Hepatotoxic Drugs Research Articles

Cisplatin monotherapy as a treatment option for patients with HER-2–negative breast cancer facing hepatic visceral crisis or impending visceral crisis: A single-center cohort study.

e13057 Background: The international consensus guidelines, ESO-ESMO's fifth edition, characterize visceral crisis (VC) in advanced breast cancer (ABC) as a swift rise in bilirubin during disease progression. The guidelines also briefly address the impending VC (IVC) definition. Systemic treatment data for hepatic VC/IVC are scarce and lacking in international guidelines regarding BC treatment. This study explores cisplatin monotherapy's safety and efficacy in HER2-negative BC patients with hepatic IVC/VC. Methods: In this retrospective cohort study conducted at a Reference Cancer Center in Southern Poland, data from HER2 negative ABC patients who underwent cisplatin monotherapy (60-80mg/m2, every 3-4 weeks) between 2016 and 2023 were examined. Hepatic VC followed ABC5 definition of rapid bilirubin elevation >1.5 times the upper limit of normal (ULN) due to diffuse liver metastases, in the absence of biliary tract obstruction or Gilbert's syndrome; IVC was characterized by rapid, symptomatic liver progression, a majority of liver involvement, with ALT or AST >2 x ULN, and significant increases in LDH, alkaline phosphatase, or GGTP. Results: The study included 33 female participants (24 hormonal positive) with a mean age of 53.8 years (range 34-77). Among them, 10 were identified with hepatic VC, and 23 with IVC. Median number of previous palliative systemic treatment lines was 2 (range: 0-5). The median progression-free survival was 1.87 months and the median overall survival was 2.67 months. Patients received median 1 cycle of cisplatin (1-6): 17 patients received only one cycle, 6 patients two cycles and 10 patients ≥three cycles. Using the Conditional Inference Trees algorithm allowed to assess that patients with performance status (PS) 0 or 1 (15 patients) had a 66.67% chance of achieving stable disease (SD) or partial regression (PR) as the best response, while patients with PS ≥2 (18 patients) had a 5.6% chance of achieving SD or PR as per Response Evaluation in Solid Tumors 1.1 Criteria (median time from cisplatin initiation to imaging studies 2.23 months). Eight patients experienced adverse events of grade ≥3, such as fatigue or nephrotoxicity leading to dose reduction in 5 cases and treatment discontinuation in 2. Conclusions: The differentiation between IVC and VC lacks precision. Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are lacking. Our study explored cisplatin's potential use, finding it to be a feasible choice in patients with PS ≤1 experiencing hepatic IVC/VC, regardless of liver function parameters. Almost one-third of our patients were administered treatment in the last 30 days of life, potentially adversely affecting their quality of life and causing unwarranted suffering and costs. Academic clinical trials should be organized to address this pressing medical gap.

Hepatotoxicity of first-line anti-tuberculosis drugs

Hepatotoxicity of first-line anti-tuberculosis drugs

Hipertensión portal no cirrótica

Portal hypertension of non-cirrhotic origin encompasses a heterogeneous group of diseases of intrahepatic and extrahepatic etiology. In most cases there is a vascular lesion, which are classified as pre-hepatic, hepatic, and post-hepatic according to the area where the blood flow obstruction occurs. Despite its low prevalence, they can cause significant morbidity and mortality in patients, who are generally young. Therefore, it is essential for the clinician to have a high degree of suspicion and start treatment as soon as possible. In regard to its diagnosis, Doppler ultrasound and computed tomography angiography are the tests with the greatest yield. Measuring portal pressures and a liver biopsy may be necessary depending on the context. Treatment will depend on the disease's etiology. Treating the underlying cause when known, suspending hepatotoxic drugs, and starting anticoagulation early will be the basis for most treatment. Endovascular therapies are becoming increasingly important and liver transplantation may be an option in cases in which liver failure is established or when complications of portal hypertension have been refractory to other treatments.

A deep learning approach for acute liver failure prediction with combined fully connected and convolutional neural networks.

