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Drug-induced hepatotoxicity

Laia Tolosa, Nuria Jiménez, María Pelechá, José V Castell, Mª José Gómez-Lechón, M Teresa Donato
Drug-induced liver injury (DILI) constitutes one of the most frequent reasons of restricted-use warnings as well as withdrawals of drugs in postmarketing and poses an important concern for the pharmaceutical industry. The current hepatic in vivo and in vitro models for DILI detection have shown clear limitations, mainly for studies of long-term hepatotoxicity. For this reason, we here evaluated the potential of using Upcytes human hepatocytes (UHH) for repeated-dose long-term exposure to drugs. The UHH were incubated with 15 toxic and non-toxic compounds for up to 21 days using a repeated-dose approach, and, in addition to conventional examination of effects on viability, the mechanisms implicated in cell toxicity were also assessed by means of high-content screening...
November 13, 2018: Archives of Toxicology
Pritam Kataria, Pradip Kendre, Apurva Patel, Nahush Tahiliani, Sushant Ikhar
Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients, and it is characterized by the presence of malignant lymphoblasts within the bone marrow and peripheral blood. The treatment of ALL involves induction, consolidation, reinduction, and maintenance therapy. Consolidation therapy in ALL-Berlin-Frankfurt-Münster 90 protocol involves the use of high-dose methotrexate (HDMTX, 5 g/m2 ) over 24 h as continuous infusion. The adverse effects due to HDMTX include renal dysfunction in 2%-12% patients, which can lead to increased systemic MTX exposure, leading to further myelosuppression, mucositis, hepatotoxicity, skin toxicity, and, in severe cases, multiorgan failure...
October 2018: Indian Journal of Critical Care Medicine
Christian Bock, Kristin Beirow, Abdrrahman S Surur, Lukas Schulig, Anja Bodtke, Patrick J Bednarski, Andreas Link
Flupirtine, an opener of neuronal voltage gated potassium channels (KV7.2/3), has been used as a therapeutic alternative for pain treatment in patients refractory to NSAIDs and opioids. Because flupirtine is associated with rare but fatal drug-induced liver injury that may result from the formation of toxic metabolites upon metabolic oxidation, we synthesized novel derivatives with the goal of identifying equally active and ultimately safer KV7.2/3 channel openers. Four thioether analogues were designed to lack a nitrogen atom that would be a prerequisite for the formation of toxic para-quinone diimines, and form sulfoxide and sulfone metabolites instead...
November 7, 2018: Organic & Biomolecular Chemistry
Yongxia Yin, Yanguo Zhang, Haijun Li, Yan Zhao, Enbo Cai, Hongyan Zhu, Pingya Li, Jinping Liu
Drug-related hepatotoxicity has become a serious social issue nowadays. Acetaminophen (APAP) was widely used in clinical treatment, although commonly acknowledged that it is a general material that caused drug-related hepatotoxicity. In this study, triterpenoids (Trds) which are mainly composed of ursolic acid and oleanolic acid, were isolated and prepared from fruits of Sorbus pohuashanensis. Further, the effect of Trds against APAP-induced liver injury and the pharmacological mechanism were investigated. The results showed that Trds treatment significantly restrained the increase of serum aspartate transaminase (AST), alanine aminotransferase (ALT), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and hepatic malondialdehyde (MDA) levels, as well as evidently reversed the decrease of hepatic superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) levels induced by APAP...
November 3, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mei Wang, Yu Chen, Zhen Guo, Changcheng Yang, Jiaomei Qi, Yujuan Fu, Zuohong Chen, Ping Chen, Ying Wang
Amanitin-induced apoptosis is proposed to have a significant effect on the pathogenesis of liver damage. However, few reports have focused on proteome changes induced by α-amanitin (α-AMA). Here, we evaluated changes in mitochondrial proteins of hepatocytes in response to 2 μM α-AMA, a concentration at which α-AMA-induced cell damage could be rescued at cellular level by common clinical drugs. We found 56 proteins were differentially expressed in an α-AMA-treated group. Among them, 38 proteins were downregulated and 18 were upregulated...
November 3, 2018: Toxicon: Official Journal of the International Society on Toxinology
Ahmed Abdeen, Afaf Abdelkader, Mohamed Abdo, Gamal Wareth, Mohamed Aboubakr, Lotfi Aleya, Mohamed Abdel-Daim
Acetaminophen, APAP, is a common over-the-counter drug with antipyretic-analgesic action. When APAP is used in large doses, it causes hepatotoxicity and nephrotoxicity but safe at therapeutic doses. Cinnamon (Cinnamomum zeylanicum) is extensively used in folk medicine due to its high content of natural antioxidants. The current investigation was planned to study the possible ameliorative effect of cinnamon toward induced APAP-apoptosis and cellular damage in renal cells. Four groups (nine rats each) were used; negative control group administrated distilled water for 15 days; positive control APAP group administrated a single dose of APAP (1 g/kg) orally on the last day; APAP+Cin L (200 mg/kg) and APAP+Cin H (400 mg/kg) aqueous extract of cinnamon orally once a day for 15 days...
