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https://www.readbyqxmd.com/read/28238947/identification-of-novel-mrp3-inhibitors-based-on-computational-models-and-validation-using-an-in-vitro-membrane-vesicle-assay
#1
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 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28208716/cell-imaging-counting-as-a-novel-ex-vivo-approach-for-investigating-drug-induced-hepatotoxicity-in-zebrafish-larvae
#2
Xuan-Bac Nguyen, Stanislav Kislyuk, Duc-Hung Pham, Angela Kecskés, Jan Maes, Deirdre Cabooter, Pieter Annaert, Peter De Witte, Annelii Ny
Drug-induced liver injury (DILI) is the most common reason for failures during the drug development process and for safety-related withdrawal of drugs from the pharmaceutical market. Therefore, having tools and techniques that can detect hepatotoxic properties in drug candidates at an early discovery stage is highly desirable. In this study, cell imaging counting was used to measure in a fast, straightforward, and unbiased way the effect of paracetamol and tetracycline, (compounds known to cause hepatotoxicity in humans) on the amount of DsRed-labeled hepatocytes recovered by protease digestion from Tg(fabp10a:DsRed) transgenic zebrafish...
February 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28206647/fasiglifam-tak-875-mechanistic-investigation-and-retrospective-identification-of-hazards-for-drug-induced-liver-injury-dili
#3
Monicah A Otieno, Jan Snoeys, Wing Lam, Avi Ghosh, Mark R Player, Alessandro Pocai, Rhys Salter, Damir Simic, Hollie Skaggs, Bhanu Singh, Lim Heng-Keang
No abstract text is available yet for this article.
February 16, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28184227/using-ceres-maize-and-enso-as-decision-support-tools-to-evaluate-climate-sensitive-farm-management-practices-for-maize-production-in-the-northern-regions-of-ghana
#4
Dilys S MacCarthy, Samuel G K Adiku, Bright S Freduah, Francis Gbefo, Alpha Y Kamara
Maize (Zea mays) has traditionally been a major cereal staple in southern Ghana. Through breeding and other crop improvement efforts, the zone of cultivation of maize has now extended to the northern regions of Ghana which, hitherto, were the home to sorghum and millet as the major cereals. Maize yield in the northern Ghana is hampered by three major biophysical constraints, namely, poor soil fertility, low soil water storage capacity and climate variability. In this study we used the DSSAT crop model to assess integrated water and soil management strategies that combined the pre-season El-Niño-Southern Oscillation (ENSO)-based weather forecasting in selecting optimal planting time, at four locations in the northern regions of Ghana...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28166913/novel-risk-factors-and-early-detection-of-anti-tubercular-treatment-induced-liver-injury-looking-beyond-american-thoracic-society-guidelines
#5
Muzamil Latief, Waseem Raja Dar, Najeebullah Sofi, Imtiyaz Ahmad Dar, Basharat Kasana, Moomin Hussain, Faheem Arshad, Bashir Ahmad Shah, Parvaiz Ahmad Koul
INTRODUCTION: ATT remains the standard treatment for tuberculosis. Drug-induced liver injury (DILI) has been a long-standing concern in the treatment of tuberculosis (TB) infection. AIMS AND OBJECTIVES: To study the occurrence and risk factors of DILI in patients on ATT by regular clinical and biochemical monitoring. MATERIALS AND METHODS: 200 patients, in whom ATT was started, were enrolled in the study. None of the patients with established risk factor for DILI as recognized by ATS guidelines was included in our study population...
January 2017: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/28166633/predicting-drug-induced-cholestasis-with-the-help-of-hepatic-transporters-an-in-silico-modeling-approach
#6
Eleni Kotsampasakou, Gerhard F Ecker
Cholestasis represents one out of three types of drug induced liver injury (DILI), which comprises a major challenge in drug development. In this study we applied a two-class classification scheme based on k-nearest neighbors in order to predict cholestasis, using a set of 93 2D physicochemical descriptors and predictions of selected hepatic transporters' inhibition (BSEP, BCRP, P-gp, OATP1B1 and OATP1B3). In order to assess the potential contribution of transporter inhibition, we compared whether the inclusion of the transporters' inhibition predictions contributes to a significant increase in model performance in comparison to the plain use of the 93 2D physicochemical descriptors...
February 7, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28161910/associations-of-gender-and-a-proxy-of-female-menopausal-status-with-histological-features-of-drug-induced-liver-injury
#7
Ayako Suzuki, Huiman Barnhart, Jiezhun Gu, Herbert L Bonkovsky, Hans L Tillmann, Robert J Fontana, David E Kleiner
Gender and menopause may contribute to type and severity of drug-induced liver injury (DILI) by influencing host responses to injury. The aim of this study was to assess the associations of gender and female age 50 [a proxy of menopause] with histologic features of liver injury in 212 adults enrolled in the Drug-Induced Liver Injury Network (DILIN) registry METHODS: All participants had a causality score of at least 'probable', a liver biopsy within 30 days of DILI onset, and no prior chronic liver disease...
