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https://www.readbyqxmd.com/read/28350954/integrating-drug-s-mode-of-action-into-quantitative-structure-activity-relationships-for-improved-prediction-of-drug-induced-liver-injury
#1
Leihong Wu, Zhichao Liu, Scott S Auerbach, Ruili Huang, Minjun Chen, Kristin McEuen, Joshua Zhihua Xu, Hong Fang, Weida Tong
Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a dataset of 333 drugs...
March 28, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28346810/an-automated-multiplexed-hepatotoxicity-and-cyp-induction-assay-using-heparg-cells-in-2d-and-3d
#2
Lindsey M Ott, Karthik Ramachandran, Lisa Stehno-Bittel
Drug-induced liver injury (DILI) and drug-drug interactions (DDIs) are concerns when developing safe and efficacious compounds. We have developed an automated multiplex assay to detect hepatotoxicity (i.e., ATP depletion) and metabolism (i.e., cytochrome P450 1A [CYP1A] and cytochrome P450 3A4 [CYP3A4] enzyme activity) in two-dimensional (2D) and three-dimensional (3D) cell cultures. HepaRG cells were cultured in our proprietary micromold plates and produced spheroids. HepaRG cells, in 2D or 3D, expressed liver-specific proteins throughout the culture period, although 3D cultures consistently exhibited higher albumin secretion and CYP1A/CYP3A4 enzyme activity than 2D cultures...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28341748/drug-induced-liver-injury-recent-advances-in-diagnosis-and-risk-assessment
#3
REVIEW
Gerd A Kullak-Ublick, Raul J Andrade, Michael Merz, Peter End, Andreas Benesic, Alexander L Gerbes, Guruprasad P Aithal
Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI...
March 23, 2017: Gut
https://www.readbyqxmd.com/read/28340562/drug-induced-liver-injury-from-antituberculous-treatment-a-retrospective-study-from-a-large-tb-centre-in-the-uk
#4
Aula Abbara, Sarah Chitty, Jennifer K Roe, Rohma Ghani, Simon M Collin, Andrew Ritchie, Onn Min Kon, John Dzvova, Harriet Davidson, Thomas E Edwards, Charlotte Hateley, Matthew Routledge, Jim Buckley, Robert N Davidson, Laurence John
BACKGROUND: We describe drug-induced liver injury (DILI) secondary to antituberculous treatment (ATT) in a large tuberculosis (TB) centre in London; we identify the proportion who had risk factors for DILI and the timing and outcome of DILI. METHODS: We identified consecutive patients who developed DILI whilst on treatment for active TB; patients with active TB without DILI were selected as controls. Comprehensive demographic and clinical data, management and outcome were recorded...
March 24, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/28323125/minocycline-hepatotoxicity-clinical-characterization-and-identification-of-hla-b%C3%A2-35-02-as-a-risk-factor
#5
Thomas Jacob Urban, Paola Nicoletti, Naga Chalasani, Jose Serrano, Andrew Stolz, Ann Daly, Guruprasad Aithal, John Dillon, Victor Navarro, Joseph Odin, Huiman Barnhart, David Ostrov, Nanye Long, Elizabeth Theresa Cirulli, Paul Brent Watkins, Robert John Fontana
BACKGROUND & AIMS: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline DILI in a well-phenotyped cohort of patients. METHODS: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina...
March 17, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28321390/metabonomics-research-progress-on-liver-diseases
#6
REVIEW
Mengqian Yu, Ying Zhu, Qingwei Cong, Chunyan Wu
Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score...
2017: Canadian Journal of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28319122/can-a-simulation-based-training-program-impact-the-use-of-evidence-based-routine-practices-at-birth-results-of-a-hospital-based-cluster-randomized-trial-in-mexico
#7
Jimena Fritz, Dilys M Walker, Susanna Cohen, Gustavo Angeles, Hector Lamadrid-Figueroa
BACKGROUND: In Mexico, although the majority of births are attended in hospitals, reports have emerged of obstetric violence, use of unsafe practices, and failure to employ evidence-based practices (EBP). Recent attention has refocused global efforts towards provision of quality care that is both patient-centered and evidence-based. Scaling up of local interventions should rely on strong evidence of effectiveness. OBJECTIVE: To perform a secondary analysis to evaluate the impact of a simulation and team-training program (PRONTO) on the performance of EBP in normal births...
