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Drug-induced hepatotoxicity

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https://www.readbyqxmd.com/read/28918038/strategies-for-in%C3%A2-vivo-screening-and-mitigation-of-hepatotoxicity-associated-with-antisense-drugs
#1
Piotr J Kamola, Klio Maratou, Paul A Wilson, Kay Rush, Tanya Mullaney, Tom McKevitt, Paula Evans, Jim Ridings, Probash Chowdhury, Aude Roulois, Ann Fairchild, Sean McCawley, Karen Cartwright, Nigel J Gooderham, Timothy W Gant, Kitty Moores, Stephen A Hughes, Mark R Edbrooke, Kenneth Clark, Joel D Parry
Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28912805/antifibrotic-effect-of-lactulose-on-a-methotrexate-induced-liver-injury-model
#2
Banu Taskin, Mümin Alper Erdoğan, Gürkan Yiğittürk, Damla Günenç, Oytun Erbaş
The most severe side effect of prolonged MTX treatment is hepatotoxicity. The aim of this study is to investigate the effect of lactulose treatment on MTX-induced hepatotoxicity in a rat model. Twenty-four male rats were included in the study. Sixteen rats were given a single dose of 20 mg/kg MTX to induce liver injury. Eight rats were given no drugs. 16 MTX-given rats were divided into two equal groups. Group 1 subjects were given lactulose 5 g/kg/day, and group 2 subjects were given saline 1 ml/kg/day for 10 days...
2017: Gastroenterology Research and Practice
https://www.readbyqxmd.com/read/28911608/effect-of-goat-milk-on-hepatotoxicity-induced-by-antitubercular-drugs-in-rats
#3
Sonam Miglani, Rakesh Raman Patyar, Sazal Patyar, Mohammad Rafi Reshi
Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 ± 25...
October 2016: Journal of Food and Drug Analysis
https://www.readbyqxmd.com/read/28904294/assessment-of-amiodarone-induced-phospholipidosis-in-chimeric-mice-with-a-humanized-liver
#4
Seigo Sanoh, Yuto Yamachika, Yuka Tamura, Yaichiro Kotake, Yasumi Yoshizane, Yuji Ishida, Chise Tateno, Shigeru Ohta
It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Drug-induced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity. In this study, we examined whether chimeric mice can reveal species differences in DIPL. Changes in various phosphatidylcholine (PhC) molecules were investigated in the liver of chimeric mice after administering amiodarone, which induces phospholipidosis...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28900877/genetic-polymorphisms-of-slco1b1-cyp2e1-and-ugt1a1-and-susceptibility-to-anti-tuberculosis-drug-induced-hepatotoxicity-a-chinese-population-based-prospective-case-control-study
#5
Qin Sun, Hai-Peng Liu, Rui-Juan Zheng, Peng Wang, Zhi-Bin Liu, Wei Sha, He-Ping Xiao
BACKGROUND: Drug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH). METHODS: Thirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case-control study...
September 12, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/28887915/hepatoprotective-naphthalene-diglucoside-from-neanotis-wightiana-aerial-parts
#6
Niranjan Das, Atanas G Atanasov, Prashanta Kumar Deb, Andrei Mocan, Seyed Mohammad Nabavi, Ranjib Ghosh, Biswanath Dinda
BACKGROUND: Neanotis wightiana (Wall. ex Wight & Arn) W.H. Lewis has been used in traditional medicine in India for the treatment of liver disorders. In fact, this plant is frequently used by the local people of Tripura for the treatment of liver disorder problems. In previous study on this plant we have isolated a hepatoprotective saponin, neanoside A. PURPOSE: Evaluation of in vivo hepatoprotective effects of isolated compounds from N. wightiana aerial parts on serum hepatic-biomarkers in CCl4- induced hepatotoxicity in rats to validate the traditional use of the plant...
September 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28878168/metabolomics-analysis-of-urine-samples-from-children-after-acetaminophen-overdose
#7
Laura K Schnackenberg, Jinchun Sun, Sudeepa Bhattacharyya, Pritmohinder Gill, Laura P James, Richard D Beger
Acetaminophen (APAP), a commonly used over-the-counter analgesic, accounts for approximately fifty percent of the cases of acute liver failure (ALF) in the United States due to overdose, with over half of those unintentional. Current clinical approaches for assessing APAP overdose rely on identifying the precise time of overdose and quantitating acetaminophen alanine aminotransferase (ALT) levels in peripheral blood. Novel specific and sensitive biomarkers may provide additional information regarding patient status post overdose...
September 6, 2017: Metabolites
https://www.readbyqxmd.com/read/28875055/pilot-algorithm-designed-to-help-early-detection-of-hmg-coa-reductase-inhibitor-induced-hepatotoxicity
#8
Joo Young Hong, Hun-Sung Kim, In Young Choi
OBJECTIVES: To enable early detection of adverse drug reactions (ADRs) in patients using HMG-CoA reductase inhibitors (statins), we developed an algorithm that automatically detects liver injury caused by statins from Electronic Medical Record (EMR) data. We verified the performance of our algorithm through manual ADR assessment and a direct chart review. METHODS: The subjects in this study were patients who had been prescribed a statin for the first time among outpatients in Seoul St...