Acute Liver Failure (ALF) is a critical medical condition with rapid development, often caused by viral infections, hepatotoxic drug abuse, or other severe liver diseases. Timely and accurate prediction of ALF occurrence is clinically crucial. However, predicting ALF poses challenges due to the diverse physiological differences among patients and the dynamic nature of the disease. This study introduces a deep learning approach that combines fully connected and convolutional neural networks for effective ALF prediction. The goal is to overcome limitations of traditional machine learning methods and enhance predictive model performance and generalization. The proposed model integrates a fully connected neural network for handling basic patient features and a convolutional neural network dedicated to capturing temporal patterns in patient data. The combination allows automatic learning of complex patterns and abstract features present in highly dynamic medical data associated with ALF. The model's effectiveness is demonstrated through comprehensive experiments and performance evaluations. It outperforms traditional machine learning methods, achieving 94.8% accuracy and superior generalization capabilities. The study highlights the potential of deep learning in ALF prediction, emphasizing the importance of considering individualized medical factors. Future research should focus on improving model robustness, addressing imbalanced data, and further exploring personalized features for enhanced predictive accuracy in real-world clinical scenarios.

Efficient hepatocyte differentiation of primary human hepatocyte-derived organoids using three dimensional nanofibers (HYDROX) and their possible application in hepatotoxicity research

Human liver organoids are in vitro three dimensionally (3D) cultured cells that have a bipotent stem cell phenotype. Translational research of human liver organoids for drug discovery has been limited by the challenge of their low hepatic function compared to primary human hepatocytes (PHHs). Various attempts have been made to develop functional hepatocyte-like cells from human liver organoids. However, none have achieved the same level of hepatic functions as PHHs. We here attempted to culture human liver organoids established from cryopreserved PHHs (PHH-derived organoids), using HYDROX, a chemically defined 3D nanofiber. While the proliferative capacity of PHH-derived organoids was lost by HYDROX-culture, the gene expression levels of drug-metabolizing enzymes were significantly improved. Enzymatic activities of cytochrome P450 3A4 (CYP3A4), CYP2C19, and CYP1A2 in HYDROX-cultured PHH-derived organoids (Org-HYDROX) were comparable to those in PHHs. When treated with hepatotoxic drugs such as troglitazone, amiodarone and acetaminophen, Org-HYDROX showed similar cell viability to PHHs, suggesting that Org-HYDROX could be applied to drug-induced hepatotoxicity tests. Furthermore, Org-HYDROX maintained its functions for up to 35 days and could be applied to chronic drug-induced hepatotoxicity tests using fialuridine. Our findings demonstrated that HYDROX could possibly be a novel biomaterial for differentiating human liver organoids towards hepatocytes applicable to pharmaceutical research.

Contribution to the world of 3D cell products created by bio 3D printing technology and to the life science field

We have been making 3D tissues consist of cells only, based on the corporate philosophy of "contributing to dramatic advances in medical care through the practical application of innovative 3D cell stacking technology." Currently, in the field of regenerative medicine, we are working toward obtaining approval from the Ministry of Health, Labor and Welfare and commercializing large artificial organs that are made from patients' own cells and have functions such as nerve regeneration, osteochondral regeneration, and blood vessels. On the other hand, this three-dimensional cell stacking technology can be extended to technology for culturing cells in an environment similar to the human body, and is expected to serve as a new methodology for evaluating the effects of new products in various fields on living organisms. Therefore, we are planning a business to provide developers of pharmaceuticals, foods, cosmetics, etc. with a small device called "Functional Cell Device (FCD)" that reproduces some of the functions of human organs outside the body. As the first step, we have developed a three-dimensional liver construct (3D mini-liver). The in vitro human liver model has a wide range of usage, such as evaluation of hepatotoxicity of drugs, elucidation of drug metabolism mechanism, and model of liver disease. In this report, we will outline it together with actual examples in regenerative medicine.