November 3, 2018: Environmental Science and Pollution Research International
Amany Balah, Omnia Ezzat, El-Sayed Akool
Cyclosporin A (CsA) is the most common immunosuppressive drug used in organ transplantation. However, the clinical use of CsA is often limited by several side effects including hepatotoxicity. In the present study, it was found that administration of CsA causes a rapid activation of TGF-β/Smad signaling cascade and subsequent expression of the profibrotic genes connective tissue growth factor (CTGF) and tissue inhibitors of matrix metallproteinases-1 (TIMP-1) in rat liver. In addition, Smad phosphorylation and subsequent CTGF and TIMP-1 expression were markedly reduced in the presence of neutralizing monoclonal TGFβ1-3 antibody...
November 1, 2018: International Immunopharmacology
Muhammed A Saad, Alyasaa A Rastanawi, Muhammed F El-Yamany
AIMS: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome. Paracetamol (APAP) causes, in high doses, a hepatic injury. Alogliptin (ALO), with its 100% oral bioavailability, may be able to reverse the acute hepatic injury and memory impairments. MATERIALS AND METHODS: Forty rats were divided into four groups as follows; Normal Control Group, APAP intoxicated group, ALO and SIL groups. Behavioral tests (Morris water maze, Y-maze spontaneous alteration, and novel object recognition test) were performed together with evaluating HE score...
October 31, 2018: Life Sciences
Yan Yi, Shuang-Rong Gao, Jing Xia, Chun-Ying Li, Yong Zhao, Yu-Shi Zhang, Ai-Hua Liang, Shen-Ji
ETHNOPHARMACOLOGICAL RELEVANCE: Realgar (As4 S4 ) has been traditionally incorporated as a chief ingredient in traditional Chinese medicine formulations used to treat inflammation, poisoning, cancer, convulsion, and parasites. However, because of the toxicity of arsenic (As), the safety of realgar has been questioned. AIM OF THE STUDY: Because the toxicity and efficacy of As are closely related to its chemical species, we conducted examinations of As species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different As species in the short-term toxicity of realgar...
October 29, 2018: Journal of Ethnopharmacology
Suresh Kumar Bunker, Abinash Dutta, Jyotsnarani Pradhan, Jagneshwar Dandapat, G B N Chainy
6-n-propyl-2-thiouracil (PTU), a thioamide drug, is used as an effective anti-thyroid agent to treat hyperthyroidism and Graves' disease. However, acute liver oxidative damage is an important side effect of the drug. In the present study, we report that PTU administration to rat induces hepatic epigenetic changes by upregulating expression of DNMT1, DNMT3a, DNMT3b, MBD4, MeCP2, p53 and Gadd45a and down-regulation of PCNA and C/EBP-β. This is accompanied by decrease in the cell population and augmentation of cellular lipid peroxidation, an index of oxidative stress, in liver...
October 24, 2018: Food and Chemical Toxicology
Dasom Jung, Ji Min Han, Jeong Yee, Jae Youn Kim, Hye Sun Gwak
Crizotinib is an orally available tyrosine kinase inhibitor for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC). Despite that crizotinib-induced hepatotoxicity may cause a dose reduction or interruption that can affect the patient's treatment, there is no study to investigate factors for crizotinib-induced hepatotoxicity. The purpose of this study was to evaluate factors affecting crizotinib-induced hepatotoxicity. From February 2012 to April 2018, a retrospective study was performed on NSCLC patients treated with crizotinib...
October 26, 2018: Medical Oncology
Fang Zhang, Yue Zhou, Xiao Yang, Ai-Zhen Xiong, Zheng-Tao Wang, Li Yang
Recently, hepatic sinusoidal obstruction syndrome (HSOS) caused by herbal preparations containing pyrrolizidine alkaloids (PAs), such as Gynura Rhizoma (Tusanqi), has gained global attention. However, the lack of a reliable and reproducible animal model has greatly hampered mechanistic studies. Therefore, we aimed to establish a reproducible HSOS mouse model and investigate the hepatotoxic mechanism. The model was established by intragastrical administration of Gynura Rhizoma extract, i.e., 1.0 g extract/kg per day (equal to 16...
October 26, 2018: Acta Pharmacologica Sinica
Yaqing Wang, Hui Wang, Pengwei Deng, Wenwen Chen, Yaqiong Guo, Tingting Tao, Jianhua Qin
Liver organoids derived from human pluripotent stem cells (PSCs) represent a new type of in vitro liver model for understanding organ development, disease mechanism and drug testing. However, engineering liver organoids with favorable functions in a controlled cellular microenvironment remains challenging. In this work, we present a new strategy for engineering liver organoids derived from human induced PSCs (hiPSCs) in a 3D perfusable chip system by combining stem cell biology with microengineering technology...
