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drug induced liver toxicity

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https://www.readbyqxmd.com/read/28934241/hla-dr7-and-hla-dq2-transgenic-mouse-strains-tested-as-a-model-system-for-ximelagatran-hepatotoxicity
#1
Hanna Lundgren, Klara Martinsson, Karin Cederbrant, Johan Jirholt, Daniel Mucs, Katja Madeyski-Bengtson, Said Havarinasab, Per Hultman
The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients...
2017: PloS One
https://www.readbyqxmd.com/read/28931315/the-liver-toxicity-knowledge-base-lktb-and-drug-induced-liver-injury-dili-classification-for-assessment-of-human-liver-injury
#2
Shraddha Thakkar, Weida Tong, Minjun Chen, Hong Fang, Zhichao Liu, Ruth Roberts
Drug-induced liver injury (DILI) is challenging drug development, clinical practice and regulation. The Liver Toxicity Knowledge Base (LTKB) provides essential data for DILI study. Areas Covered: The LTKB provided various types of data that can be used to assess and predict DILI. Among much information available, several reference drug lists with annotated human DILI risk are of important. The LTKB DILI classification data include DILI severity concern determined by the FDA drug labeling, DILI severity score from the NIH LiverTox database, and other DILI classification schemes from the literature...
September 21, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28930776/a-phase1b-dose-escalation-study-of-recombinant-circularly-permuted-trail-in-patients-with-relapsed-or-refractory-multiple-myeloma
#3
Jian Hou, Lugui Qiu, Yaozhong Zhao, Xuejun Zhang, Yan Liu, Zhao Wang, Fang Zhou, Yun Leng, Shifang Yang, Hao Xi, Fuxu Wang, Bing Zhu, Wenming Chen, Peng Wei, Xiangjun Zheng
OBJECTIVES: Circularly permuted tumor necrosis factor-related apoptosis-inducing ligand (CPT), or CPT, is a novel antitumor drug candidate. This phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of single-agent CPT in patients with relapsed or refractory multiple myeloma (RRMM), and aimed to identify the recommended dose for the phase 2 study. MATERIALS AND METHODS: Patients received single or multiple doses (once daily for 5 consecutive days per 21-d cycle) of CPT intravenous infusion at doses of 5, 6...
September 19, 2017: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28919711/protective-role-of-quercetin-against-manganese-induced-injury-in-the-liver-kidney-and-lung-and-hematological-parameters-in-acute-and-subchronic-rat-models
#4
Entaz Bahar, Geum-Hwa Lee, Kashi Raj Bhattarai, Hwa-Young Lee, Hyun-Kyoung Kim, Mallikarjun Handigund, Min-Kyung Choi, Sun-Young Han, Han-Jung Chae, Hyonok Yoon
Manganese (Mn) is an important mineral element required in trace amounts for development of the human body, while over- or chronic-exposure can cause serious organ toxicity. The current study was designed to evaluate the protective role of quercetin (Qct) against Mn-induced toxicity in the liver, kidney, lung, and hematological parameters in acute and subchronic rat models. Male Sprague Dawley rats were divided into control, Mn (100 mg/kg for acute model and 15 mg/kg for subchronic model), and Mn + Qct (25 and 50 mg/kg) groups in both acute and subchronic models...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28918124/polyphenols-reported-to-shift-apap-induced-changes-in-mapk-signaling-and-toxicity-outcomes
#5
REVIEW
Ngoc Uy Nguyen, Brendan David Stamper
Due to its widespread availability, acetaminophen (APAP) is the leading cause for drug-induced liver injury in many countries including United States and United Kingdom. When used as recommended, APAP is relatively safe. However, in overdose cases, increased metabolism of APAP to N-acetyl-para-benzoquinoneimine (NAPQI), a reactive metabolite, leads to glutathione (GSH) depletion, oxidative stress, and cellular injury. Throughout this process, a variety of factors play important roles in propagating toxicity, including c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family...