Hepatic Cirrhosis with Esophageal Varices: A Case Report

Background: In adults, portal hypertension is generally caused by hepatic cirrhosis, whereas in children it is more commonly caused by extrahepatic abnormalities with normal liver function. Portal hypertension causes hemodynamic abnormalities. Gastrointestinal bleeding is the most severe clinical manifestation of portal hypertension in both children and adults. Pathogenetically, increased pressure in the portal vein can be caused by increased vascular resistance and increased portal blood flow. The site of obstruction can be prehepatic (portal vein obstruction), intrahepatic (presinusoidal: eg congenital hepatic fibrosis; para sinusoidal: cirrhosis, hepatotoxic drug therapy, vitamin A hepatotoxicity; post sinusoidal: venocclusive disease) and/or post hepatic (Budd-Chiari syndrome, constrictive pericarditis). Case presentation: The study reports the results of observations of a case of a boy, FAA, aged 12 years and 2 months who came to the emergency room at Dr. M. Djamil General Hospital Padang with the main complaint of hematemesis and splenomegaly from physical examination. Non cirrhotic portal fibrosis is a cause that is not uncommon in the population in the early second decade of life. Some children with non-cirrhotic portal fibrosis as adults can end up with end stage liver disease. Conclusion: Patients with noncirrhotic or cirrhotic portal hypertension can be assessed using the Child Pugh instrument as an instrument that is still used to determine the survival rate if patients with portal hypertension.

Non-alcoholic Fatty Liver Disease Among Iraqi Patients With Psoriasis: A Case-Control Study.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Several studies have shown that patients with psoriasis have a higher risk of developing NAFLD. Obesity, metabolic syndrome, and cytokine-mediated inflammation might be the link between psoriasis and NAFLD. This study aims to investigate the prevalence of NAFLD among psoriatic Iraqi patients and examine the relationship with disease severity using the Psoriasis Area and Severity Index (PASI) score and the correlation with different clinical and laboratory parameters. A case-control study on 130 psoriatic patients and 130 age-, sex-, and BMI-matched healthy controls was conducted at the Department of Dermatology in Basra Teaching Hospital from November 2022 to October 2023. All demographic and clinical data were collected using a pre-designed questionnaire, and NAFLD was diagnosed through a FibroScan examination performed on each participant. The severity of psoriasis was determined using the PASI score. Fasting glucose, liver enzymes, and lipid profile levels were investigated, and metabolic syndrome was identified. The prevalence of NAFLD was significantly higher in our psoriatic patients than in the control group (66.2% vs. 42.3%, OR=2.6, P<0.01). Psoriatic patients were found to have more severe NAFLD than the controls, as evidenced by their steatosis and fibrosis staging (P<0.01). In patients with psoriasis, NAFLD was associated with a higher prevalence of diabetes (17.4%) and metabolic syndrome (55.8%). Furthermore, psoriatic patients with NAFLD had significantly higher values of BMI, waist circumference, PASI score, as well as serum alanine transaminase (ALT), triglyceride, cholesterol, low-density lipoprotein (LDL), and fasting glucose levels.The study also found a significant positive correlation between the psoriasis severity based on PASI and the steatosis score. Metabolic syndrome, PASI, BMI, serum triglycerides, LDL, and age are the independent predictors of NAFLD. NAFLD is highly prevalent among psoriatic patients affecting more than half of them and closely associated with metabolic syndrome and severity of psoriasis. Routine screening for NAFLD may be necessary in psoriatic patients particularly when considering the use of hepatotoxic drug therapy.

In Vitro Hepatotoxicity of Routinely Used Opioids and Sedative Drugs.

