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drug induced liver toxicity

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https://www.readbyqxmd.com/read/28092841/phytochemical-study-and-protective-effect-of-trigonella-foenum-graecum-fenugreek-seeds-against-carbon-tetrachloride-induced-toxicity-in-liver-and-kidney-of-male-rat
#1
Sakhria Mbarki, Hichem Alimi, Hafsia Bouzenna, Abdelfettah Elfeki, Najla Hfaiedh
Liver and kidney diseases are a global concern, therefore considerable efforts to obtain fine herbs useful as drugs from medicinal plants are currently in progress. The aim of this work was to study the antioxidant effects of previous supplementation with fenugreek seeds (FS) against carbon tetrachloride (CCl4) toxicity in the liver and kidney. CCl4 toxicity was induced by one dose (i.g. 5ml CCl4/kg of body weight, 50% CCl4 in olive oil) after 7 weeks of normal diet or diet rich in 10% of grinded fenugreek seeds (20g of pellet rat food/rat/day)...
January 13, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28092840/suppressive-effect-of-spirulina-fusiformis-on-diclofenac-induced-hepato-renal-injury-and-gastrointestinal-ulcer-in-wistar-albino-rats-a-biochemical-and-histological-approach
#2
Jerine Peter S, Kadar Basha S, R Giridharan, Udhaya Lavinya B, Evan Prince Sabina
CONTEXT: The non-steroidal anti-inflammatory drug (NSAID), diclofenac causes hepato-renal toxicity and gastric ulcer. The aim of this study was to investigate the protective effect of Spirulina fusiformis on Diclofenac-induced toxicity in Wistar albino rats. METHODS: Rats were treated as follows: normal control (group I); diclofenac (50mg/kgb.w., i.p.) treated rats (group II); diclofenac-induced (50mg/kgb.w., i.p.) rats treated with Spirulina fusiformis (400mg/kgb...
January 13, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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/28073113/in-vitro-to-in-vivo-extrapolation-for-drug-induced-liver-injury-using-a-pair-ranking-method
#4
Zhichao Liu, Hong Fang, Jürgen Borlak, Ruth Roberts, Weida Tong
Preclinical animal toxicity studies may not accurately predict human toxicity. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. We examined in vitro to in vivo extrapolation (IVIVE) of gene expression data obtained from The Open Japanese Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) for 131 compounds given to rats for 28 days, and to human or rat hepatocytes for 24 hours. Notably, a Pair Ranking (PRank) method was developed to assess IVIVE potential with a PRank score based on the preservation of the order of similarity rankings of compound pairs between the platforms using a receiver operating characteristic (ROC) curve analysis to measure area under the curve (AUC)...
January 11, 2017: ALTEX
https://www.readbyqxmd.com/read/28070111/a-monkey-model-of-acetaminophen-induced-hepatotoxicity-phenotypic-similarity-to-human
#5
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/28069987/transgenic-zebrafish-reporter-lines-as-alternative-in-vivo-organ-toxicity-models
#6
Kar Lai Poon, Xingang Wang, Serene Gp Lee, Ashley S Ng, Wei Huang Goh, Zhonghua Zhao, Muthafar Al-Haddawi, Haishan Wang, Sinnakaruppan Mathavan, Phillip W Ingham, Claudia Mcginnis, Tom J Carney
Organ toxicity, particularly liver toxicity, remains one of the major reasons for termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would therefore find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults...
January 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28065578/acute-liver-injury-and-failure
#7
REVIEW
Vincent Thawley
Acute liver injury and acute liver failure are syndromes characterized by a rapid loss of functional hepatocytes in a patient with no evidence of pre-existing liver disease. A variety of inciting causes have been identified, including toxic, infectious, neoplastic, and drug-induced causes. This article reviews the pathophysiology and clinical approach to the acute liver injury/acute liver failure patient, with a particular emphasis on the diagnostic evaluation and care in the acute setting.
