoxicity, we investigated the effect of five frequently used cathinones on two human cell lines. Bupropion was included as structurally related drug used therapeutically. In HepG2 cells, bupropion, MDPV, mephedrone and naphyrone depleted the cellular ATP content at lower concentrations (0...
June 20, 2017: Toxicology
https://www.readbyqxmd.com/read/28645575/prediction-of-drug-induced-immune-mediated-hepatotoxicity-using-hepatocyte-like-cells-derived-from-human-embryonic-stem-cells
#3
Dong Eon Kim, Mi-Jin Jang, Young Ran Kim, Joo-Young Lee, Eun Byul Cho, Eunha Kim, Yeji Kim, Mi Young Kim, Won-Il Jeong, Seyun Kim, Yong-Mahn Han, Seung-Hyo Lee
Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events...
June 20, 2017: Toxicology
https://www.readbyqxmd.com/read/28644367/oral-cholic-acid-is-efficacious-and-well-tolerated-in-patients-with-bile-acid-synthesis-and-zellweger-spectrum-disorders
#4
James E Heubi, Kevin E Bove, Kenneth D R Setchell
BACKGROUND/AIMS: Patients with bile acid synthesis disorders (BASD) due to single enzyme defects (SED) or Zellweger spectrum disorders (ZSD) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD. METHODS: In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg/kg/day...
June 21, 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28640225/herb-drug-interaction-between-the-traditional-hepatoprotective-formulation-and-sorafenib-on-hepatotoxicity-histopathology-and-pharmacokinetics-in-rats
#5
Chin-Tsung Ting, Yung-Yi Cheng, Tung-Hu Tsai
Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole...
June 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28640208/associations-of-drug-lipophilicity-and-extent-of-metabolism-with-drug-induced-liver-injury
#6
Kristin McEuen, Jürgen Borlak, Weida Tong, Minjun Chen
Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI...
June 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28636348/the-development-of-an-aryloxazole-class-of-hepatitis-c-virus-inhibitors-targeting-the-entry-stage-of-the-viral-replication-cycle
#7
Shanshan He, Kelin Li, Billy Lin, Zonyi Hu, Jingbo Xiao, Xin Hu, Amy Q Wang, Xin Xu, Marc Ferrer, Noel Southall, Wei Zheng, Jeffrey Aubé, Frank J Schoenen, Juan J Marugan, T Jake Liang, Kevin J Frankowski
Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps, such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure-activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28636309/quantitative-chemical-proteomic-profiling-of-the-in-vivo-targets-of-reactive-drug-metabolites
#8
Landon R Whitby, R Scott Obach, Gabriel M Simon, Matthew M Hayward, Benjamin F Cravatt
Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e...
June 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28627888/investigation-of-drug-induced-hepatotoxicity-and-its-remediation-pathway-with-reaction-based-fluorescent-probes
#9
Dan Cheng, Wang Xu, Lin Yuan, Xiao-Bing Zhang
Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO-) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction based fluorescent probes (Naph-ONOO- and Rhod-ONOO-) for ONOO- through a novel and universally applicable mechanism: ONOO- mediated deprotection of -keto caged fluorophores. Among them, Rhod-ONOO- can selectively accumulate and react in mitochondria, one of the main sources of ONOO-, with a substantial lower nano-molar sensitivity of 43 nM...
June 19, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28619387/evaluation-of-ameliorative-ability-of-silibinin-against-zidovudine-and-isoniazid-induced-hepatotoxicity-and-hyperlipidaemia-in-rats-role-of-silibinin-in-phase-i-and-ii-drug-metabolism
#10
Raghu Ramanathan, Karthikeyan Sivanesan
HIV/AIDS patients have suppressed immune system, making them vulnerable to many opportunistic infections including tuberculosis (TB). The patients who are co-infected with TB undergo combined regimens with anti-retroviral drugs such as zidovudine (AZT) and anti-tubercular drug such as isoniazid (INH) for therapy leading to hepatotoxicty. Silibinin (SBN), extracted from Silybum marianum commonly called as "Milk thistle" is used against several drugs-induced hepatotoxicity. The present study evaluates the ameliorative effect of SBN against AZT alone, INH alone, and INH + AZT-induced toxic insults to liver of rats...
June 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28617756/optimizing-thiopurine-therapy-in-inflammatory-bowel-disease-among-2-real-life-intercept-cohorts-effect-of-allopurinol-comedication
#11
Berrie Meijer, Margien L Seinen, Remco van Egmond, Gerd Bouma, Chris J J Mulder, Adriaan A van Bodegraven, Nanne K H de Boer
BACKGROUND: Thiopurines (azathioprine and mercaptopurine) are frequently used immunosuppressive drugs to maintain remission in patients with inflammatory bowel disease. Half of the conventional thiopurine-derivative users have to discontinue treatment within 5 years, mainly because of intolerable adverse events. Over recent years, different strategies to optimize thiopurine treatment were suggested, yet, studies describing the clinical effectiveness of these strategies remain scarce. The aims of this study were to compare tolerability and sustained clinical benefit of conventional thiopurine derivatives therapy among two 5-year real-life intercept cohorts and to assess the clinical value of specifically allopurinol cotherapy...