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). The incubation time was 2 × 3 days with clinically relevant (Cmax) and higher concentrations (C5× and C10×) of each drug in cell culture medium or human plasma. Afterward, we measured the cell count, vitality, lactate dehydrogenase (LDH), mitochondrial dehydrogenase activity, cytochrome P 450 1A2 (CYP1A2), and albumin synthesis. All tested substances reduced the viability of hepatocyte cells, but sufentanil and remifentanil showed more pronounced effects. The cell count was diminished by sufentanil in both the medium and plasma and by remifentanil only in plasma. Sufentanil and remifentanil also led to higher values of LDH in the cell culture supernatant. A reduction of mitochondrial dehydrogenase activity was seen with the use of midazolam and s-ketamine. Microalbumin synthesis was reduced in plasma after its incubation with higher concentrations of sufentanil and remifentanil. Remifentanil and s-ketamine reduced CYP1A2 activity, while propofol and thiopental increased it. Our findings suggest that none of the tested sedatives and opioids have pronounced hepatotoxicity. Sufentanil, remifentanil, and s-ketamine showed moderate hepatotoxic effects in vitro. These drugs should be given with caution to patients vulnerable to hepatotoxic drugs, e.g., patients with pre-existing liver disease or liver impairment as part of their underlying disease (e.g., hypoxic hepatitis or cholestatic liver dysfunction in sepsis). Further studies are indicated for this topic, which may use more complex cell culture models and global pharmacovigilance reports, addressing the limitation of the used cell model: HepG2/C3A cells have a lower metabolic capacity due to their low levels of CYP enzymes compared to primary hepatocytes. However, while the test model is suitable for parental substances, it is not for toxicity testing of metabolites.

COVID-19 liver damage. Features of laboratory and instrumental diagnostics

The aim of the study - to analyze the pathogenesis of liver damage in COVID-19, as well as to study the features of diagnosis. Research materials: literature and own data on the peculiarities of the pathogenesis of liver damage were analyzed, as well as an assessment of laboratory and instrumental diagnostics in patients with COVID-19. The results of the research. In patients, liver damage was manifested by an increase in liver enzymes, as well as a diffuse decrease in its density during CT. The severity of the disease is caused by a cytokine storm caused by a dysfunctional immune response to the virus, viral virulence factors, as well as the presence of concomitant diseases, especially those associated with liver pathology, such as cirrhosis or steatosis. Conclusions. The new COVID-19 coronavirus infection caused by SARS-CoV-2 continues to spread worldwide. The main target is the organs of the respiratory system. However, among the patients with COVID-19, there were lesions of the central nervous system, intestines, myocardium and liver. Liver dysfunction in most cases should be considered as a result of secondary damage due to CVD, ARDS, hypoxia, multiple organ failure, exposure to immune factors, and taking hepatotoxic drugs.

Elevated liver transaminases among patients with psychiatric disorders.

Hepatocyte injury is assessed by serum aspartate transaminase and alanine transaminase estimation. In psychiatric populations, antipsychotic drugs (AD) are culprit in hepatic dysfunction. To assess transaminitis among psychiatric patients treated by AD. This cross-sectional study was conducted in Zagazig University Hospitals in Egypt, from December 2022 to February 2023. A total of 135 adult patients aged ≥ 18 years, were diagnosed with psychiatric disorders after exclusion of patients receiving any hepatotoxic drugs, viral hepatitis, having chronic liver or kidney diseases, diabetes mellitus, mental retardation, and pregnant females. Among the 135 patients, 104 (77.0%) were males. Their age was 32 ± 9, The most popular used class of AD was atypical AD 84 (62.2%). The overall incidence of transaminitis among patients receiving AD was 23/135 (17.04%) of patients; 13 (56.5%) were on atypical AD compared to 10 (43.5%) patients receiving combined AD, without any statistically significant difference. The use of AD in patients with psychiatric disorders is potentially safe with minimal transaminitis (<one-fold elevation). However, baseline and regular monitoring of serum aminotransferase is recommended during treatment.

Managing Hepatotoxicity Caused by Anti-tuberculosis Drugs: A Comparative Study of Approaches.