January 5, 2017: Veterinary Clinics of North America. Small Animal Practice
https://www.readbyqxmd.com/read/28063906/pyrazinamide-induced-hepatotoxicity-is-alleviated-by-4-pba-via-inhibition-of-the-perk-eif2%C3%AE-atf4-chop-pathway
#8
Hong-Li Guo, Hozeifa M Hassan, Ping-Ping Ding, Shao-Jie Wang, Xi Chen, Tao Wang, Li-Xin Sun, Lu-Yong Zhang, Zhen-Zhou Jiang
Pyrazinamide (PZA)-induced serious liver injury, but the exact mechanism of PZA-induces hepatotoxicity remains controversial. Endoplasmic reticulum (ER) stress-caused cell apoptosis plays a critical role in the development of drug-induced liver injury (DILI). However, the direct connection between PZA toxicity and ER stress is unknown. In this study, we describe the role of ER stress in PZA induced hepatotoxicity in vivo and in vitro. We found that PZA induces apoptosis in HepG2 cells, and causes liver damage in rats, characterized by increased serum ALT, AST and TBA levels...
January 4, 2017: Toxicology
https://www.readbyqxmd.com/read/28058783/characterization-of-phase-i-and-phase-ii-hepatic-metabolism-and-reactive-intermediates-of-larrea-nitida-cav-and-its-lignan-compounds
#9
Hyesoo Jeong, Soolin Kim, Jimin Lee, Jin Young Park, Wenmei Zhou, Xiyuan Liu, So Dam Kim, Yun Seon Song, Chang-Young Jang, Sei-Ryang Oh, Sangho Choi, Minsun Chang
Larrea nitida Cav. (LNC), which belongs to the family Zygophyllaceae, is widely indigenous and used in South America to treat various pathological conditions. It contains the antioxidant and antiinflammatory but toxic nordihydroguaiaretic acid (NDGA) as well as O-methylated metabolite of NDGA (MNDGA) as bioactive compounds. The hepatic metabolism-based toxicological potential of extracts of LNC (LNE), NDGA, and MNDGA has not previously been reported. The present study aimed to characterize the phase I and phase II hepatic metabolism and reactive intermediates of LNE, NDGA, and MNDGA and their effects on the major drug-metabolizing enzymes in vitro and ex vivo...
January 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28056947/triptolide-induces-hepatotoxicity-via-inhibition-of-cyp450s-in-rat-liver-microsomes
#10
Yan Lu, Tong Xie, Yajie Zhang, Fuqiong Zhou, Jie Ruan, Weina Zhu, Huaxu Zhu, Zhe Feng, Xueping Zhou
BACKGROUND: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored. METHODS: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28053072/the-promise-of-new-technologies-to-reduce-refine-or-replace-animal-use-while-reducing-risks-of-drug-induced-liver-injury-in-pharmaceutical-development
#11
Frank D Sistare, William B Mattes, Edward L LeCluyse
Drug induced liver injury (DILI) has contributed more to marketed pharmaceutical withdrawals and clinical development failures than any other human organ toxicity. DILI seen in animal studies also frequently leads to the discontinuation of promising drug candidates very early in the pipeline. This manuscript reviews and critically assesses the current regulatory expectations; the current drug development approaches, strategies, and gaps; and the numerous exciting opportunities becoming available to address these gaps through technological advances...
December 2016: ILAR Journal
https://www.readbyqxmd.com/read/28052641/protective-effects-of-melatonin-on-the-activity-of-sod-cat-gsh-px-and-gsh-content-in-organs-of-mice-after-administration-of-snp
#12
Zofia Goc, Waldemar Szaroma, Edyta Kapusta, Karol Dziubek
Sodium nitroprusside (SNP) is an antihypertensive drug with proven dose-dependent toxic effects attributed mainly to the production of cyanide but also excesive nitric oxide (NO) and derived reactive species. The present study evaluated whether melatonin administration would have time-dependent protective effect against SNP−induced toxicity. Male Swiss mice were used in this study. Control mice were treated with 0.9% NaCl; the second group was injected with 10 mg melatonin (MEL)/kg body weight (b.w.); the third group was given SNP at the dose of 3,6 mg/kg b...
28, 2017: Chinese Journal of Physiology
https://www.readbyqxmd.com/read/28032146/effects-of-31-fda-approved-small-molecule-kinase-inhibitors-on-isolated-rat-liver-mitochondria
#13
Jun Zhang, Alec Salminen, Xi Yang, Yong Luo, Qiangen Wu, Matthew White, James Greenhaw, Lijun Ren, Matthew Bryant, William Salminen, Thomas Papoian, William Mattes, Qiang Shi
The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans. The KIs were incubated with mitochondria or submitochondrial particles at concentrations ranging from therapeutic maximal blood concentrations (Cmax) levels to 100-fold Cmax levels...
