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https://www.readbyqxmd.com/read/28640208/associations-of-drug-lipophilicity-and-extent-of-metabolism-with-drug-induced-liver-injury
#1
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/28627888/investigation-of-drug-induced-hepatotoxicity-and-its-remediation-pathway-with-reaction-based-fluorescent-probes
#2
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/28617228/prediction-models-for-drug-induced-hepatotoxicity-by-using-weighted-molecular-fingerprints
#3
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/28616908/-the-correlation-between-micrornas-in-serum-and-the-extent-of-liver-injury
#4
Yi-Nan Zuo, Xue-Ling He, Xue-Ni Shi, Shi-Hang Wei, Hai-Lin Yin
OBJECTIVES: To investigate the correlation between the absolute quantification of the microRNAs (miR-122, miR-451, miR-92a, miR-192) in serum during acute liver injury and the extent of liver injury on rat models of CCl4 induced acute liver injury and mice models of acetaminophen (APAP) induced acute liver injury. Furthermore, to investigate the correlation between the absolute quantification of microRNAs in serum and the drug induced liver injury pathological scoring system (DILI-PSS)...
May 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28615926/mechanistic-modelling-of-drug-induced-liver-injury-investigating-the-role-of-innate-immune-responses
#5
Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration...
2017: Gene Regulation and Systems Biology
https://www.readbyqxmd.com/read/28612260/utility-of-spherical-human-liver-microtissues-for-prediction-of-clinical-drug-induced-liver-injury
#6
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/28603098/comparison-of-efficacy-of-folic-acid-and-silymarin-in-the-management-of-antiepileptic-drug-induced-liver-injury-a-randomized-clinical-trial
#7
Masoumeh Asgarshirazi, Mamak Shariat, Mahdi Sheikh
BACKGROUND: Liver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries (DILI) in children. Although withdrawal of the causative agent is the only proved treatment for DILI, in some clinical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with antioxidant actions for the management of DILI. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy...
June 2017: Hepatobiliary & Pancreatic Diseases International: HBPD INT
https://www.readbyqxmd.com/read/28602170/treatment-options-for-metastatic-colorectal-cancer-in-patients-with-liver-dysfunction-due-to-malignancy
#8
REVIEW
L Faugeras, A Dili, A Druez, B Krug, C Decoster, L D'Hondt
BACKGROUND: The survival of colorectal cancer patients is frequently determined by the extent of metastatic invasion to the liver; in cases of major involvement, therapeutic strategies are limited because the liver is necessary for drug metabolism. MATERIAL AND METHODS: We have reviewed articles about the pharmacokinetic profiles of each drug used in colorectal cancer patients with hepatic dysfunction to determine which of these treatments are most feasible. RESULTS: Some drugs appear to be feasible options for patients with hepatic insufficiency...
July 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28566469/visceral-adipose-tissue-activated-macrophage-content-and-inflammatory-adipokine-secretion-is-higher-in-pre-eclampsia-than-in-healthy-pregnancy
#9
Shahzya Huda, FIona Jordan, JAck Bray, Gillian Love, Reba Payne, Naveed Sattar, Dilys J Freeman
Obesity increases preeclampsia risk. Adipose tissue inflammation may contribute to the clinical syndrome of pre-eclampsia. We compared adipose tissue macrophage infiltration and release of pro-inflammatory adipokines in pre-eclampsia and healthy pregnancy. Subcutaneous and visceral adipose tissue biopsies were collected from healthy (n=13) and preeclampsia (n=13) mothers. Basal and lipopolysaccharide stimulated adipocyte TNFα, IL-6, CCL-2 and CRP release was measured. Adipose tissue cell densities of activated (cfms(+)) and total (CD68(+)) macrophages were determined...