Tuberculosis (TB) is one of the oldest and most well-known diseases that has been associated with humans for many years and remains a global health challenge today. Timely diagnosis and proper treatment are crucial for controlling and preventing the spread of the disease. While anti-TB drugs offer many benefits, inadequate monitoring can lead to a range of side effects, including hepatotoxicity, which is a major concern and can cause treatment discontinuation. The aim of this study was to determine the approach to the hepatotoxicity of anti-TB drugs and to investigate potential relationships between demographic factors, underlying medical conditions, and successful retreatment outcomes for hepatotoxicity induced by anti-TB drugs. For this study, we reviewed the medical records of patients who experienced hepatotoxicity due to anti-TB treatment and were admitted to the infectious ward of Imam Khomeini Hospital between April 2015 and February 2019. The data were collected using a questionnaire. The findings indicated that the female gender, weight loss at the beginning of hospitalization, hepatitis C virus, hepatitis B virus (HBV), heart disease, and high levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) at the beginning of hepatotoxicity are risk factors for failure to the retreatment of hepatotoxicity. There were two different approaches to the anti-TB retreatment regimen. The first approach involved gradually starting the drugs in full dose, while the second approach encompassed starting the drugs in the minimum dose and then increasing to the maximum dose. The results demonstrated no significant difference between the two approaches to managing hepatotoxicity induced by anti-TB drugs. Drug-induced hepatotoxicity is a common occurrence that often results in treatment discontinuation. Understanding the prevalence of this complication and identifying appropriate methods of rechallenge treatment is crucial to reducing complications and mortality rates.

A259 METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE IS ASSOCIATED WITH MULTI-ORGAN COMORBIDITIES AND FIBROSIS PROGRESSION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD)

Abstract Background Patients with IBD are at risk for metabolic dysfunction-associated steatotic liver disease (MASLD) due to chronic inflammation, hepatotoxic drugs, alteration of gut microbiota. MASLD, formerly known as non-alcoholic fatty liver disease, provides a positive rather than negative diagnosis, appropriately assigns a metabolic basis for hepatic steatosis (HS), avoids any potentially stigmatizing term, and excludes alcohol abuse. MASLD carries higher risk of both liver fibrosis progression and extra-hepatic involvement, including cardiovascular disease , extra-hepatic cancer, hypothyroidism, chronic kidney disease (CKD). Data on the effect of MASLD on fibrosis progression and multi-organ co-morbidities are lacking in this population. Aims We aimed to determine if MASLD and liver fibrosis carry a higher risk of extra-hepatic co-morbidities in IBD. Methods We prospectively included consecutive IBD patients who underwent liver stiffness measurement (LSM) with controlled attenuation parameter (CAP) by Fibroscan at a single centre. MASLD was defined as any grade HS without alcohol abuse and viral hepatitis. HS progression was defined as any grade HS (CAPampersand:003E270 dB/m), or transition to severe HS (CAPampersand:003E330 dB/m) with CAPampersand:003E270 but ampersand:003C330 dB/m at baseline. Fibrosis progression was defined as significant liver fibrosis (LSM≥8 kPa), or transition to cirrhosis (LSM≥13 kPa) with LSMampersand:003E8 but ampersand:003C13 kPa at baseline. We estimated incidence rates of HS and fibrosis progression by dividing participants with the outcome by number of person-years (PY) of follow-up. Covariate adjustments for HS progression were evaluated by multivariable Cox regression models and predictors of extra-hepatic conditions by multivariable logistic regression analysis. Results 430 patients were included with mean age 43 years, BMI 25 Kg/m2, IBD duration 14 years, CRP 5.2, ALT 22; females 45%, ulcerative colitis (UC) 31.8%, T2DM 4.7%. Patients with MASLD had higher proportion of CV events (12% vs. 6%), CKD (8% vs. 3%) and hypothyroidism (12% vs. 6%) vs. those without. After adjusting for age, male sex and Crohn’s IBD subtype, MASLD remained an independent predictor of extra-hepatic comorbidities (aOR 1.79, 95% CI 1.15–2.78; p=0.01) with T2DM (aOR 3.53, 95% CI 1.68-7.42; p=0.001). Patients were followed for 26 months (SD 16.4). Rate of HS progression was 16.2 per 100 PY (95% CI, 11.5-22.8) and liver fibrosis progression was 6.12 per 100 PY (95% CI 3.48-10.44). In multivariable analysis, after adjusting for IBD duration and BMI,UC was associated with faster progression of HS (aHR 2.21, 95% CI 1.02-4.91). Conclusions MASLD is associated with extra-hepatic diseases in patients with IBD and can progress to liver fibrosis and cirrhosis. Figure 1. Evolution of NAFLD and associated liver fibrosis in patients with IBD. Funding Agencies CIHR