2017: PloS One
https://www.readbyqxmd.com/read/28304119/serum-markers-for-mitochondrial-dysfunction-and-cell-death-are-possible-predictive-indicators-for-drug-induced-liver-injury-by-direct-acting-antivirals
#8
Keisuke Kakisaka, Yuichi Yoshida, Yuji Suzuki, Takuro Sato, Hidekatsu Kuroda, Akio Miyasaka, Yasuhiro Takikawa
BACKGROUND & AIM: We prospectively screened patients treated with direct-acting antivirals (DAAs) in order to detect and analyze serum markers that are present prior to the development of drug-induced liver injury (DILI). METHODS: The levels of various serum markers among DILI, non-DILI, and control groups were compared. The DILI group consisted of 8 patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non-DILI group via a matched-group design based on age, gender, and disease severity...
March 17, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/28295448/drug-rechallenge-following-drug-induced-liver-injury
#9
REVIEW
Christine M Hunt, Julie I Papay, Vid Stanulovic, Arie Regev
Drug induced hepatocellular injury is identified internationally by ALT 5x upper limits normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decreases by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT 3-5xULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials, central nervous system, cardiovascular and oncology therapeutics...
March 13, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28294319/grpr-antagonist-protects-from-drug-induced-liver-injury-by-impairing-neutrophil-chemotaxis-and-motility
#10
Rafael S Czepielewski, Natália Jaeger, Pedro E Marques, Maísa M Antunes, Maurício M Rigo, Débora M Alvarenga, Rafaela V Pereira, Rodrigo D da Silva, Tiago G Lopes, Vinícius D da Silva, Bárbara N Porto, Gustavo B Menezes, Cristina Bonorino
Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXCR2 ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration and mechanisms underlying this phenomenon...
March 10, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28292360/acute-on-chronic-liver-failure-causes-clinical-characteristics-and-predictors-of-mortality
#11
Abbas Ali Tasneem, Nasir Hassan Luck
OBJECTIVE: To determine the causes, characteristics and predictors of mortality in patients with acute-on-chronic liver failure (ACLF). STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, from July 2014 to June 2016. METHODOLOGY: All patients with acute-on-chronic liver disease (ACLD) with ages > 12 were included...
January 2017: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
https://www.readbyqxmd.com/read/28289388/hla-b-57-allele-is-associated-with-concomitant-anti-tuberculosis-and-antiretroviral-drugs-induced-liver-toxicity-in-ethiopians
#12
Zelalem Petros, Junko Kishikawa, Eyasu Makonnen, Getnet Yimer, Abiy Habtewold, Eleni Aklillu
Drug-induced liver injury (DILI) is a known adverse effect of both anti-tuberculosis (anti-TB) and antiretroviral (ARV) drugs. Recent studies highlight the implications of genetic predispositions to DILI. We performed a case-control study to identify Human Leukocyte Antigen-B (HLA-B) variant alleles associated with anti-TB and ARV co-treatment induced liver toxicity in Ethiopian TB and HIV co-infected patients. A total of 495 newly diagnosed TB and HIV co-infected patients were enrolled and received rifampicin based anti-TB and efavirenz based ARV therapy...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28276919/-they-say-god-punishes-people-with-hiv-experiences-of-stigma-and-discrimination-among-adults-with-hiv-in-dili-timor-leste
#13
Kate Williams, Bridget G Haire, Sally Nathan
Little is known about the experiences of people with HIV in the small island nation of Timor-Leste. This study explored the HIV-related stigma experiences of adults aged between 18 and 40 living with HIV in Dili, Timor-Leste. Participants were interviewed on topics related to living with HIV, both as key informants describing the experience of others with HIV known to them, and also with respect to their own personal experiences. Findings suggest that people with HIV in Timor-Leste face stigma and discrimination in various contexts...
February 22, 2017: Culture, Health & Sexuality
https://www.readbyqxmd.com/read/28276834/drug-induced-liver-injury-due-to-antibiotics
#14
Einar S Björnsson
Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion...
