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Ajit Dash, Robert A Figler, Arun J Sanyal, B R Wamhoff
Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH). Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved...
October 19, 2016: Expert Opinion on Drug Metabolism & Toxicology
Katherine J Hahn, Shannon J Morales, James H Lewis
Anticoagulants are a well known cause of drug-induced liver injury (DILI). We recently encountered a 45-year-old male who developed DILI during treatment with enoxaparin, a low-molecular-weight heparin (LMWH), for dural venous thrombosis. The man received enoxaparin 80 mg subcutaneously, twice daily. After 4 days, the patient was asymptomatic but he developed liver aminotransferase elevations: AST 340 U/L and ALT 579 U/L. Investigation revealed an R ratio of 19.9 by day 5 and a Roussel Uclaf Causality Assessment Method score of 10, giving a high probable likelihood that enoxaparin was the cause of hepatic injury...
December 2015: Drug Saf Case Rep
Shu-Jing Yu, Rong Jiang, Ying Z Mazzu, Cai-Bing Wei, Zong-Liang Sun, Yu-Zhen Zhang, Lian-Di Zhou, Qi-Hui Zhang
Drug-induced liver injury (DILI) is the most common cause of acute liver failure. Disruption of the Th17/Treg balance can lead to hepatic inflammation, which causes the main symptoms of DILI. Here we investigate the protective mechanisms of (-)-Epigallocatechin-3-gallate (EGCG) on triptolide (TP)-induced DILI that shows the Th17/Treg imbalance. Pretreatment with EGCG (5[Formula: see text]mg/kg) for 10 days before TP (0.5[Formula: see text]mg/kg) administration in mice significantly reduced the increased alanine aminotransferase (ALT) level ([Formula: see text]) induced by TP treatment...
2016: American Journal of Chinese Medicine
Christine Lin, Salman R Khetani
Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions...
2016: BioMed Research International
S Wattanapokayakit, T Mushiroda, H Yanai, N Wichukchinda, C Chuchottawon, S Nedsuwan, A Rojanawiwat, S Denjanta, T Kantima, J Wongyai, W Suwankesawong, W Rungapiromnan, R Kidkeukarun, W Bamrungram, A Chaiwong, S Suvichapanich, S Mahasirimongkol, K Tokunaga
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI. OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients. METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls...
October 2016: International Journal of Tuberculosis and Lung Disease
Elena Cabb, Shanna Baltar, David Wes Powers, Karthik Mohan, Antonio Martinez, Eric Pitts
Drug-induced liver injury (DILI) presents as a broad spectrum of adverse drug reactions which can range from a mild elevation in liver enzymes to fulminant liver failure. The primary goal is to identify DILI early when the patient's liver enzymes are elevated and to discontinue the offending agent as soon as possible to prevent further injury. Herbal, dietary supplements and anabolic steroids represent a significant component of the drugs thought to cause DILI in the United States. Unlike all other drugs known to cause DILI, these drugs fall into a category of injury that is neither intrinsic nor idiosyncratic due to overlapping characteristics between the two...
May 2016: Case Reports in Gastroenterology
Katalin Jemnitz, Attila Bátai-Konczos, Mónika Szabó, Enikő Ioja, Orsolya Kolacsek, Tamás I Orbán, György Török, László Homolya, Eszter Kovács, István Jablonkai, Zsuzsa Veres
Increasing number of papers demonstrate that Kupffer cells (KCs) play a role in the development of drug induced liver injury (DILI). Furthermore, elevated intracellular Ca(2+) level of hepatocytes is considered as a common marker of DILI. Here we applied an in vitro model based on hepatocyte mono- and hepatocyte/KC co-cultures (H/KC) isolated from transgenic rats stably expressing the GCaMP2 fluorescent Ca(2+) sensor protein to investigate the effects of polycationic (G5), polyanionic (G4.5) and polyethylene-glycol coated neutral (G5 Peg) dendrimers known to accumulate in the liver, primarily in KCs...
October 4, 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Ren-Jie Lu, Yan Zhang, Feng-Lei Tang, Zhong-Wei Zheng, Zheng-Da Fan, Shan-Mei Zhu, Xian-Feng Qian, Na-Na Liu
Drug-induced liver injury (DILI) is often undiagnosed or misdiagnosed clinically because of diagnostic difficulties caused by lack of laboratory-specific serological markers. In this study, we comprehensively assessed the clinical characteristics, laboratory indices, hepatotoxic drugs, risk factors and outcomes concerning DILI, and explored the similarities in mechanisms between Chinese and Western drug-induced DILI. Patients with a first diagnosis of DILI and a Roussel Uclaf Causality Assessment Method (RUCAM) score >3 points were enrolled for systematic retrospective study...
October 2016: Experimental and Therapeutic Medicine
Franck A Atienzar, Eric A Blomme, Minjun Chen, Philip Hewitt, J Gerry Kenna, Gilles Labbe, Frederic Moulin, Francois Pognan, Adrian B Roth, Laura Suter-Dick, Okechukwu Ukairo, Richard J Weaver, Yvonne Will, Donna M Dambach
Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions...
2016: BioMed Research International
Simon H J Brown, Samuel R Eather, Dilys J Freeman, Barbara J Meyer, Todd W Mitchell
In preeclampsia, maternal insulin resistance leads to defective expansion of adipocytes, enhanced adipocyte lipolysis, up-regulation of very low density lipoprotein synthesis, maternal hypertriglyceridaemia and the potential for ectopic fat storage. Our aim was to quantitate and compare the total amount and type of lipid in placenta from pregnancies complicated with preeclampsia and healthy pregnancies. Quantitative lipid analysis of lipid extracts from full thickness placental biopsies was carried out by shotgun lipidomics...