May 31, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28559049/attenuation-of-thioacetamide-induced-hepatocellular-injury-by-short-term-repeated-injections-associated-with-down-regulation-of-metabolic-enzymes-and-relationship-with-mhc-class-ii-presenting-cells
#10
Mizuki Kuramochi, Takeshi Izawa, Munmun Pervin, Alexandra Bondoc, Mitsuru Kuwamura, Jonathan LaMarre, Jyoji Yamate
The liver is the primary organ participating in the metabolism of xenobiotics and is therefore an important target in the safety assessment of drugs, chemicals and environmental toxins. Drug-induced liver injury (DILI) has recently become widely recognized in human medicine as an adverse event. The progression of DILI often involves "damage-associated molecular patterns" (DAMPs) of gene and protein expression such as high-mobility group boxes (HMGBs), S100 proteins and heat shock proteins (Hsp). DAMPs are released from injured or necrotic cells and are bound to Toll-like receptors (TLRs) and modulate inflammatory reactions...
May 27, 2017: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
https://www.readbyqxmd.com/read/28555362/the-incidence-of-drug-and-herbal-and-dietary-supplement-induced-liver-injury-preliminary-findings-from-gastroenterologist-based-surveillance-in-the-population-of-the-state-of-delaware
#11
Maricruz Vega, Manisha Verma, David Beswick, Stephanie Bey, Jared Hossack, Nathan Merriman, Ashish Shah, Victor Navarro
BACKGROUND AND AIM: The population-based incidence rate of drug-induced liver injury (DILI) in the USA is not known. The Drug-Induced Liver Injury Network (DILIN) accrues cases of hepatotoxicity due to medications and herbal and dietary supplements (HDS) from limited geographical areas. The current analysis was an ancillary study of DILIN aimed at determining the annual incidence of DILI in the USA on a population basis, through surveillance in the state of Delaware. METHODS: At the outset of the study, there were 41 gastroenterologists in the state of Delaware and all agreed to participate in surveillance for DILI, which comprised active reporting of suspected cases to the DILIN...
May 29, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/28553770/involvement-of-reactive-metabolites-of-diclofenac-in-cytotoxicity-in-sandwich-cultured-rat-hepatocytes
#12
Atsushi Kawase, Ryota Hashimoto, Mai Shibata, Hiroaki Shimada, Masahiro Iwaki
BACKGROUND AND OBJECTIVES: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-β-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4'hydroxydiclofenac (4'OH-DIC) in acute DILI...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28543844/death-and-liver-transplantation-within-two-years-of-onset-of-drug-induced-liver-injury
#13
Paul H Hayashi, Don Rockey, Robert J Fontana, Hans L Tillmann, Neil Kaplowitz, Huiman Barnhart, Jiezhan Gu, Naga P Chalasani, K Rajender Reddy, Averell H Sherker, Jay H Hoofnagle
Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, contributory or no role in the fatality...
May 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28539989/hepatic-complications-induced-by-immunosuppressants-and-biologics-in-inflammatory-bowel-disease
#14
REVIEW
My-Linh Tran-Minh, Paula Sousa, Marianne Maillet, Matthieu Allez, Jean-Marc Gornet
The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate...
May 8, 2017: World Journal of Hepatology
https://www.readbyqxmd.com/read/28529062/quantitative-targeted-bile-acid-profiling-as-new-markers-for-dili-in-a-model-of-methapyrilene-induced-liver-injury-in-rats
#15
Markus Slopianka, Anne Herrmann, Mira Pavkovic, Heidrun Ellinger-Ziegelbauer, Rainer Ernst, Angela Mally, Matthias Keck, Bjoern Riefke
Recently, bile acids (BAs) were reported as promising markers for drug-induced liver injury (DILI). BAs have been suggested to correlate with hepatocellular and hepatobiliary damage; however a clear connection of BA patterns with different types of DILI remains to be established. To investigate if BAs can improve the assessment of liver injury, 20 specific BAs were quantitatively profiled via LC-MS/MS in plasma and liver tissue in a model of methapyrilene-induced liver injury in rats. Methapyrilene, a known hepatotoxin was dosed daily over 14-days at doses of 30 and 80mg/kg, followed by a recovery phase of 10days...