February 20, 2017: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/28263289/establishment-of-a-mouse-model-of-enalapril-induced-liver-injury-and-investigation-of-the-pathogenesis
#15
Yuji Shirai, Shingo Oda, Sayaka Makino, Koichi Tsuneyama, Tsuyoshi Yokoi
Drug-induced liver injury (DILI) is a major concern in drug development and clinical drug therapy. Since the underlying mechanisms of DILI have not been fully understood in most cases, elucidation of the hepatotoxic mechanisms of drugs is expected. Although enalapril (ELP), an angiotensin-converting enzyme inhibitor, has been reported to cause liver injuries with a low incidence in humans, the precise mechanisms by which ELP causes liver injury remains unknown. In this study, we established a mouse model of ELP-induced liver injury and analyzed the mechanisms of its hepatotoxicity...
March 6, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28257576/evaluation-of-dili-predictive-hypotheses-in-early-drug-development
#16
Rosa Chan, Leslie Z Benet
Drug-induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals. DILI has been shown to be dependent on both daily dose and extent of hepatic metabolism. Yet, early in drug development daily dose is unknown. Here, we perform a comprehensive analysis of the published hypotheses that attempt to predict DILI, including a new analysis of the Biopharmaceutics Drug Disposition Classification System (BDDCS) in evaluating the severity of DILI warnings in drug labels approved by the FDA and the withdrawal status due to adverse drug reactions (ADRs)...
March 15, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28257154/microrna-122-can-be-measured-in-capillary-blood-which-facilitates-point-of-care-testing-for-drug-induced-liver-injury
#17
A D Bastiaan Vliegenthart, Cécile Berends, Carmelita M J Potter, Maiwenn Kersaudy-Kerhoas, James W Dear
AIM: Liver-enriched microRNA-122 (miR-122) is a novel circulating biomarker for drug-induced liver injury (DILI). To date, miR-122 has been measured in serum or plasma venous samples. If miR-122 could be measured in capillary blood obtained from a finger prick it would facilitate point-of-care testing, such as in resource-limited settings that have a high burden of DILI. METHODS: In this study, in healthy subjects, miR-122 was measured by PCR in 3 capillary blood drops taken from different fingers and in venous blood and plasma (N = 20)...
March 3, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28250999/a-rare-case-of-rivaroxaban-causing-delayed-symptomatic-hepatocellular-injury-and-hyperbilirubinemia
#18
Keith Glenn, Patrick Chen, Mustafa Musleh, Rao Pallivi, Melissa Grilliot
Importance. As Rivaroxaban has increased in popularity, it has been accompanied with a growing body of evidence displaying its ability to cause drug induced liver injury (DILI). Observation. A 74-year-old Caucasian female developed Rivaroxaban DILI two weeks after finishing a 14-day course. The patient was symptomatic and jaundiced with elevated transaminases and hyperbilirubinemia with normal lab values two months priorly. Liver biopsies showed mixed inflammatory infiltrate of lymphocytes, neutrophils and eosinophils, rare necrotic hepatocytes, and canalicular and intrahepatocellular cholestasis, all of which are consistent with DILI...
2017: Case Reports in Gastrointestinal Medicine
https://www.readbyqxmd.com/read/28246565/diphenhydramine-as-a-cause-of-drug-induced-liver-injury
#19
Yunseok Namn, Yecheskel Schneider, Isabelle H Cui, Arun Jesudian
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status...
2017: Case Reports in Hepatology
https://www.readbyqxmd.com/read/28238947/identification-of-novel-mrp3-inhibitors-based-on-computational-models-and-validation-using-an-in-vitro-membrane-vesicle-assay
#20
Izna Ali, Matthew A Welch, Yang Lu, Peter W Swaan, Kim L R Brouwer
INTRODUCTION: Multidrug resistance-associated protein 3 (MRP3), an efflux transporter on the hepatic basolateral membrane, may function as a compensatory mechanism to prevent the accumulation of anionic substrates (e.g., bile acids) in hepatocytes. Inhibition of MRP3 may disrupt bile acid homeostasis and is one hypothesized risk factor for the development of drug-induced liver injury (DILI). Therefore, identifying potential MRP3 inhibitors could help mitigate the occurrence of DILI. METHODS: Bayesian models were developed using MRP3 transporter inhibition data for 86 structurally diverse drugs...
February 24, 2017: European Journal of Pharmaceutical Sciences
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