December 28, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/28031524/adenosine-5-monophosphate-blocks-acetaminophen-toxicity-by-increasing-ubiquitination-mediated-ask1-degradation
#14
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...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/28029653/antitumor-effect-of-an-adeno-associated-virus-expressing-apolipoprotein-a-1-fused-to-interferon-alpha-in-an-interferon-alpha-resistant-murine-tumor-model
#15
Marcos Vasquez, Vladimir Paredes-Cervantes, Fernando Aranda, Nuria Ardaiz, Celia Gomar, Pedro Berraondo
Interferon alpha (IFNα) is a cytokine approved for the treatment of several types of cancer. However, the modest effect on overall survival and the high toxicity associated with the treatment has reduced the clinical use of this cytokine. In this study, we have developed a tumor model that reproduces this clinical setting. A high dose of an adeno-associated virus encoding IFNα (AAV-IFNα) was able to eradicate a liver metastases model of colon cancer but induced lethal pancytopenia. On the other hand, a safe dose of AAV-IFNα was not able to eliminate the liver metastases of colon cancer...
December 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028769/are-polymorphisms-in-genes-relevant-to-drug-disposition-predictors-of-susceptibility-to-drug-induced-liver-injury
#16
Ann K Daly
Despite considerable progress in identifying specific HLA alleles as genetic risk factors for some forms of drug-induced liver injury, progress in understanding whether genetic polymorphisms relevant to drug disposition also contribute to risk for developing this serious toxicity has been more limited. Evidence from both candidate-gene case control studies and genome-wide association studies is now discussed. In the case of genes relevant to drug metabolism, polymorphisms in cytochromes P450, UDP-glucuronosyltransferases, N-acetyltransferases and glutathione S-transferases as risk factors for DILI are assessed...
December 27, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/28028586/role-of-mirna-and-its-potential-as-a-novel-diagnostic-biomarker-in-drug-induced-liver-injury
#17
REVIEW
Sukumaran Sanjay, Chandrashekaran Girish
PURPOSE: MicroRNAs (miRNA or miR) are the most abundant and stable class of small RNA. Unlike the typical RNA molecules present in the cell, they do not encode proteins but can control translation. and Hhence, they are found to play a major role in the regulation of cellular processes. miRNAs have been shown to differentially regulate various genes, and the expression levels of some miRNAs changes several fold in liver and serum, during drug- induced toxicity. This review summarises some of the latest findings about the biological functions of miRNA and its potential use as diagnostic biomarkers in drug- induced liver injury...
December 27, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28018221/metabolomic-study-on-idiosyncratic-liver-injury-induced-by-different-extracts-of-polygonum-multiflorum-in-rats-integrated-with-pattern-recognition-and-enriched-pathways-analysis
#18
Chun-Yu Li, Can Tu, Dan Gao, Rui-Lin Wang, Hai-Zhu Zhang, Ming Niu, Rui-Yu Li, Cong-En Zhang, Rui-Sheng Li, Xiao-He Xiao, Mei-Hua Yang, Jia-Bo Wang
Currently, numerous liver injury cases related to a famous Chinese herb- Polygonum Multiflorum (Heshouwu in Chinese) have attracted great attention in many countries. Our previous work showed that Heshouwu-induced hepatotoxicity belonged to idiosyncratic drug-induced liver injury (IDILI). Unfortunately, the components and mechanisms attributed to IDILI of Heshouwu are difficult to determine and thus remain unknown. Attempts to explore puzzles, we prepared the chloroform (CH)-, ethyl acetate (EA)-, and residue (RE) extracts of Heshouwu to investigate IDILI constituents and underlying mechanisms, using biochemistry, histopathology, and metabolomics examinations...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28017537/human-leukocyte-antigen-and-idiosyncratic-adverse-drug-reactions
#19
REVIEW
Toru Usui, Dean J Naisbitt
A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis...
November 18, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28012798/generation-of-human-pluripotent-stem-cell-derived-hepatocyte-like-cells-for-drug-toxicity-screening
#20
REVIEW
Kazuo Takayama, Hiroyuki Mizuguchi
Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes are limited, making it difficult to supply the abundant quantities required for large-scale drug toxicity screening. Therefore, there is an urgent need for a novel unlimited, efficient, inexpensive, and predictive model which can be applied for large-scale drug toxicity screening...
October 26, 2016: Drug Metabolism and Pharmacokinetics
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