February 5, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28161274/valproate-acid-vpa-induced-dysmetabolic-function-in-clinical-and-animal-studies
#8
Rong Li, Lisheng Liang, Xinmou Wu, Xianli Ma, Min Su
BACKGROUND: Valproate acid (VPA), a commonly used antiepileptic medicine, is found to be linked to developing dysmetabolic risk. However, the proposed mechanism remains completely unknown. METHODS: In this study, we collected data from patients with epilepsy and further investigated the preclinical study in mice. RESULTS: As results, the clinical data showed that VPA-used patients resulted in higher levels of blood glucose, urine acid, triglyceride (TG), and immune cells (leucocyte, neutrophil leucocyte) when compared to clinically diagnosed references, while circulating apolipoprotein A1 (Apob A1) and fatty acid binding protein 4 (FABP4) were reduced without visible drug-induced liver injury (DILI)...
February 2, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28146280/assessment-of-bile-salt-export-pump-bsep-inhibition-in-membrane-vesicles-using-radioactive-and-lc-ms-based-detection-methods
#9
Lisa D Marroquin, Paul D Bonin, Julie Keefer, Thomas Schroeter
The bile salt export pump (BSEP, ABCB11) belongs to the ATP-binding-cassette superfamily of transporters and is predominately found in the liver. BSEP is an efflux transporter that plays a critical role in the secretion of bile salts into the bile. Inhibition of BSEP function by drugs can result in the buildup of bile salts in the liver and eventually leads to cholestasis and drug-induced liver injury (DILI). DILI is a major cause of withdrawal of drugs from the pharmaceutical market and accounts for >50% of acute liver failures...
February 1, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28145637/in-silico-identification-of-proteins-associated-with-drug-induced-liver-injury-based-on-the-prediction-of-drug-target-interactions
#10
Sergey Ivanov, Maxim Semin, Alexey Lagunin, Dmitry Filimonov, Vladimir Poroikov
Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs)...
February 1, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/28138970/prediction-of-drug-induced-liver-injury-using-keratinocytes
#11
Rika Hirashima, Tomoo Itoh, Robert H Tukey, Ryoichi Fujiwara
Drug-induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI-associated genes such as S100 calcium-binding protein A and interleukin (IL)-1β are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI-associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL-1β basal expression...
January 31, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28130428/hla-gene-expression-is-altered-in-whole-blood-and-placenta-from-women-who-later-developed-preeclampsia
#12
Heather Yvonne Small, Christine Akehurst, Lilya Sharafetdinova, Martin W McBride, John D McClure, Scott Robinson, David Carty, Dilys Freeman, Christian Delles
Preeclampsia is a multi-system disease that significantly contributes to maternal and fetal morbidity and mortality. In this study, we used a non-biased microarray approach to identify dysregulated genes in maternal whole blood samples which may be associated with the development of preeclampsia. Whole blood samples were obtained at 28 weeks of gestation from 5 women who later developed preeclampsia (cases) and 10 matched women with normotensive pregnancies (controls). Placenta samples were obtained from an independent cohort of 19 women with preeclampsia matched with 19 women with normotensive pregnancies...
January 27, 2017: Physiological Genomics
https://www.readbyqxmd.com/read/28123443/liver-illness-and-psychiatric-patients
#13
REVIEW
Paul Carrier, Marilyne Debette-Gratien, Murielle Girard, Jérémie Jacques, Philippe Nubukpo, Véronique Loustaud-Ratti
Patients with psychiatric disorders are usually more exposed to multiple somatic illnesses, including liver diseases. Specific links are established between psychiatric disorders and alcohol hepatitis, hepatitis B, and hepatitis C in the population as a whole, and specifically in drug abusers. Metabolic syndrome criteria, and associated steatosis or non-alcoholic steato-hepatitis (NASH) are frequent in patients with chronic psychiatric disorders under psychotropic drugs, and should be screened. Some psychiatric medications, such as neuroleptics, mood stabilizers, and a few antidepressants, are often associated with drug-induced liver injury (DILI)...