July 2017: Healthcare Informatics Research
https://www.readbyqxmd.com/read/28873351/frequency-and-pathological-characteristics-of-drug-induced-liver-injury-in-a-tertiary-medical-center
#9
Mark Ettel, Gabriel Acosta Gonzalez, Shweta Gera, Ogechukwu Eze, Samuel Sigal, James S Park, Ruliang Xu
Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI...
September 2, 2017: Human Pathology
https://www.readbyqxmd.com/read/28869866/synergistic-antitumor-effect-mediated-by-a-paclitaxel-conjugated-polymeric-micelle-coated-oncolytic-adenovirus
#10
Dayananda Kasala, Soo-Hwan Lee, Jin Woo Hong, Joung-Woo Choi, Kihoon Nam, Yoon Ho Chung, Sung Wan Kim, Chae-Ok Yun
Combination treatment consisting of oncolytic adenovirus (Ad) and paclitaxel (PTX) is a promising strategy to achieve synergistic antitumor effect. However, a co-administration approach is subject to inherent limitations due to the poor solubility of PTX and chemoresistance of tumor cells. In order to overcome these limitations, an oncolytic Ad expressing a p53 variant (oAd-vp53) that is resistant to p53 inactivation in the tumor microenvironment was complexed with PEGylated and PTX-conjugated polymeric micelle (APP)...
August 23, 2017: Biomaterials
https://www.readbyqxmd.com/read/28865237/dose-dependent-acute-liver-injury-with-hypersensitivity-features-in-humans-due-to-a-novel-microsomal-prostaglandin-e-synthase-1-inhibitor
#11
Yan Jin, Arie Regev, Jeanelle Kam, Krista Phipps, Claire Smith, Judith Henck, Kristina Campanale, Leijun Hu, D Greg Hall, Xiao Yan Yang, Masako Nakano, Terry Ann McNearney, Jack Uetrecht, William Landschulz
AIM: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety, and tolerability profile. METHODS: Healthy subjects were randomised to receive LY3031207 (25, 75, and 275 mg), placebo, or celecoxib (400 mg) once daily for 28 days. The safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated...
September 2, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28861933/desmosterol-accumulation-in-users-of-amiodarone
#12
Piia Simonen, Jukka Lehtonen, Anna-Maija Lampi, Vieno Piironen, Ulf-Håkan Stenman, Markku Kupari, Helena Gylling
BACKGROUND: Amiodarone is an effective and widely used antiarrhythmic drug with many possible adverse effects including hypercholesterolemia and hepatotoxicity. OBJECTIVE: Our aim was to evaluate how long-term amiodarone treatment affects cholesterol metabolism. METHODS: The study population consisted of 56 cardiac patients, of whom 20 were on amiodarone (amiodarone + group) and 36 did not use the drug (amiodarone - group). We also studied a control group of 124 individuals selected randomly from the population...
September 1, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28857200/by-inhibiting-pfkfb3-aspirin-overcomes-sorafenib-resistance-in-hepatocellular-carcinoma
#13
Sainan Li, Weiqi Dai, Wenhui Mo, Jingjing Li, Jiao Feng, Liwei Wu, Tong Liu, Qiang Yu, Shizan Xu, Wenwen Wang, Xiya Lu, Qinghui Zhang, Kan Chen, Yujing Xia, Jie Lu, Yingqun Zhou, Xiaoming Fan, Ling Xu, Chuanyong Guo
Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In the present study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo...
August 31, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28842351/screening-of-pharmacokinetic-properties-of-fifty-dihydropyrimidin-thi-one-derivatives-using-a-combo-of-in-vitro-and-in-silico-assays
#14
Mariana Matias, Ana Fortuna, Joana Bicker, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, but their pharmacokinetic properties remain almost unknown. Herein, fifty dihydropyrimidin(thi)ones were submitted to in vitro screening tests using parallel artificial membrane permeability assays (PAMPA) to evaluate their apparent permeability (Papp) through intestinal membrane and blood-brain barrier models, and cell-based assays to assess their interference on the efflux transporter P-glycoprotein (P-gp). Moreover, a set of kinetic and toxicological parameters was also estimated employing a new computational tool, the pkCSM...
