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Drug induced liver dysfunction

John J Guardiola, Juliane I Beier, K Cameron Falkner, Benjamin Wheeler, Craig James McClain, Matt Cave
BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS(2) analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed...
October 17, 2016: Toxicology and Applied Pharmacology
Derrick P McCarthy, Jonathan Woon-Teck Yap, Christopher T Harp, W Kelsey Song, Jeane Chen, Ryan M Pearson, Stephen D Miller, Lonnie D Shea
Tolerogenic nanoparticles (NPs) are rapidly being developed as specific immunotherapies to treat autoimmune disease. However, many NP-based therapies conjugate antigen (Ag) directly to the NP posing safety concerns due to antibody binding or require the co-delivery of immunosuppressants to induce tolerance. Here, we developed Ag encapsulated NPs comprised of poly(lactide-co-glycolide) [PLG(Ag)] and investigated the mechanism of action for Ag-specific tolerance induction in an autoimmune model of T helper type 1/17 dysfunction - relapse-remitting experimental autoimmune encephalomyelitis (R-EAE)...
October 6, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Sophie Restellini, Olivier Chazouillères, Jean-Louis Frossard
Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders, reported both in Crohn's disease (CD) and ulcerative colitis (UC). They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions. Fatty liver is considered as the most common hepatobiliary complication in IBD whilst primary sclerosing cholangitis (PSC) the most specific one. Less frequently, IBD-associated hepatobiliary disorders include: autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cholangitis (PBC), hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, and liver abscess...
October 6, 2016: Liver International: Official Journal of the International Association for the Study of the Liver
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
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
Raida Zouari, Khaled Hamden, Abdelfattah El Feki, Khansa Chaabouni, Fatma Makni-Ayadi, Choumous Kallel, Fahima Sallemi, Semia Ellouze-Chaabouni, Dhouha Ghribi-Aydi
This study was aimed to assess the plausible anti-obesity effects of Bacillus subtilis SPB1 crude lipopeptide biosurfactant on high fat high fructose diet-fed rats (HFFD). Male Wistar rats were divided into five groups with the following treatment schedule: normal diet (CD), HFFD, HFFD supplemented with SPB1 biosurfactant from the first day of the experiment (HFFD+Bios1, 10mg/kg/day), HFFD receiving standard drug (HFFD+Torva, 10mg/kg/day) or SPB1 biosurfactant (HFFD+Bios2, 10mg/kg/day) during the last 4 weeks of the study...
September 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Nalini Mishra, V N Mishra, Parineeta Thakur
INTRODUCTION: Abnormal liver function tests (LFTs) in pregnancy require proper interpretation in order to avoid pitfalls in the diagnosis. The underlying disorder can have a significant effect on the outcome of both mother and foetus. The present study was done with the objective to study the clinical profile, incidence and possible causes of derangements of liver function tests. MATERIAL AND METHOD: Eighty pregnant women with abnormal liver dysfunction were studied prospectively...
October 2016: Journal of Obstetrics and Gynaecology of India
P Cuny, M Houot, S Ginisty, S Horowicz, F Plassart, H Mentec, P Eftekhari
INTRODUCTION: The aim of this paper is to underline the need for systematic monitoring of patients treated with anticholinergic antipsychotic drugs. We present the clinical history of a 34-year-old adult, treated with quetiapine in combination with other drugs with anticholinergic effects. CASE REPORT: A 34-year-old male adult had been suffering from bipolar disorder since 2001. He was treated with risperidone, but he was not compliant due to adverse effects, including decreased libido and erectile dysfunction...
September 13, 2016: L'Encéphale
Mari Paz Serrano, Raquel Herrero-Labrador, Hunter S Futch, Julia Serrano, Alejandro Romero, Ana Patricia Fernandez, Abdelouahid Samadi, Mercedes Unzeta, Jose Marco-Contelles, Ricardo Martínez-Murillo
BACKGROUND: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-β aggregation as well as antioxidant and antiapoptotic properties...
September 20, 2016: Journal of Psychiatry & Neuroscience: JPN
Tahir Mehmood, Amara Maryam, He Zhang, Yongming Li, Muhammad Khan, Tonghui Ma
Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone present in Chinese medicinal herb, Elephantopus scaber has been shown to exert anti-inflammatory as well as anticancer effects in various cancer cells of human origin in vitro. However, the exact molecular mechanism underlying DET-induced apoptosis remains largely unexplored, particularly in human hepatocellular carcinoma G2 (HepG2) cells. In the present study, we found that DET inhibits proliferation and induces apoptosis in HepG2 cells in a dose-dependent manner...
September 15, 2016: BioFactors
Rajeshwary Ghosh, Sumanta K Goswami, Luis Felipe B B Feitoza, Bruce Hammock, Aldrin V Gomes
BACKGROUND: One of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) used worldwide, diclofenac (DIC), has been linked to increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which DIC causes CVD is unknown. METHODS: Proteasome activities were studied in hearts, livers, and kidneys from male Swiss Webster mice treated with either 100mg/kg DIC for 18h (acute treatment) or 10mg/kg DIC for 28days (chronic treatment). Cultured H9c2 cells and neonatal cardiomyocytes were also treated with different concentrations of DIC and proteasome function, cell death and ROS generation studied...