Methylene blue-assisted molecularly-imprinted film modified nitrogen and sulfur co-doped molybdenum carbide for simultaneous electrochemical determination of two hepatotoxic drugs.

A novel electrochemical sensor with a dual-template molecular imprinting technology was fabricated for the simultaneous detection of paracetamol (PAR) and isoniazid (INZ). The sensor was constructed using nitrogen and sulfur co-doped molybdenum carbide (N, S@Mo2C) and a thin layer of electro-polymerized methylene blue was applied onto the surface of the N, S@Mo2C. The electrochemical sensor demonstrated remarkable analytical efficiency for the concurrent PAR and INZ quantification under optimal circumstances. The system achieved an exceptionally low limit of detection (S/N = 3) of 3.7 nM for PAR, with a concentration range of 0.013 and 140 µM. ALOD of7.6 nM was attained for INZ, with a linear range between 0.025 and 140 µM. Furthermore, the platform's selectivity was evaluated using differential pulse voltammetry (DPV). The designed platform successfully detected PAR and INZ in authentic samples with recoveries varying between 98.3% and 104.9%. The relative standard deviations (RSD) for these measurements ranged from 2.7 to 4.0%, demonstrating that the proposed sensor is extremely stable, repeatable, and reproducible. These promising results suggest that the sensor holds potential for the detection of various (bio) molecules, paving the way for future applications in sensing fields.

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD. SIGNIFICANCE STATEMENT: This review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration-approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.

Kinase Inhibitors FDA Approved 2018-2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities.

Small molecule kinase inhibitors are one of the fastest growing classes of drugs, which are approved by the US Food and Drug Administration (FDA) for cancer and noncancer indications. As of September 2023, there were over 70 FDA-approved small molecule kinase inhibitors on the market, 42 of which were approved in the past five years (2018-2023). This minireview discusses recent advances in our understanding of the pharmacology, metabolism, and toxicity profiles of recently approved kinase inhibitors with a central focus on tyrosine kinase inhibitors (TKIs). In this minireview we discuss the most common therapeutic indications and molecular target(s) of kinase inhibitors FDA approved 2018-2023. We also describe unique aspects of the metabolism, bioactivation, and drug-drug interaction (DDI) potential of kinase inhibitors; discuss drug toxicity concerns related to kinase inhibitors, such as drug-induced liver injury; and highlight clinical outcomes and challenges relevant to TKI therapy. Case examples are provided for common TKI targets, metabolism pathways, DDI potential, and risks for serious adverse drug reactions. The minireview concludes with a discussion of perspectives on future research to optimize TKI therapy to maximize efficacy and minimize drug toxicity. SIGNIFICANCE STATEMENT: This minireview highlights important aspects of the clinical pharmacology and toxicology of small molecule kinase inhibitors FDA approved 2018-2023. We describe key advances in the therapeutic indications and molecular targets of TKIs. The major metabolism pathways and toxicity profiles of recently approved TKIs are discussed. Clinically relevant case examples are provided that demonstrate the risk for hepatotoxic drug interactions involving TKIs and coadministered drugs.

Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.

Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.

