Hepatotoxic Drugs Research Articles

Effectiveness of combined proton pump inhibitors and posaconazole prophylaxis against invasive fungal infections in patients with hematologic malignancies: a retrospective study.

Posaconazole is widely recommended for preventing and treating invasive fungal infections (IFIs) in immunocompromised patients, especially those with prolonged neutropenia. However, the concentration of the oral suspension formulation can be affected by factors such as co-administration with acid-suppressing medications, influencing its efficacy and safety. This study examined the impact of proton pump inhibitors (PPIs) and other factors on posaconazole concentrations and the concentration-to-dose ratio (C/D) while also evaluating adverse drug reactions in patients with hematologic malignancies. We conducted a retrospective analysis of patients who received posaconazole for IFI prophylaxis or treatment, assessing demographic and clinical data, adverse reactions, treatment outcomes, and drug concentration assays. The study focused on the effects of PPIs on Cmin and C/D. Data from 283 posaconazole Cmin measurements in 86 patients were analyzed. The incidence of probable or proven IFIs was 6.4% (5/78). PPI use reduced posaconazole Cmin levels but did not significantly impact prophylactic efficacy. Esomeprazole and rabeprazole were explicitly associated with decreased Cmin. Hepatotoxicity was linked to the co-administration of hepatotoxic drugs, indicating that posaconazole was not the sole contributor. Co-administration of esomeprazole or rabeprazole lowers posaconazole plasma concentrations without compromising prophylactic efficacy against IFIs. Nonetheless, caution is advised when combining these drugs in high-risk immunocompromised patients.

Novel Endoplasmic Reticulum-Targeted Luminescent Probe for Visualization of Carbon Monoxide in Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a major hepatic dysfunction commonly caused by hepatotoxic drug overdose, resulting in a considerable number of fatalities worldwide. Recent studies have highlighted the regulatory and hepatoprotective effects of carbon monoxide (CO) during the liver injury process. However, precisely tracking the dynamic changes in the composition of CO in DILI is still a great challenge. In this work, leveraging the innovative "quencher-insertion" strategy, a unique endoplasmic reticulum (ER)-targetable lanthanide complex-based luminescence probe, ER-ANBTTA-Eu3+/Tb3+, has been developed for the selective and accurate monitoring of CO fluxes in live cells and laboratory animals. The new probe is composed of three covalently linked functional moieties: the terpyridine polyacid-Eu3+/Tb3+-mixed chelates as the long-lived luminophore, a p-toluenesulfonamide moiety as the ER-anchoring motif, and an allyloxy-nitrobenzyl ether moiety as the CO-specific recognition unit. Upon reaction with CO in the presence of Pd2+ ions, the Tsuji-Trost reaction leads to the cleavage of the allyloxy-nitrobenzyl group from the Eu3+/Tb3+-mixed chelates, which results in the restoration of Tb3+ emission at 538 nm and the attenuation of Eu3+ emission at 688 nm, leading to a dramatic increase of the I538/I688 ratio. In addition to the exceptional response sensitivity and selectivity toward CO, ER-ANBTTA-Eu3+/Tb3+ also exhibits the outstanding ER-locating capability, which allows the probe to be used for imaging of CO in the ER of live cells. Using this probe, combined with the time-gated luminescence imaging mode, the exogenous and endogenous CO in ER of live cells were monitored without the interference of background autofluorescence. Moreover, the upregulation of hepatic CO in DILI mice was successfully visualized. The results suggested the potential of ER-ANBTTA-Eu3+/Tb3+ for deeply exploring the functions of CO in DILI pathogenesis.

Comparison of Non-invasive Liver Fat Scoring Systems as Markers of Metabolic Dysfunction-Associated Liver Disease.