September 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28918038/strategies-for-in%C3%A2-vivo-screening-and-mitigation-of-hepatotoxicity-associated-with-antisense-drugs
#6
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/28911678/averrhoa-bilimbi-fruits-attenuate-hyperglycemia-mediated-oxidative-stress-in-streptozotocin-induced-diabetic-rats
#7
Surya B Kurup, S Mini
Hyperglycemia-mediated oxidative stress plays a major role in the development of diabetic complications. Averrhoa bilimbi Linn. (Oxalidaceae) is a medicinal plant with fruits reported to possess antidiabetic activity. This study evaluated the beneficial effects of the ethyl acetate fraction of A. bilimbi fruit (ABAEE) on the antioxidant/oxidant status in diabetes mellitus. Diabetic rats were treated orally with the ethyl acetate fraction of A. bilimbi fruits at a dose of 25 mg/kg body weight for 60 days. Serum glucose, glycated hemoglobin, plasma insulin, hepatic toxicity markers, antioxidant enzymes, lipid peroxidation products, and liver histopathology were assayed checked after 60 days of extract treatment...
April 2017: Journal of Food and Drug Analysis
https://www.readbyqxmd.com/read/28904294/assessment-of-amiodarone-induced-phospholipidosis-in-chimeric-mice-with-a-humanized-liver
#8
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/28887915/hepatoprotective-naphthalene-diglucoside-from-neanotis-wightiana-aerial-parts
#9
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/28882992/novel-pathways-of-ponatinib-disposition-catalyzed-by-cyp1a1-involving-generation-of-potentially-toxic-metabolites
#10
De Lin, Rumen Kostov, Jeffrey T-J Huang, Colin J Henderson, C Roland Wolf
Ponatinib, a pan-BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML), causes severe side effects including vascular occlusions, pancreatitis, and liver toxicity, although the underlying mechanisms remain unclear. Modifications of critical proteins through reactive metabolites are thought to be responsible for a number of adverse drug reactions. In vitro metabolite screening of ponatinib with human liver microsomes and glutathione revealed unambiguous signals of ponatinib-glutathione (P-GSH) adducts...
October 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28882625/drug-induced-bile-duct-injury
#11
REVIEW
Michele Visentin, Daniela Lenggenhager, Zhibo Gai, Gerd A Kullak-Ublick
Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis...
September 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28878168/metabolomics-analysis-of-urine-samples-from-children-after-acetaminophen-overdose
#12
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/28865237/dose-dependent-acute-liver-injury-with-hypersensitivity-features-in-humans-due-to-a-novel-microsomal-prostaglandin-e-synthase-1-inhibitor
#13
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/28863380/effect-of-two-andrographolide-derivatives-on-cellular-and-rodent-models-of-non-alcoholic-fatty-liver-disease
#14
Erenius Toppo, S Sylvester Darvin, S Esakkimuthu, Mahesh Kumar Nayak, K Balakrishna, K Sivasankaran, P Pandikumar, S Ignacimuthu, N A Al-Dhabi
The prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) is increasing and there is an increasing interest in natural products to treat NAFLD. This study aimed to evaluate the hepatoprotective effect of andrographolide and two of its derivatives; in one the OH group at C-14 was removed and in the other OH groups at C-3 and C-19 were protected. Andrographolide (AN) was isolated from the aerial parts of Andrographis paniculata Wall. Isoandrographolide (IAN) and 3,19-acetonylidene andrographolide (ANA) were derivatized from AN...
August 29, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28855630/ppar%C3%AE-activation-protects-against-cholestatic-liver-injury
#15
Qi Zhao, Rui Yang, Jing Wang, Dan-Dan Hu, Fei Li
Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which ultimately may lead to liver fibrosis and cirrhosis. Here, the preventive and therapeutic effects of peroxisome proliferator-activated receptor α (PPARα) signaling activated by fenofibrate was evaluated on cholestatic liver damage. Metabolomic analysis revealed that alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis resulted in the accumulation of serum long-chain acylcarnitines and triglyceride, and the reduced expression of four fatty acid β-oxidation (β-FAO) relevant genes (Cpt1b, Cpt2, Mcad and Hadha), indicating the disruption of β-FAO...