December 2016: Hepatitis Monthly
https://www.readbyqxmd.com/read/28123241/a-cross-sectional-study-of-liver-function-tests-in-hiv-infected-persons-in-western-india
#14
Sunny Pathania, Navjyot Kaur, Sandeep Kumar, V K Sashindran, Pankaj Puri
BACKGROUND: Derangement of liver function tests (LFTs) is common in people living with human immunodeficiency virus/acquired immune deficiency syndrome (PLHA). The cause is multifactorial. Drug-induced liver injury (DILI) is the commonest cause and others being alcohol abuse and concomitant viral hepatitis. The aim of the research was to study the prevalence of LFT abnormalities in PLHA. METHODS: The study was carried out in a tertiary care hospital. Evaluation included a detailed history, thorough clinical examination and investigations including a haemogram, serum biochemistry, serology for hepatitis, and CD4 cell count...
January 2017: Medical Journal, Armed Forces India
https://www.readbyqxmd.com/read/28123239/antitubercular-therapy-induced-liver-function-tests-abnormalities-in-human-immunodeficiency-virus-infected-individuals
#15
Pankaj Puri, Navjyot Kaur, Sunny Pathania, Sandeep Kumar, P K Sharma, V K Sashindran
BACKGROUND: Both antitubercular therapy (ATT) and antiretroviral therapy (ART) can cause drug induced liver injury (DILI) in tuberculosis (TB) and human immunodeficiency virus (HIV) coinfection. The aim of this research was to study ATT-induced liver function test (LFT) abnormalities in HIV-infected patients. METHODS: HIV-infected patients diagnosed with TB were evaluated with baseline LFT and CD4 counts. ATT regimen was modified if baseline LFT was significantly abnormal...
January 2017: Medical Journal, Armed Forces India
https://www.readbyqxmd.com/read/28121193/development-of-a-modified-lymphocyte-transformation-test-for-diagnosing-drug-induced-liver-injury-associated-with-an-adaptive-immune-response
#16
Jessica Whritenour, Mira Ko, Qing Zong, Jianying Wang, Karrie Tartaro, Patricia Schneider, Ellen Olson, Maria Van Volkenburg, Jose Serrano, Paul Hayashi, Robert Fontana, Naga Chalasani, Herbert L Bonkovsky
Drug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The lymphocyte transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug...
December 2017: Journal of Immunotoxicology
https://www.readbyqxmd.com/read/28115652/candidate-risk-factors-and-mechanisms-for-tolvaptan-induced-liver-injury-are-identified-using-a-collaborative-cross-approach
#17
Merrie Mosedale, Yunjung Kim, William J Brock, Sharin E Roth, Tim Wiltshire, J Scott Eaddy, Gregory R Keele, Robert W Corty, Yuying Xie, William Valdar, Paul B Watkins
Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains...
January 23, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28115551/early-detection-of-acute-drug-induced-liver-injury-in-mice-by-non-invasive-nir-fluorescence-imaging
#18
Kristine O Vasquez, Jeffrey D Peterson
Hepatocellular and cholestatic forms of drug induced liver injury (DILI) are major reasons for late stage termination of small molecule drug discovery research projects. Biochemical serum markers are limited in their ability to sensitively and specifically detect both of these common DILI forms in preclinical models, and tissue-specific approaches to assessing this are labor intensive, requiring extensive animal dosing, tissue preparation, and pathology assessment. In vivo fluorescent imaging offers non-invasive detection of biological changes detected directly in the livers of living animals...
January 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28108666/antibiotic-induced-elevations-of-plasma-bile-acids-in-rats-independent-of-bsep-inhibition
#19
Yutai Li, Michael J Hafey, Hong Duong, Raymond Evers, Kyeongmi Cheon, Daniel J Holder, Alema Galijatovic-Idrizbegovic, Frank D Sistare, Warren E Glaab
Drug-induced liver injury (DILI) is a common toxicity observed in drug development and can lead to withdrawal of approved drugs from the market. To better understand the numerous mechanisms of DILI, recent efforts have focused on transporter inhibition, specifically liver canalicular bile salt export pump (Bsep) as one mechanism of DILI, and on the potential use of plasma bile acids as monitorable mechanism-based biomarkers of Bsep inhibition. To explore alternative mechanisms of bile acid increases in plasma, six antibiotic and two non-antibiotic drugs unlikely to be Bsep inhibitors were evaluated in rat studies...
January 20, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28105256/drug-induced-liver-injury-towards-early-prediction-and-risk-stratification
#20
REVIEW
Emanuel Raschi, Fabrizio De Ponti
Drug-induced liver injury (DILI) is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications and agents listed as causing liver damage (http://livertox.nih.gov/). As it was the case in the past decade with drug-induced QT prolongation/arrhythmia, there is an urgent unmet clinical need to develop tools for risk assessment and stratification in clinical practice and, in parallel, to improve prediction of pre-clinical models to support regulatory steps and facilitate early detection of liver-specific adverse drug events...
January 8, 2017: World Journal of Hepatology
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