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hepatotoxic drugs

Ja Min Byun, Hea-Lim Kim, Dong-Yeop Shin, Youngil Koh, Sung-Soo Yoon, Moon-Woo Seong, Sung Sup Park, Jin Hee Kim, Yun-Gyoo Lee, Inho Kim
Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population...
2016: PloS One
Jonathan G Stine, Jennifer Wang, Brian W Behm
Drug-induced liver injury is a rare but clinically important diagnosis. Vedolizumab is an α4β7 integrin inhibitor recently approved for use in patients with moderate-to-severe inflammatory bowel disease. Cases of hepatoxicity due to vedolizumab in the pre-marketing stage were rare, and all cases resolved upon drug withdrawal. We present here the first reported case of hepatotoxicity attributable to vedolizumab, which despite drug cessation persisted with chronic cholestatic liver injury.
September 28, 2016: Journal of Clinical and Translational Hepatology
Christopher Goldring, Daniel J Antoine, Frank Bonner, Jonathan Crozier, Chris Denning, Robert J Fontana, Neil A Hanley, David C Hay, Magnus Ingelman-Sundberg, Satu Juhila, Neil Kitteringham, Beatriz Silva-Lima, Alan Norris, Chris Pridgeon, James A Ross, Rowena Sison Young, Danilo Tagle, Belen Tornesi, Bob van de Water, Richard J Weaver, Fang Zhang, B Kevin Park
Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) means that no current single cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human DILI...
October 24, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Heidy Martínez-Pacheco, Guillermo Ramírez-Galicia, Midalia Vergara-Arias, Jürg Gertsch, Jonathan Manuel Fragoso-Vázquez, David Méndez-Luna, A L Abujamra, Cabrera-Pérez Laura Cristina, Rosales-Hernández Martha Cecilia, I Mendoza-Lujambio, José Correa-Basurto
Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds...
October 19, 2016: Anti-cancer Agents in Medicinal Chemistry
Martin Uhl, Stefan Schwab, Thomas Efferth
A 52-year-old male patient was treated with standard radiochemotherapy with temozolomide for glioblastoma multiforme (GBM). After worsening of his clinical condition, further tumor-specific treatment was unlikely to be successful, and the patient seeked help from an alternative practitioner, who administered a combination of dichloroacetate (DCA) and artesunate (ART). A few days later, the patient showed clinical and laboratory signs of liver damage and bone marrow toxicity (leukopenia, thrombocytopenia). Despite successful restoration of laboratory parameters upon symptomatic treatment, the patient died 10 days after the infusion...
2016: Frontiers in Oncology
Namrita Lall, Vivek Kumar, Debra Meyer, Nomasomi Gasa, Chris Hamilton, Motlalepula Matsabisa, Carel Oosthuizen
ETHNOPHARMACOLOGICAL RELEVANCE: The Natal gwarri or Natal ebony (Euclea natalensis A.DC.) is a deciduous tree found widespread throughout southern Africa, especially in Kwazulu-Natal and the southern cost. It has been widely used by indigenous communities such as the Zulus, Tsongas and Vendas for symptoms related to tuberculosis (TB). The decoctions made from the plant parts are administered for chest diseases to treat complications such as chest pains, bronchitis, pleurisy and asthma...
October 20, 2016: Journal of Ethnopharmacology
Madhusudanarao Vuda, Ashwin Kamath
Several commonly used medications impair mitochondrial function resulting in adverse effects or toxicities. Drug induced mitochondrial dysfunction may be a consequence of increased production of reactive oxygen species, altered mitochondrial permeability transition, impaired mitochondrial respiration, mitochondrial DNA damage or inhibition of beta-oxidation of fatty acids. The clinical manifestation depends on the specific drug and its effect on mitochondria. Given the ubiquitous presence of mitochondria and its central role in cellular metabolism, drug-mitochondrial interactions may manifest clinically as hepatotoxicity, enteropathy, myelosuppression, lipodystrophy syndrome or neuropsychiatric adverse effects, to name a few...
October 19, 2016: Mitochondrion
A D B Vliegenthart, R A Kimmitt, J H Seymour, N Z Homer, J I Clarke, M Eddleston, A Gray, D M Wood, P I Dargan, J G Cooper, D J Antoine, D J Webb, S C Lewis, D N Bateman, J W Dear
: Acetaminophen (paracetamol-APAP) is the commonest cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analysed from discovery (N=116) and validation (N=150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI...
October 22, 2016: Clinical Pharmacology and Therapeutics
Tshifhiwa Magoro, George Gachara, Lufuno Mavhandu, Emmaculate Lum, Helen K Kimbi, Roland N Ndip, Pascal Bessong
BACKGROUND: HBV and HIV share similar transmission routes. Concurrent infection with the two viruses usually results in more severe and progressive liver disease, and a higher incidence of cirrhosis, liver cancer and mortality. Further, this co-infection may lead to cross-resistance between HIV and HBV drugs and increased liver injury, either due to direct hepatotoxicity or drug-related immune-reconstitution hepatitis. These challenges necessitate continuous surveillance for HBV among HIV infected individuals to guide patient management...
October 21, 2016: Virology Journal
Mikael Persson, Jorrit J Hornberg
High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile...