October 25, 2018: Lab on a Chip
Vijay Gayam, Amrendra Kumar Mandal, Mazin Khalid, Binav Shrestha, Pavani Garlapati, Mowyad Khalid
Valproic acid (VPA) is a commonly used agent in the management of seizures and psychiatric disorders. Hyperammonemia is a common complication of VPA with 27.8% of patients having elevated levels - that is unrelated to hepatotoxicity and normal transaminases. Common side effects include obesity, insulin resistance, metabolic disorder and severe forms of hepatotoxicity. Other rare and idiosyncratic reactions have been reported, one of which is presented in our case. A 27-year old patient presented with hyperammonemia and encephalopathy as a consequence of idiosyncratic VPA reaction causing drug-induced liver injury (DILI) with severely elevated transaminases...
2018: Journal of Community Hospital Internal Medicine Perspectives
Nidal A Qinna, Bayan Y Ghanim
The urge of identifying new pharmacological interventions to prevent or attenuate liver injury is of critical importance and needs an expanded experimental toolbox. Hepatocyte injury and cellular death is a prominent feature behind the pathology of liver diseases. Several research activities focused on identifying chemicals and hepatotoxicants that induce cell death by apoptosis, in addition to presenting its corresponding signaling pathway. Although such efforts provided further understanding of the mechanisms of cell death, it has also raised confusion concerning identifying the involvement of several modes of cell death including apoptosis, necrosis and fibrosis...
October 23, 2018: Journal of Applied Toxicology: JAT
William Beattie, Bernard Yan, Siddharth Sood
Alemtuzumab is a monoclonal antibody used as a disease modifying agent in relapsing and remitting multiple sclerosis. It has not previously been associated with drug induced liver injury. Here we present a case of a 49 year old female developing drug induced liver injury secondary to alemtuzumab, confirmed upon rechallenge. Our patient developed severe hepatitis within two days of starting alemtuzumab, both initially and upon rechallenge. The alanine aminotransferase peaked at 577 units per litre and 426 units per litre after initial dose of alemtuzumab and rechallenge respectively...
October 19, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Mark Real, Michele S Barnhill, Cory Higley, Jessica Rosenberg, James H Lewis
Drug-induced liver injury (DILI), herbal-induced liver injury, and herbal and dietary supplement (HDS)-induced liver injury are an important aspect of drug safety. Knowledge regarding responsible drugs, mechanisms, risk factors, and the diagnostic tools to detect liver injury have continued to grow in the past year. This review highlights what we considered the most significant publications from among more than 1800 articles relating to liver injury from medications, herbal products, and dietary supplements in 2017 and 2018...
October 20, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Fahaid Al-Hashem, Suliman Al-Humayed, Shaimaa N Amin, Samaa S Kamar, Soheir S Mansy, Sarah Hassan, Lubna O Abdel-Salam, Mohamed Abd Ellatif, Mohammed Alfaifi, Mohamed A Haidara, Bahjat Al-Ani
The potential inhibitory effect of the antidiabetic and anti-inflammatory drug, metformin on thioacetamide (TAA)-induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group)...
October 18, 2018: Journal of Cellular Physiology
Min Kyoung Kim, Jeong Yee, Yoon Sook Cho, Hong Won Jang, Ji Min Han, Hye Sun Gwak
BACKGROUND: Erlotinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. Severe hepatotoxicity was observed in 4% to 31% of patients receiving erlotinib treatment prompting delay or termination of treatment. Only a few factors related to hepatotoxicity of erlotinib have been reported. No study has investigated the role of concomitant medications and erlotinib-induced hepatotoxicity. The aim of this study was to investigate the association between erlotinib-induced hepatotoxicity and various factors including concomitant medications in patients with NSCLC and pancreatic cancer...
October 16, 2018: BMC Cancer
Alauddin, Swati Chaturvedi, Mohd Yaseen Malik, Lubna Azmi, Ila Shukla, Zaiba Naseem, ChandanaVenkateswara Rao, Naresh Kumar Agarwal
AIMS: Ritonavir (RIT) is a human immune deficiency virus (HIV) protease inhibitor (PI) active against HIV-1 and HIV-2. Among various adverse effects of PIs, hepatotoxicity is a very common adverse reaction of RIT which is concentration dependent. Red clover isoflavones are found to possess anti-inflammatory, antioxidant and anti-apoptosis activity. Furthermore, recent studies have demonstrated that these isoflavones can be used to alleviate the side-effects of drugs. Hence, the present study was inquested to ascertain the effect of Formononetin (FMN) and Biochanin A (BCA) on RIT induced hepatotoxicity...
October 13, 2018: Life Sciences
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