August 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28853863/nuclear-and-mitochondrial-dna-methylation-patterns-induced-by-valproic-acid-in-human-hepatocytes
#16
Jarno E J Wolters, Simone G J van Breda, Florian Caiment, Sandra M Claessen, Theo M C M de Kok, Jos C S Kleinjans
Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs in the world. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. The aim of this study is to further investigate VPA-induced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, primary human hepatocytes (PHHs) were exposed to an incubation concentration of VPA that was shown to cause steatosis without inducing overt cytotoxicity...
September 13, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28843148/therapeutic-effects-of-syzygium-mundagam-bark-methanol-extract-on-type-2-diabetic-complications-in-rats
#17
Rahul Chandran, Blassan P George, Heidi Abrahamse, Thangaraj Parimelazhagan
Plants are considered as one of the best sources of diabetic therapy. Being a reliable and sustainable medicinal hub, this study directs the use of Syzygium mundagam in exploring the antidiabetic property. Streptozotocin-Nicotinamide (STZ-NA) induced diabetic rats were treated with Syzygium mundagam bark methanol extract (SMBM). Based on acute toxicity study, the doses of the extract were fixed as 100 and 200mg/kg. Glibenclamide was used as reference drug. The blood glucose level and body weight of the rats were monitored for 28days...
August 23, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28837153/cardioprotective-effects-of-fibroblast-growth-factor-21-against-doxorubicin-induced-toxicity-via-the-sirt1-lkb1-ampk-pathway
#18
Shudong Wang, Yonggang Wang, Zhiguo Zhang, Quan Liu, Junlian Gu
Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Fibroblast growth factor 21 (FGF21), as a well-known regulator of glucose and lipid metabolism, was recently shown to exert cardioprotective effects. The aim of this study was to investigate the possible protective effects of FGF21 against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, adult mouse cardiomyocytes, and 129S1/SyImJ mice, which clearly showed cardiac dysfunction and myocardial collagen accumulation accompanying by inflammatory, oxidative stress, and apoptotic damage...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28834334/enhanced-hepatic-functions-of-genetically-modified-mouse-hepatoma-cells-by-spheroid-culture-for-drug-toxicity-screening
#19
Joyita Sarkar, Jyoti Kumari, Jane Marie Tonello, Masamichi Kamihira, Ashok Kumar
While hepatic cell lines are mainly used for in vitro drug induced toxicity studies, they exhibit limited functionalities. To overcome this, we have employed genetically engineered mouse hepatoma cells, Hepa/8F5, wherein expression of liver enriched transcription factors is induced by doxycycline leading to increased functionality. Further enhancement in functionality was achieved by spheroid culture in a previously developed 3D cell culture platform. Cells were seeded in presence of temperature-responsive poly(N-isopropylacrylamide) on poly(N-isopropylacrylamide-co-gelatin) cryogel scaffold based high throughput platform...
August 22, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28831528/association-between-infection-and-severe-drug-adverse-reactions-an-analysis-using-data-from-the-japanese-adverse-drug-event-report-database
#20
Takuya Imatoh, Kimie Sai, Chisato Fukazawa, Yasushi Hinomura, Ryosuke Nakamura, Yoshimi Okamoto-Uchida, Katsunori Segawa, Yoshiro Saito
PURPOSE: It has been reported recently that immune reactions are involved in the pathogenesis of certain types of adverse drug reactions (ADRs). We aimed to determine the associations between infections and drug-induced interstitial lung disease (DILD), rhabdomyolysis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or drug-induced liver injury (DILI) using a spontaneous adverse drug event reporting database in Japan. METHODS: The reported cases were classified into three categories (anti-infectious drug group, concomitant infection group, and non-infection group) based on the presence of anti-infectious drugs (either as primary suspected drug or concomitant drug) and infectious disease...
August 22, 2017: European Journal of Clinical Pharmacology
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