August 24, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28837088/modulatory-effect-of-methanol-extract-of-piper-guineense-in-ccl%C3%A2-induced-hepatotoxicity-in-male-rats
#15
Babatunji Emmanuel Oyinloye, Foluso Oluwagbemiga Osunsanmi, Basiru Olaitan Ajiboye, Oluwafemi Adeleke Ojo, Abidemi Paul Kappo
This study seeks to investigate the possible protective role of the methanol extract of Piper guineense seeds against CCl₄-induced hepatotoxicity in an animal model. Hepatotoxicity was induced by administering oral doses of CCl₄ (1.2 g/kg bw) three times a week for three weeks. Group 1 (Control) and Group 2 (CCl₄) were left untreated; Piper guineense (PG; 400 mg/kg bw) was administered to Group 3 (T₁) by oral gavage for 14 days prior to the administration of CCl₄ and simultaneously with CCl₄; PG (400 mg/kg bw) was administered simultaneously with CCl₄ in Group 4 (T₂); and Livolin forte (20 mg/kg bw) was administered simultaneously with CCl₄ in Group 5 (T₃), the standard drug group...
August 24, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28831409/the-idiosyncratic-drug-induced-gene-expression-changes-in-hepg2-cells
#16
J Jiang, K Mathijs, L Timmermans, S M Claessen, A Hecka, J Weusten, R Peters, J H van Delft, J C S Kleinjans, D G J Jennen, T M de Kok
The inflammatory stress has been associated with an increase in susceptibility to idiosyncratic drug-induced liver injury (DILI). However, the molecular mechanisms of this inflammation-associated idiosyncratic drug hepatotoxicity remain unknown. We exposed HepG2 cells with high and low doses of three idiosyncratic (I) and three non-idiosyncratic (N) compounds, in the presence (I+ and N+) or absence (I- and N-) of a cytokine mix for 6, 12 and 24 h. To investigate the genome-wide expression patterns, microarray was performed using the Agilent 4×44K Whole Human Genome chips...
October 2017: Data in Brief
https://www.readbyqxmd.com/read/28822616/the-garcinia-kola-biflavonoid-kolaviron-attenuates-experimental-hepatotoxicity-induced-by-diclofenac
#17
Quadri Kunle Alabi, Rufus Ojo Akomolafe, Olaoluwa Sesan Olukiran, Wale Johnson Adeyemi, Aliyat Olajumoke Nafiu, Modinat Adebukola Adefisayo, Joseph Gbenga Omole, Deborah Ifeoluwa Kajewole, Oluwole Olaniyi Odujoko
This study sought to investigate the effects of kolaviron on diclofenac-induced hepatotoxicity in rats. Sixty male Wistar rats were divided into 6 groups of 10 rats each as follows: a control group that received oral propylene glycol and treatment groups that received diclofenac alone, diclofenac followed by Livolin Forte (a reference drug), or diclofenac followed by kolaviron at three different doses. At the end of the study period, five rats per group were sacrificed under ketamine hydrochloride anesthetic, 24h after treatment, while the other 5 rats in the group were allowed to recover for 2 weeks before being sacrificed...
August 16, 2017: Pathophysiology: the Official Journal of the International Society for Pathophysiology
https://www.readbyqxmd.com/read/28822195/-pharmacokinetics-of-%C3%AE-asarone-after-intranasal-and-intravenous-administration-with-pla-%C3%AE-asarone-nanoparticles
#18
Jin Lu, Li-Wei Guo, Ting-Ming Fu, Guo-Long Zhu, Zhen-Nan Dai, Guan-Jun Zhan, Li-Li Chen
PLA-α-asarone nanoparticles were prepared by using organic solvent evaporation method, and their in vivo distribution and brain targeting after intranasal administration were studied as compared with intravenous administration. The results showed that brain targeting coefficient of PLA-α-asarone nanoparticles after intranasal and intravenous administration was 1.65 and 1.16 respectively. The absolute bioavailability, brain-targeting efficiency and the percentage of nasal-brain delivery of PLA-α-asarone nanoparticles were 74...
June 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/28820004/drug-induced-liver-injury-in-children-clinical-observations-animal-models-and-regulatory-status
#19
Qiang Shi, Xi Yang, James J Greenhaw, Alec Thomas Salminen, Gary M Russotti, William F Salminen
Drug-induced liver injury in children (cDILI) accounts for about 1% of all reported adverse drug reactions throughout all age groups, less than 10% of all clinical DILI cases, and around 20% of all acute liver failure cases in children. The overall DILI susceptibility in children has been assumed to be lower than in adults. Nevertheless, controversial evidence is emerging about children's sensitivity to DILI, with children's relative susceptibility to DILI appearing to be highly drug-specific. The culprit drugs in cDILI are similar but not identical to DILI in adults (aDILI)...
January 1, 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28809737/acute-liver-failure-due-to-etodolac-a-selective-cycloxygenase-2-cox-2-inhibitor-non-steroidal-anti-inflammatory-drug-established-by-rucam-based-causality-assessment
#20
Sunil Taneja, Pramod Kumar, Sahaj Rathi, Ajay Duseja, Virendra Singh, Radha Krishan Dhiman, Yogesh Kumar Chawla
Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare...
August 8, 2017: Annals of Hepatology
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