October 21, 2016: Chemical Research in Toxicology
Christoph Funk, Adrian Roth
Drug-induced liver injury (DILI) is a major concern for drug developers, regulators and clinicians. It is triggered by drug and xenobiotic insults leading to liver impairment or damage, in the worst-case liver failure. In contrast to acute "intrinsic" hepatotoxicity, DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and inconsistent temporal patterns and is therefore termed an idiosyncratic event. Involved are multifactorial, compound-dependent mechanisms and host-specific factors, making the prediction in preclinical test systems very challenging...
October 20, 2016: Archives of Toxicology
M Teresa Donato, Mireia López-Riera, José V Castell, María J Gómez-Lechón, Ramiro Jover
Disruption of the vectorial bile acid transport in the liver is a key feature of cholestatic drugs, although many causal and mechanistic aspects are still unknown. The aim of the present study was to explore if cholestatic drugs can repress or induce the expression of hepatic transporters. To this end, sandwich-cultured rat hepatocytes were treated with cholestatic and non-cholestatic (steatotic, non-hepatotoxic, etc.) drugs and the mRNA expression of 10 uptake and efflux biliary transporters was measured. Results evidenced that all cholestatic drugs cause extensive alterations in the mRNA expression of most biliary transporters...
October 17, 2016: Toxicology Letters
Fadia S Youssef, Mohamed L Ashour, Mansour Sobeh, Hesham A El-Beshbishy, Abdel Nasser Singab, Michael Wink
BACKGROUND: The Australian plant Eremophila maculata F. Muell (Scrophulariaceae) is cultivated worldwide as an ornamental plant. PURPOSE: This study was designed to assess the antioxidant and hepatoprotective activities of a methanol extract from E. maculata leaves (EMM) both in vitro and in vivo (rats) experiments. Detailed phytochemical study was done on the extract followed by molecular docking experiments on TNF-α ascertain the efficacy of the isolated compounds...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Medine Cumhur Cüre, Erkan Cüre, Yıldıray Kalkan, Aynur Kırbaş, Levent Tümkaya, Arif Yılmaz, Ayşegül Küçükali Türkyılmaz, İbrahim Şehitoğlu, Süleyman Yüce
BACKGROUND: Cisplatin (Cis) is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α). Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. AIMS: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis...
September 2016: Balkan Medical Journal
Mohamed A Farag, Ahlam M El Fishawy, Sayed A El-Toumy, Khadiga F Amer, Ahmed M Mansour, Hala E Taha
BACKGROUND: Panicum turgidum, desert grass, has not reported any detailed phytochemical or biological study as yet. OBJECTIVE: To establish P. turgidum secondary metabolite profile and to assess its antihepatotoxic effect. MATERIALS AND METHODS: Ultra-performance liquid chromatography (UPLC) coupled to quadrupole high-resolution time of flight mass spectrometry (qTOF-MS) was used for large-scale secondary metabolites profiling in P. turgidum extract, alongside assessing median lethal dose (LD50) and hepatoprotective effect against carbon tetrachloride (CCl4) intoxication...
July 2016: Pharmacognosy Magazine
Delilah F G Hendriks, Lisa Fredriksson Puigvert, Simon Messner, Wolfgang Mortiz, Magnus Ingelman-Sundberg
Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound's potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days...
October 19, 2016: Scientific Reports
Jae-Woo Jang, Yeonhwa Song, Kang Mo Kim, Jin-Sun Kim, Eun Kyung Choi, Joon Kim, Haengran Seo
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in HCC patients. METHODS: Here, we developed a fluorescence image-based phenotypic screening system in vitro to identify HCC-specific drugs in co-cultures of HCC cells with hepatocytes. To this end, we identified two distinctive markers of HCC, CHALV1 and AFP, which are highly expressed in HCC cell lines and liver cancer patient-derived materials...
October 18, 2016: BMC Cancer
Imane El Dika, James J Harding, Ghassan K Abou-Alfa
PURPOSE OF REVIEW: Hepatocellular carcinoma (HCC) is becoming an important cause of mortality in patients with HIV, attributed to coinfection with hepatitis C virus, hepatitis B virus, and the longer survival advantage these patients are achieving after introducing the highly active antiretroviral therapy (HAART) regimens. RECENT FINDINGS: In addition to hepatitis infection, immunosuppression secondary to HIV infection, direct impact of the virus on liver parenchyma, and the use of hepatotoxic antiretroviral drugs, all contribute to HCC pathogenesis...
October 15, 2016: Current Opinion in HIV and AIDS
Volker M Lauschke, Magnus Ingelman-Sundberg
Responses to drugs and pharmacological treatments differ considerably between individuals. Importantly, only 50%-75% of patients have been shown to react adequately to pharmacological interventions, whereas the others experience either a lack of efficacy or suffer from adverse events. The liver is of central importance in the metabolism of most drugs. Because of this exposed status, hepatotoxicity is amongst the most common adverse drug reactions and hepatic liabilities are the most prevalent reason for the termination of development programs of novel drug candidates...
October 12, 2016: International Journal of Molecular Sciences
Frank F Vincenzi, Philippe Lunetta
While SCUBA diving, a 44-year-old Caucasian patient had an abnormal cardiac rhythm, presumably Torsade de Pointes (TdP), during the initial descent to depth. Upon surfacing, she developed ventricular fibrillation and died. The patient had been treated for mild depression for nearly a year with citalopram 60 mg per day, a drug known to cause prolonged QT interval. She had also been treated with two potentially hepatotoxic drugs. Liver impairment causes selective loss of cytochrome P450 (CYP) 2C19 activity, the major pathway for metabolism of citalopram...
December 2015: Drug Saf Case Rep
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