Background Metabolism dysfunction-associated steatotic liver disease (MASLD) is hepatic steatosis along with increased weight or obesity, type 2 diabetes, or metabolic dysregulation and without significant alcohol consumption. The clinical prediction of MASLD using simple, non-invasive indices like Fatty Liver Index (FLI), NAFLD Liver Fat Score (NAFLD LFS), Visceral Adiposity Index (VAI), Steato Test and Hepatic Steatosis Index (HSI) yielded heterogeneous results in different populations. Aim We aimed to compare five scores (Fatty Liver Index, NAFLD Liver Fat Score, Visceral Adiposity Index, Steato Test, Hepatic Steatosis Index) for prediction of liver steatosis. Method Patients with metabolic syndrome and alcohol intake less than 20 grams per day were included in the study. Patients with alcohol intake greater than 20 grams per day and known history of liver or biliary disease, infections, muscle injury, autoimmune diseases, thyroid disorders, underlying secondary diabetes mellitus, secondary hypertension, familial dyslipidemia, intake of medications like steroids, hepatotoxic drugs, chemotherapy or drugs altering liver function tests were excluded. The presence of fatty liver was confirmed on ultrasound. Five indices (Fatty Liver Index, NAFLD Liver Fat Score, Visceral Adiposity Index, Steato Test, Hepatic Steatosis Index) were applied to predict liver steatosis. The correlation of each index with presence of fatty liver was analyzed. Based on the sensitivity of the five scoring systems and prevalence of MASLD as observed in existing literature, with a 95% confidence interval and 20% allowable error, the minimum number of positive cases required is 24 and minimum sample size required is 77. Results Among 100 (100%) patients with metabolic syndrome, MASLD was seen in 65 patients (74% males, 56% females). The mean age of patients with MASLD was 59 years. Fatty Liver Index, NAFLD Liver Fat Score, Visceral Adiposity Index, Steato Test had statistically significant (p<0.005) correlation with fatty liver on ultrasound of abdomen. Fatty Liver Index had the highest Area Under the Receiver Operating Characteristic curve (AUROC) of 0.65 (Sensitivity=63, Specificity=62.9%), followed by NAFLD Liver Fat Score (AUROC=0.63, Sensitivity=64.4%, Specificity=62.9%), Visceral Adiposity Index (AUROC=0.628, Sensitivity=50.8%, Specificity=65.7%) and Steato Test (AUROC=0.61, Sensitivity=46.2%, Specificity=77%). Cut-offs for Fatty Liver Index, NAFLD Liver Fat Score, Visceral Adiposity Index, and Steato Test were 42, 0.5, 4, and 4.5 respectively. MASLD was present in 71.4% (N=35) of patients with type 2 diabetes mellitus and 58.8% (N=30) without type 2 diabetes mellitus. Conclusion Fatty Liver Index, NAFLD Liver Fat Score, Visceral Adiposity Index, and Steato Test were comparable as early markers to predict liver steatosis in patients with metabolic syndrome.

Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort.

Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil. Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset. Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A, and the genes METTL17 and PRSS57, but none achieved genome-wide significance. In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence.

Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs.

Hepatotoxicity can lead to the discontinuation of approved or investigational drugs. The evaluation of the potential hepatoxicity of drugs in development is challenging because current models assessing this adverse effect are not always predictive of the outcome in human beings. Cell lines are routinely used for early hepatotoxicity screening, but to improve the detection of potential hepatotoxicity, in vitro models that better reflect liver morphology and function are needed. One such promising model is human liver microtissues. These are spheroids made of primary human parenchymal and nonparenchymal liver cells, which are amenable to high throughput screening. To test the predictivity of this model, the cytotoxicity of 152 FDA (US Food & Drug Administration)-approved small molecule drugs was measured as per changes in ATP content in human liver microtissues incubated in 384-well microplates. The results were analyzed with respect to drug label information, drug-induced liver injury (DILI) concern class, and drug class. The threshold IC50ATP-to-Cmax ratio of 176 was used to discriminate between safe and hepatotoxic drugs. "vMost-DILI-concern" drugs were detected with a sensitivity of 72% and a specificity of 89%, and "vMost-DILI-concern" drugs affecting the nervous system were detected with a sensitivity of 92% and a specificity of 91%. The robustness and relevance of this evaluation were assessed using a 5-fold cross-validation. The good predictivity, together with the in vivo-like morphology of the liver microtissues and scalability to a 384-well microplate, makes this method a promising and practical in vitro alternative to 2D cell line cultures for the early hepatotoxicity screening of drug candidates.