May 19, 2017: Toxicology
https://www.readbyqxmd.com/read/28521054/in-silico-prediction-of-drug-induced-liver-injury-based-on-adverse-drug-reaction-reports
#16
Xiang-Wei Zhu, Shao-Jing Li
Drug-induced liver injury (DILI) is a major cause of drug attrition. Currently existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for DILI. Furthermore, their practical applications were limited by lack of new hepatotoxicity data. In this study, we first collected and curated a novel set of 122 DILI-positive and 932 DILI-negative drugs from online adverse drug reports using proportional reporting ratios as the signal detection method. Second, three strategies (under-sampling the majority class, synthetic minority over-sampling technique, and adjusting decision threshold approach) were employed to develop predictive classification models to cope with the unbalanced dataset...
May 17, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28511055/professional-midwifery-in-guatemala-a-qualitative-exploration-of-perceptions-attitudes-and-expectations-among-stakeholders
#17
Anna Summer, Sylvia Guendelman, Edgar Kestler, Dilys Walker
BACKGROUND: Despite recommendations that women give birth with a skilled birth attendant (SBA), 70% of births in Guatemala occur outside health facilities with informally trained traditional birth attendants (TBAs). To increase SBA in rural, indigenous communities, a professional midwifery school accredited by the government is scheduled to open in 2017. Drawing from Filby's model on barriers to the successful integration of professional midwifery into health systems, this paper aims to identify threats - and facilitators-toward professional midwifery's re-introduction in Guatemala...
May 4, 2017: Social Science & Medicine
https://www.readbyqxmd.com/read/28508325/preliminary-results-of-a-novel-algorithmic-method-aiming-to-support-initial-causality-assessment-of-routine-pharmacovigilance-case-reports-for-medication-induced-liver-injury-the-pv-rucam
#18
Erik Scalfaro, Henk Johan Streefkerk, Michael Merz, Christoph Meier, David Lewis
INTRODUCTION: Data incompleteness in pharmacovigilance (PV) health records limits the use of current causality assessment methods for drug-induced liver injury (DILI). In addition to the inherent complexity of this adverse event, identifying cases of high causal probability is difficult. OBJECTIVE: The aim was to evaluate the performance of an improved, algorithmic and standardised method called the Pharmacovigilance-Roussel Uclaf Causality Assessment Method (PV-RUCAM), to support assessment of suspected DILI...
May 15, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/28506365/drug-induced-liver-injury-the-hepatic-pathologist-s-approach
#19
REVIEW
David E Kleiner
The evaluation of liver biopsies in suspected drug-induced liver injury (DILI) can be complex. The biopsy may be approached systematically, by identification of histologic lesions and then identification of the overall pattern of injury. Potential DILI must be separated from concomitant non-DILI liver disease. The findings can be analyzed with respect to the various prescription and nonprescription medications and dietary supplements under suspicion to provide a complete interpretation of the findings. The pathologic findings, the histologic differential diagnosis, and expert interpretation are part of a complete biopsy assessment and provide information that is of greatest value in patient management...
June 2017: Gastroenterology Clinics of North America
https://www.readbyqxmd.com/read/28494844/west-nile-virus-surveillance-in-europe-moving-towards-an-integrated-animal-human-vector-approach
#20
Céline M Gossner, Laurence Marrama, Marianne Carson, Franz Allerberger, Paolo Calistri, Dimitrios Dilaveris, Sylvie Lecollinet, Dilys Morgan, Norbert Nowotny, Marie-Claire Paty, Danai Pervanidou, Caterina Rizzo, Helen Roberts, Friedrich Schmoll, Wim Van Bortel, Andrea Gervelmeyer
This article uses the experience of five European countries to review the integrated approaches (human, animal and vector) for surveillance and monitoring of West Nile virus (WNV) at national and European levels. The epidemiological situation of West Nile fever in Europe is heterogeneous. No model of surveillance and monitoring fits all, hence this article merely encourages countries to implement the integrated approach that meets their needs. Integration of surveillance and monitoring activities conducted by the public health authorities, the animal health authorities and the authorities in charge of vector surveillance and control should improve efficiency and save resources by implementing targeted measures...
May 4, 2017: Euro Surveillance: Bulletin Européen sur les Maladies Transmissibles, European Communicable Disease Bulletin
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