Liver pathology in COVID-19 after end of pandemic: Modern view of problem

The COVID‑19 pandemic, first reported in late 2019, despite ending in May 2023, continues to have a devastating impact on global health with significant associated morbidity and mortality rates. Liver injury is a common feature in patients with COVID‑19 and ranges from mild and temporary elevation of liver enzymes to severe liver damage and even acute liver failure. The purpose of this review is to present data on the prevalence, pathophysiological mechanisms, clinical manifestations, diagnosis, course features, complications, and treatment options for liver damage in patients with SARS-CoV‑2. Several pathophysiological mechanisms are responsible for liver damage in COVID‑19, including the direct cytotoxic effect of the virus, cytokine storm, hypoxia and ischemia of the organ, and drug hepatotoxicity. Patients with underlying chronic liver disease (CLD) (liver cirrhosis, non-alcoholic fatty liver disease, alcohol-related liver disease, hepatocellular carcinoma, etc.) may have greater risk to develop both severe COVID‑19 and further liver deterioration. Some COVID‑19 patients experience post-covid syndrome, also known as post-acute COVID‑19, long-term COVID‑19 or long COVID‑19. The most common manifestations of post-covid syndrome in patients with liver pathology, both developed directly in connection with SARS-Cov‑2 infection, and in people with pre-existing CLD, include the phenomena of astheno-vegetative syndrome, as well as clinical and biochemical signs of moderate cytolysis and cholestasis syndrome.

High-Voltage Electrostatic Field Hydrogel Microsphere 3D Culture System Improves Viability and Liver-like Properties of HepG2 Cells.

Three-dimensional (3D) hepatocyte models have become a research hotspot for evaluating drug metabolism and hepatotoxicity. Compared to two-dimensional (2D) cultures, 3D cultures are better at mimicking the morphology and microenvironment of hepatocytes in vivo. However, commonly used 3D culture techniques are not suitable for high-throughput drug screening (HTS) due to their high cost, complex handling, and inability to simulate cell-extracellular matrix (ECM) interactions. This article describes a method for rapid and reproducible 3D cell cultures with ECM-cell interactions based on 3D culture instrumentation to provide more efficient HTS. We developed a microsphere preparation based on a high-voltage electrostatic (HVE) field and used sodium alginate- and collagen-based hydrogels as scaffolds for 3D cultures of HepG2 cells. The microsphere-generating device enables the rapid and reproducible preparation of bioactive hydrogel microspheres. This 3D culture system exhibited better cell viability, heterogeneity, and drug-metabolizing activity than 2D and other 3D culture models, and the long-term culture characteristics of this system make it suitable for predicting long-term liver toxicity. This system improves the overall applicability of HepG2 spheroids in safety assessment studies, and this simple and controllable high-throughput-compatible method shows potential for use in drug toxicity screening assays and mechanistic studies.

A pumpless liver-on-a-chip for drug hepatotoxicity analysis.

This study presents the development and validation of an innovative microfluidic liver-on-a-chip device utilizing gravity-driven perfusion for the evaluation of drug hepatotoxicity. This research involved the construction of a hydrogel-based coculture chip that integrates liver parenchymal and stellate cells within a tri-channel configuration. The assembly and operation of the liver-on-a-chip and its accompanying custom rocker were straightforward. The cells in the chip maintained high viability and continuously synthesized liver albumin over extended culture durations. Acetaminophen (APAP), a hepatic injury-inducing drug, was utilized as a positive control in hepatic toxicity assays on the chip. The liver chip exhibited hepatotoxic responses comparable to those observed in 2D models. Furthermore, in this study we evaluated the effects of two plant-derived natural compounds, aristolochic acid I (AA) and its analog aristolactam AII (AL), in both 2D cell models and the liver-on-a-chip system. AA, known for its hepatorenal toxicity, was observed to cause hepatotoxicity in both the 2D models and on the chip. The flow cytometry and mRNA sequencing results confirmed the propensity of these compounds to induce liver cell apoptosis. Notably, AL, previously considered nontoxic, provoked a significant decrease in the hepatic functionality marker albumin exclusively in the liver chip but not in 2D models, indicating the liver chip's enhanced sensitivity to toxic substances. In summary, this pumpless liver-on-a-chip is a simple yet powerful tool for drug hepatotoxicity studies.