Drug-induced hepatotoxicity

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals...

Differentiated HepaRG cells are popular in vitro cell models for hepatotoxicity studies. Their differentiation is usually supported by the addition of dimethyl sulfoxide (DMSO), an amphipathic solvent widely used in biomedicine, for example, in potential novel therapeutic drugs and cryopreservation of oocytes. Recent studies have demonstrated drastic effects, especially on epigenetics and extracellular matrix composition, induced by DMSO, making its postulated inert character doubtful. In this work, the influence of DMSO and DMSO-mediated modulation of differentiation on human adenovirus (HAdV) infection of HepaRG cells was investigated...

Methotrexate (MTX) is the first drug of choice to treat several diseases, including rheumatoid arthritis. However, its administration is accompanied by severe side effects, most commonly hepatotoxicity. Hence, alternative therapies with a lower toxicity and fewer side effects are needed. This study aimed to investigate the antioxidant and hepatoprotective effects of silibinin (SIL, natural agent) against MTX-induced hepatotoxicity in an adjuvant-induced arthritis (AIA) rat model. Arthritic rats were treated with SIL (100 mg/kg) and/or methotrexate (2 mg/kg)...

Rifampicin (RFP) has demonstrated potent antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver intensively limit the clinical usage of the drug. Deacetylation greatly reduces the toxicity of RFP but also retains its curative activity. Here, we found that krüppel-like factor 15 (KLF15) repressed the expression of the major RFP detoxification enzyme Cyp3a11 in mice via both direct and indirect mechanisms. Knockout of hepatocyte KLF15 induced the expression of Cyp3a11 and robustly attenuated the hepatotoxicity of RFP in mice...

A hepatocyte cell line was used to determine the hepatotoxicity of sedatives and opioids, as the hepatotoxicity of these drugs has not yet been well characterized. This might pose a threat, especially to critically ill patients, as they often receive high cumulative doses for daily analgosedation and often already have impaired liver function due to an underlying disease or complications during treatment. A well-established biosensor based on HepG2/C3A cells was used for the determination of the hepatotoxicity of commonly used sedatives and opioids in the intensive care setting (midazolam, propofol, s-ketamin, thiopental, fentanyl, remifentanil, and sufentanil)...

BACKGROUND AND AIM: Morinda citrifolia fruit juice (noni) is an herbal remedy documented to have antioxidant properties. It has been suggested that prevention of carcinogen-DNA adduct formation and the antioxidant activity of NJ may contribute to the cancer preventive effect. In the present study, the antitumor activity of noni was investigated in the presence of cyclophosphamide (CYL) in vitro and in vivo. METHODS: In vitro breast cancer cells (MDA-MB-468) were used to measure the percentage of inhibition and the IC50 ...

BACKGROUND: The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. METHODS: This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed ( pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN)...

Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis...

Flutamide is frequently used in the management of prostate cancer, hirsutism, and acne. It is a non-steroidal anti-androgenic drug and causes hepatotoxicity. The current study's objective is to evaluate sophorin's hepatoprotective effectiveness against flutamide-induced hepatotoxicity in Wistar rats. Sophorin is a citrus flavonoid glycoside, also known as rutin, which is a low molecular weight polyphenolic compound with natural antioxidant properties and reported to have promising hepatoprotective efficacy...

Poisoning with a large variety of drugs and naturally occurring toxins may result in acute liver injury and failure. Drug-induced liver injury is a major cause of liver failure nationwide, and it is likely that nephrologists will be involved in treating patients with these conditions. A number of xenobiotics resulting in liver toxicity may cause acute kidney injury or other organ injury as well. Most agents causing drug- or toxin-induced liver failure lack specific therapies, although a few xenobiotics such as acetaminophen have effective antidotal therapies if administered prior to development of hepatotoxicity...

Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor used as adjuvant therapy in Parkinson's disease. However, it has a highly hepatotoxic profile, as recognized by the U.S. Food and Drug Administration. As a possible solution, nanoscience brought us several tools in the development of new functional nanomaterials with tunable physicochemical properties, which can be part of a solution to solve several drawbacks, including drug's short half-life and toxicity. This work aims to use PEGylated poly(lactic- co -glycolic acid) (PLGA) nanoparticles as a stable carrier with lower hydrodynamic size and polydispersity to encapsulate tolcapone in order to overcome its therapeutic drawbacks...

Drug-induced liver injury (DILI) presents a significant challenge in clinical practice, particularly with the rising popularity of herbal and dietary supplements (HDS) in the United States. Tongkat Ali (Eurycoma longifolia Jack), a Southeast Asian herb, has garnered attention for its purported health benefits, including enhancing testosterone levels. Here, we present a case of a 47-year-old male with acute liver injury following Tongkat Ali use, the first reported case of its kind in the literature. The patient exhibited worsening scleral icterus, elevated liver enzymes, and jaundice shortly after initiating Tongkat Ali supplementation, prompting hospitalization and subsequent clinical improvement upon discontinuation of the supplement...

BACKGROUND: Tuberculosis is still one of the biggest causes of infection-related death around the world. Disseminated tuberculosis is a potentially fatal disease caused by the haematogenous spread of Mycobacterium tuberculosis. First-line anti-tuberculosis drugs in-clude isoniazid, rifampicin, pyrazinamide, and ethambutol. The first three drugs are known to cause hepatotoxicity. CASE PRESENTATION: We have, herein, reported a case of Drug-induced Liver Injury (DILI) due to anti-tuberculosis therapy in a one-year-old male child with disseminated tuberculosis...

INTRODUCTION: On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. OBJECTIVE: The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values...

OBJECTIVES: Contamination of surface waters is a major health threat for all living creatures. Some types of blue-green algae that naturally occur in fresh water, are able to produce various toxins, like Microcystins (MCs). Microcystin-leucine arginine (MC-LR) produced by Microcystis aeruginosa is the most toxic and abundant isoforms of MCs, and it causes hepatotoxicity. The present article reviews preclinical experiments examined different treatments, including herbal derivatives, dietary supplements and drugs against MC-LR hepatotoxicity...

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1,418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4...

Baicalin (BG), a natural product, has been used in the prevention and treatment of drug-induced liver injury (DILI); however, its poor solubility and extensive liver metabolism limit its pharmacological use. The aim of the present study was the formulation of fast-dissolving freeze-dried sublingual tablets (FFSTs) to increase BG dissolution, avoid first-pass metabolism, and overcome swallowing difficulties. FFSTs were prepared following a 23 factorial design. The effect of three independent variables namely matrix former, Maltodextrin, concentration (4%, and 6%), binder concentration (2%, and 3%), and binder type (Methocel E5, and Methocel E15) on the FFSTs' in-vitro disintegration time and percentage dissolution was studied along with other tablet characteristics...

Methotrexate (MTX) is recognized as the golden standard for rheumatoid arthritis (RA) treatment. However, it can cause liver damage in long-term application. Although nanomedicines can target to inflamed sites, most of them tend to accumulate in liver. Glycyrrhizinic acid (GA) holds potential to reverse MTX-associated hepatotoxicity. The combination of GA and MTX might achieve a synergistic anti-inflammatory efficacy and reduced hepatotoxicity. As MTX and GA have totally different in vivo performance, it is necessary to co-encapsulate them in one carrier to coordinate their in vivo fates...

The study explored the hepatoprotective activity and metabolic profile of Verbena bonariensis L. methanol extract (VBM) and fractions using isoniazid as well as rifampicin-triggered liver toxicity in Wistar albino rats. Metabolite profiling of VBM using HPLC-PDA-ESI-MS identified 12 compounds, mainly iridoids, phenylpropanoids, and flavonoids, where verbascoside represents the major compound. Different biochemical parameters such as aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), bilirubin, and total protein levels were used to assess liver functions...

A new series of imidazothiazole derivatives bearing thiazolidinone moiety (4a-g and 5a-d) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound 4c inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC50 value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound 4c with binding site of EGFR...