November 15, 2016: International Journal of Cardiology
Kuo Du, Anup Ramachandran, James L Weemhoff, Hemantkumar Chavan, Yuchao Xie, Partha Krishnamurthy, Hartmut Jaeschke
Overdose of acetaminophen (APAP) causes severe liver injury and even acute liver failure in both mice and human. A recent study by Kim et al. (2015) showed that metformin, a first-line drug to treat type 2 diabetes mellitus, protected against APAP hepatotoxicity in mice. However, its exact protective mechanism has not been well clarified. To investigate this, C57BL/6J mice were treated with 400 mg/kg APAP and 350 mg/kg metformin was given 0.5h pre- or 2h post-APAP. Our data showed that pretreatment with metformin protected against APAP hepatotoxicity, as indicated by the over 80% reduction in plasma ALT activities and significant decrease in centrilobular necrosis...
August 25, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Cintia Zimmermann Meireles, Marcos Pasarin, Juan Jose Lozano, Héctor García-Calderó, Jordi Gracia-Sancho, Juan Carlos García-Pagán, Jaime Bosch, Juan G Abraldes
Liver function deterioration is a major cause of death in variceal bleeding. The effects of bleeding on intrahepatic microvascular dysfunction, which contributes to liver injury in cirrhosis, are largely unknown. The aims of this study were to evaluate the impact of hemorrhage/resuscitation (H/R) on cirrhotic microcirculation, and whether simvastatin, a drug that improves liver microcirculation, has hepatoprotective effects. The study was performed in three groups of rats: controls, rats with biliary cirrhosis (CBDL) and CBDL rats pre-treated with 3 doses (5 mg*Kg-1*day-1) of simvastatin...
August 24, 2016: Shock
Feng Li, Pengcheng Wang, Ke Liu, Mariana G Tarrago, Jie Lu, Eduardo N Chini, Xiaochao Ma
Overdose of isoniazid (INH), an antituberculosis drug, can be life-threatening because of neurotoxicity. In clinical practice for management of INH overdose and acute toxicity, the potential of INH-induced hepatotoxicity is also considered. However, the biochemical basis of acute INH toxicity in the liver remains elusive. In the current study, we used an untargeted metabolomic approach to explore the acute effects of INH on endobiotic homeostasis in mouse liver. We found that overdose of INH resulted in accumulation of oleoyl-l-carnitine and linoleoyl-l-carnitine in the liver, indicating mitochondrial dysfunction...
November 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Hossein Niknahad, Akram Jamshidzadeh, Reza Heidari, Zeynab Hosseini, Keivan Mobini, Forouzan Khodaei, Mohammad Mehdi Ommati, Narges Abdoli, Nahid Keshavarz, Mandana Bazyari, Asma Najibi
Methimazole is the most frequently prescribed antithyroid agent. On the other hand, several cases of liver injury are attributed to this drug. The mechanism of methimazole-induced liver injury is obscure. Hepatocytes mitochondria seem to be a target for methimazole cytotoxicity. Current investigation aimed to evaluate the effects of methimazole on the hepatocytes mitochondria in different experimental models. In the in vivo model, methimazole (100, 200 and 400mg/kg, i.p) was administered to mice and liver mitochondria were isolated and assessed...
September 30, 2016: Toxicology Letters
Nelly Buron, Mathieu Porceddu, Célestin Roussel, Karima Begriche, Viviane Trak-Smayra, Thomas Gicquel, Bernard Fromenty, Annie Borgne-Sanchez
Pharmaceuticals are found in the environment but the impact of this contamination on human and animal health is poorly known. The liver could be particularly targeted since a significant number of these drugs are hepatotoxic, in particular via oxidative stress and mitochondrial dysfunction. Notably, the latter events can also be observed in liver diseases linked to obesity, so that the obese liver might be more sensitive to drug toxicity. In this study, we determined the effects of a chronic exposure to low doses of pharmaceuticals in wild-type and obese mice, with a particular focus on mitochondrial function...
August 8, 2016: Environmental Toxicology
Jaymon Patel, Saqib Walayat, Nikhil Kalva, Sidney Palmer-Hill, Sonu Dhillon
Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well...
July 21, 2016: World Journal of Gastroenterology: WJG
Shizuya Yamashita, Yuji Matsuzawa
PURPOSE OF REVIEW: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. RECENT FINDINGS: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events...
October 2016: Current Opinion in Lipidology
Takayuki Kobayashi, Jyunichi Tomomatsu, Ippei Fukada, Tomoko Shibayama, Natsuki Teruya, Yoshinori Ito, Takuji Iwase, Shinji Ohno, Shunji Takahashi
BACKGROUND: Eribulin is a non-taxane, microtubule dynamics inhibitor that increases survival of patients with metastatic breast cancer. Although eribulin is well tolerated in patients with heavily pretreated disease, eribulin-induced liver dysfunction (EILD) can occur, resulting in treatment modification and subsequent poor disease control. We aimed to clarify the effect of EILD on patient survival. METHODS: The medical records of 157 metastatic breast cancer patients treated with eribulin between July 2011 and November 2013 at Cancer Institute Hospital were retrospectively analyzed...
2016: BMC Cancer
Z Ailing, Y Jing, L Jingli, X Yun, Z Xiaojian
WHAT IS KNOWN AND OBJECTIVE: Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians...
October 2016: Journal of Clinical Pharmacy and Therapeutics
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