B-034 Performance Evaluation of the Total Bile Acids (TBA) Assay on Mindray BS-2800M Analyzer

Abstract Background Bile acids (BA) are synthesized in the liver and secreted into bile. The function of BA is to promote absorption of lipids including fat-soluble vitamins. During liver diseases such as viral hepatitis and liver injury by hepatotoxic drugs, and cholestasis condition, BA secretion to bile is impaired, causing serum BA level to rise. Therefore, the determination of serum BA can be used as a sensitive indicator of liver function. TBA reagent contains NADH that requires pH ≥ 9 to be stable that is usually difficult to be maintained during reagent opened and stored on the analyzer. Meanwhile, 3α-Hydroxysteroid Dehydrogenase (3α-HSD) is required for the reaction. 3α-HSD is sensitive to pH condition. Minor changes in pH results in significant changes of enzyme activity. We formulated our TBA reagent with prolonged stability when reagent is onboard on the analyzer. This study evaluated the performance of the new Mindray TBA assay on Mindray BS-2800M. Methods TBA assay was based on the method with coupled Thio-NAD and NADH reaction for BA. The R1 contains Thio-NAD. The R2 contains NADH and 3α-HSD. R1 is incubated with serum sample containing BA for 5 min at 37°C and R2 is then added. During further incubation in the presence of Thio-NAD, 3α-HSD converts BA to 3-ketosteroids and Thio-NADH. The reaction is reversible, and 3α-HSD can convert 3-keto steroids and Thio-NADH to BA and Thio-NAD. In the presence of excess NADH, enzyme cycling occurs efficiently and the rate of formation of Thio-NADH is determined by measuring specific change of absorbance at 412 nm. Two-point-line calibration is used by this assay. The TBA concentrations for the test samples are obtained by the absorbances of test samples from the calibration line. The performances of precision, linearity, onboard stability, interference (hemolysis, lipid and bilirubin), correlation are evaluated following CLSI protocols. Results The precision study was run according to EP05A3 with two commercial controls (about 21 and 36μmol/L) and two serum sample pools(about 9.9 and 24.2 μmol/L)on the Mindray BS-2800M system. The repeatability and within-lab CVs ranged from 0.74% to 1.97%, respectively. The linearity of the assay was determined as from 2.0 μmol/L to 180 μmol/L. The reagent onboard stability is for 28 days without recalibration that is superior to TBA reagents from other manufacturers. The interference of hemolysis, lipid and bilirubin are with less than ±10% impact with hemolysate Hemoglobin up to 500 mg/dL, Intralipids up to 500 mg/dL, and Conjugated bilirubin up to 30 mg/dL, Unconjugated bilirubin up to 30mg/dL. This assay (Y) also correlated well with SEKISUI TBA assay (x), (Y = 0.9965X + 0.2694, r= 0.9993). Conclusions From this evaluation, we concluded that Mindray TBA assay can measure serum TBA precisely and accurately with good performances, especially for onboard stability. It is suitable for use in routine clinical laboratories.

Liver Injury in People With HIV on Antituberculosis and/or Antiretroviral Therapy-Assessing Causality Using the Updated Roussel Uclaf Causality Assessment Method.

We compared performance of the Roussel Uclaf Causality Assessment Method (RUCAM) with multidisciplinary expert panel review in identifying a drug-induced liver injury (DILI) due to antituberculosis therapy (ATT) and/or antiretroviral therapy (ART). Cases were drawn from a prospective registry of hospitalised adults with suspected DILI due to ATT and/or ART in Cape Town, South Africa. Participants had to fulfil American Thoracic Society criteria for ATT interruption (alanine transaminase [ALT] ≥5 times upper limit of normal [ULN]/ALT ≥3 times [ULN] and symptomatic). Causality assessment by expert panel review served as reference standard. The panel ranked potentially implicated drugs as certain, probable, possible or unlikely causes guided by World Health Organization Uppsala Monitoring Centre criteria. The RUCAM was performed for each potentially implicated drug. We calculated sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause for liver injury. We included 48 participants. All were people with HIV (PWH). Twenty-seven were on concomitant ART and ATT, with a median of six potentially hepatotoxic drugs per case. Sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause of liver injury compared with expert panel review was 7% and 100% respectively. Implicated drugs (times ranked probable/certain by panel) were isoniazid (18/0), pyrazinamide (17/0), rifampicin (15/1), efavirenz (6/4) and lopinavir/ritonavir (1/0). PWH with liver injury received multiple potentially implicated drugs, which may increase liver injury risk and complicate causality assessment. Compared with expert panel review, the RUCAM had low sensitivity in detecting probable or certain drug causes of liver injury.