June 14, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28617228/prediction-models-for-drug-induced-hepatotoxicity-by-using-weighted-molecular-fingerprints
#12
Eunyoung Kim, Hojung Nam
BACKGROUND: Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. RESULTS: In this study, we used 881 bits of molecular fingerprint and used as features describing presence or absence of each substructure of compounds...
May 31, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28614776/nonsteroidal-anti-inflammatory-drugs-induced-failure-of-lower-esophageal-and-pyloric-sphincter-and-counteraction-of-sphincters-failure-with-stable-gatric-pentadecapeptide-bpc-157-in-rats
#13
S Vitaic, M Stupnisek, D Drmic, L Bauk, A Kokot, R Klicek, A Vcev, K Luetic, S Seiwerth, P Sikiric
The sphincters failure is a part of NSAIDs-toxicity that can be accordingly counteracted. We used a safe stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), LD1 not achieved, since successful in inflammatory bowel disease trials, and counteracts esophagitis, sphincters failure, gastrointestinal ulcer and skin ulcer, external and internal fistulas in rats, and particularly counteracts all NSAIDs-lesions. We assessed lower esophageal sphincter and pyloric sphincter pressure (cmH2O) in rats treated with various NSAIDs regimens, at corresponding time points, known to produce stomach, small intestine lesions, hepatotoxicity and encephalopathy...
April 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28612260/utility-of-spherical-human-liver-microtissues-for-prediction-of-clinical-drug-induced-liver-injury
#14
William R Proctor, Alison J Foster, Jennifer Vogt, Claire Summers, Brian Middleton, Mark A Pilling, Daniel Shienson, Monika Kijanska, Simon Ströbel, Jens M Kelm, Paul Morgan, Simon Messner, Dominic Williams
Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models...
June 13, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28612092/involvement-of-cytochrome-p450-in-cisplatin-treatment-implications-for-toxicity
#15
REVIEW
Júlia Coelho França Quintanilha, Vanessa Marcilio de Sousa, Marília Berlofa Visacri, Laís Sampaio Amaral, Roseane Maria Maia Santos, Tomás Zambrano, Luis Antonio Salazar, Patricia Moriel
PURPOSE: The aim of this study is to evaluate the relationship between the CYP450 enzyme family and cisplatin toxicity. METHODS: This article examined a collection of studies suggesting that CYP450 enzymes may influence cisplatin toxicity. We performed a narrative mini-review. RESULTS: The studies review showed that CYP450 enzymes have an important role in drug-induced hepatotoxicity and nephrotoxicity, mainly CYP2E1 and CYP4A11. The studies also suggested that the cisplatin and CYP2E1 interaction leads to the generation of reactive oxygen species (ROS) and other oxidants resulting in renal injury; and that ROS generated by both the use of cisplatin and by the CYP2E1 increases tissue damage, induces apoptosis, and causes liver failure...
June 13, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28606126/pooled-safety-analyses-of-alk-tki-inhibitor-in-alk-positive-nsclc
#16
Qian Zhu, Hao Hu, De-Sheng Weng, Xiao-Fei Zhang, Chang-Long Chen, Zi-Qi Zhou, Yan Tang, Jian-Chuan Xia
BACKGROUND: The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear. METHODS: We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials...
June 12, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28604316/when-students-become-patients-tb-disease-among-medical-undergraduates-in-cape-town-south-africa
#17
Helene-Mari Van der Westhuizen, Angela Dramowski
BACKGROUND: Medical students acquire latent tuberculosis (TB) infection at a rate of 23 cases/100 person-years. The frequency and impact of occupational TB disease in this population are unknown. METHODS: A self-administered questionnaire was distributed via email and social media to current medical students and recently graduated doctors (2010 - 2015) at two medical schools in Cape Town. Individuals who had developed TB disease as undergraduate students were eligible to participate...
May 24, 2017: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
https://www.readbyqxmd.com/read/28604124/test-systems-in-drug-discovery-for-hazard-identification-and-risk-assessment-of-human-drug-induced-liver-injury
#18
Richard J Weaver, Catherine Betts, Eric A G Blomme, Helga H J Gerets, Klaus Gjervig Jensen, Philip G Hewitt, Satu Juhila, Gilles Labbe, Michael J Liguori, Natalie Mesens, Monday O Ogese, Mikael Persson, Jan Snoeys, James L Stevens, Tracy Walker, B Kevin Park
Introduction The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities...
June 12, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28603092/crosstalk-of-liver-immune-cells-and-cell-death-mechanisms-in-different-murine-models-of-liver-injury-and-its-clinical-relevance
#19
Hilal Ahmad Khan, Muhammad Zishan Ahmad, Junaid Ali Khan, Muhammad Imran Arshad
BACKGROUND: Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions...
June 2017: Hepatobiliary & Pancreatic Diseases International: HBPD INT
https://www.readbyqxmd.com/read/28598687/lomitapide-for-the-treatment-of-hypercholesterolemia
#20
Amanda J Berberich, Robert A Hegele
Homozygous familial hypercholesterolemia (HoFH) is a serious rare inherited condition that leads to extremely elevated levels of low density lipoprotein cholesterol (LDL-C), and predisposes affected individuals to high risk of atherosclerotic vascular disease. Traditional therapies are largely ineffective in managing the hypercholesterolemia in these patients; diet and regular LDL-apheresis are the mainstays of management. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP) that blocks the assembly of metabolic precursors of LDL particles...
June 9, 2017: Expert Opinion on Pharmacotherapy
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