2016: PloS One
Kathleen M Gura, Andrew E Mulberg, Paul D Mitchell, John Yap, Clara Y Kim, Minjun Chen, Alexis Potemkin, Mark Puder
BACKGROUND: Intestinal failure-associated liver disease (IFALD) is complex and diagnosed by concurrent use of parenteral nutrition, clinical presentation, and alterations in hepatic biomarkers exclusive of other causes of liver disease. In comparison with individual measures, composite biomarkers may provide a more effective means for assessing disease progression and response to treatment than single parameters. Since IFALD is considered by some to be a type of drug-induced liver injury (DILI), those diagnostic criteria could potentially be used in this population...
September 28, 2016: JPEN. Journal of Parenteral and Enteral Nutrition
Jun Yang, Ya-Li Yu, Yu Jin, Ying Zhang, Chang-Qing Zheng
AIM: To summarize and compare the clinical characteristics of drug-induced liver injury (DILI) and primary biliary cirrhosis (PBC). METHODS: A total of 124 patients with DILI and 116 patients with PBC treated at Shengjing Hospital Affiliated to China Medical University from 2005 to 2013 were included. Demographic data (sex and age), biochemical indexes (total protein, albumin, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, and gamma glutamyltransferase), immunological indexes [immunoglobulin (Ig) A, IgG, IgM, antinuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, and anti-mitochondrial antibodies] and pathological findings were compared in PBC patients, untyped DILI patients and patients with different types of DILI (hepatocellular type, cholestatic type and mixed type)...
September 7, 2016: World Journal of Gastroenterology: WJG
Zelalem Petros, Ming-Ta Michael Lee, Atsushi Takahashi, Yanfei Zhang, Getnet Yimer, Abiy Habtewold, Wondwossen Amogne, Getachew Aderaye, Ina Schuppe-Koistinen, Taisei Mushiroda, Eyasu Makonnen, Michiaki Kubo, Eleni Aklillu
BACKGROUND: Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations. The objective of this study was to perform genome-wide association study (GWAS) to identify genetic variants associated with the risk for ATD induced liver toxicity in Ethiopian patients. RESULT: Treatment-naïve newly diagnosed tuberculosis patients (n = 646) were enrolled prospectively and treated with rifampicin based short course anti-tuberculosis therapy...
September 26, 2016: BMC Genomics
Keisuke Goda, Tadakazu Takahashi, Akio Kobayashi, Toshiyuki Shoda, Hideyuki Kuno, Shoichiro Sugai
Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown...
2016: Journal of Toxicological Sciences
Sanja Dragovic, Nico P E Vermeulen, Helga H Gerets, Philip G Hewitt, Magnus Ingelman-Sundberg, B Kevin Park, Satu Juhila, Jan Snoeys, Richard J Weaver
The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The 'MIP-DILI' project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms...
September 22, 2016: Archives of Toxicology
Glenn D Guest, David F Scott, Joao P Xavier, Nelson Martins, Eric Vreede, Antony Chennal, Daliah Moss, David A Watters
BACKGROUND: Timor-Leste suffered a destructive withdrawal by the Indonesian military in 1999, leaving only 20 Timorese-based doctors and no practising specialists for a population of 700 000 that has now grown to 1.2 million. METHODS: This article assesses the outcomes and impact of Royal Australasian College of Surgeons (RACS) specialist medical support from 2001 to 2015. Three programmes were designed collaboratively with the Timor-Leste Ministry of Health and Australian Aid...
September 20, 2016: ANZ Journal of Surgery
Hui Zhang, Lan Ding, Yi Zou, Shui-Qing Hu, Hai-Guo Huang, Wei-Bao Kong, Ji Zhang
Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier...
September 17, 2016: Journal of Computer-aided Molecular Design
C Trigo, P E A A do Brasil, M J M Costa, L de Castro
Occult hepatitis B virus infection (OBI) is characterized by the absence of HBsAg and persistence of the virus genome (HBV-DNA) in liver tissue and/or blood. OBI has been reported in several clinical contexts. However, the clinical significance of OBI in tuberculosis (TB) treatment is unknown. We investigated the OBI prevalence and its impact on the risk of drug-induced liver injury (DILI) during TB treatment. This was a prospective cohort study with one hundred patients who were treated for TB from 2008 to 2015...
September 13, 2016: Journal of Viral Hepatitis
Lucio Frederico Babo Soares, Penny Allen, Silvana Bettiol, Leonard Crocombe
Timor-Leste is one of the poorest countries in the world. The aim of this article was to investigate the association between socioeconomic status (SES) and dental caries experience in children living in Dili. Four out of 6 Dili subdistricts and 40 schools were randomly selected. Equal numbers of school children from 4 age groups (6-8, 9-11, 12-14, 15-17 years) were invited to participate. Data were gathered via a questionnaire and an oral examination by dental practitioners. In bivariate analysis, decayed, missing, and filled teeth index for deciduous + permanent teeth (dmft) was higher in children from mid- to high-SES than low-SES schools (1...
September 11, 2016: Asia-Pacific Journal of Public Health
Camilla Stephens, Antonia Moreno-Casares, Miguel-Ángel López-Nevot, Miren García-Cortés, Inmaculada Medina-Cáliz, Hacibe Hallal, German Soriano, Eva Roman, Francisco Ruiz-Cabello, Manuel Romero-Gomez, M Isabel Lucena, Raúl J Andrade
Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown...
2016: Frontiers in Pharmacology
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