MicroRNAs in Anticancer Drugs Hepatotoxicity: From Pathogenic Mechanism and Early Diagnosis to Therapeutic Targeting by Natural Products.

Patients receiving cancer therapies experience severe adverse effects, including hepatotoxicity, even at therapeutic doses. Consequently, monitoring patients on cancer therapy for hepatic functioning is necessary to avoid permanent liver damage. Several pathways of anticancer drug-induced hepatotoxicity involve microRNAs (miRNAs) via targeting mRNAs. These short and non-coding RNAs undergo rapid modulation in non-targeted organs due to cancer therapy insults. Recently, there has been an interest for miRNAs as useful and promising biomarkers for monitoring toxicity since they have conserved sequences across species and are cellular-specific, stable, released during injury, and simple to analyze. Herein, we tried to review the literature handling miRNAs as mediators and biomarkers of anticancer drug-induced hepatotoxicity. Natural products and phytochemicals are suggested as safe and effective candidates in treating cancer. There is also an attempt to combine anticancer drugs with natural compounds to enhance their efficiencies and reduce systemic toxicities. We also discussed natural products protecting against chemotherapy hepatotoxicity via modulating miRNAs, given that miRNAs have pathogenic and diagnostic roles in chemotherapy-induced hepatotoxicity and that many natural products can potentially regulate their expression. Future studies should integrate these findings into clinical trials by formulating suitable therapeutic dosages of natural products to target miRNAs involved in anticancer drug hepatotoxicity.

New finding based on Comparative Toxicogenomics Database: Hepatic YY1 mediates drug-induced liver injury

BackgroundYY1 plays a crucial part in the onset and progression of numerous liver diseases, yet the significant contribution of YY1 to drug-induced liver injury (DILI) appears to have been underestimated by researchers. PurposeTo reveal the underlying role of YY1 in DILI. MethodThe compounds that interact with YY1 were queried in the Comparative Toxicogenomics Database (CTD), with the majority found to be hepatotoxic, which includes certain widely used drugs. Molecular docking and SPR characterized the robust binding of hepatotoxic compounds to YY1. The duty of YY1 in DILI was investigated in Diosbulbin B (DIOB), a recently identified hepatotoxic compound that tightly associates with YY1, and further validated on ANIT, LCA, APAP, and CDDP. Transcriptomic analysis disclosed the underlying mechanisms involved in DIOB-induced liver injury. RT-qPCR, immunohistochemistry, immunofluorescence, western blotting, and cellular transfection techniques were employed to validate the specific mechanism. ResultsAmong the 94 compounds affecting YY1 expression in the CTD, 59 compounds exhibited hepatotoxicity, showing close interactions with YY1 and almost consistent binding sites by molecular docking. The SPR validated the tough binding of several hepatotoxic compounds to YY1, including five FDA-approved hepatotoxic drugs. Mechanistically, the involvement of YY1 in DILI was uncovered through the cholestasis lens, mice hepatic YY1 was up-regulated by hepatotoxic DIOB and transcriptionally inhibited FXR and its downstream BSEP and MRP2 expression, initiating early in cholestatic liver injury and persisting to drive the progression of cholestasis. ANIT and LCA-induced model of cholestasis provided evidence for the hypothesis that YY1 frequently mediates drug induced cholestasis (DIC). APAP and CDDP indicated that YY1 may also be involved in hepatocellular and mixed type DILI. ConclusionYY1 widely mediated the development of DIC and also might be engaged in other types of DILI. YY1 presented a common target for hepatotoxic medications and the targeting of liver YY1 for drug development may offer a novel approach for managing DILI.

Study of transport, tissue distribution, depletion, and hepatotoxicity of Cyadox, a quinoxaline-1,4-dioxide derivative.

Cyadox (CYA) is a derivative of quinoxaline 1,4-dioxide and a safe and effective synthetic antibacterial agent. This study aimed to explore the drug transport in blood, distribution, depletion and hepatotoxicity of drugs in animals. The transport of CYA in blood was studied using fluorescence, circular dichroism (CD) and molecular docking methods. Tissue distribution and depletion of CYA in rats were evaluated following oral administration of [3H]-CYA at different doses. Hepatotoxicity of drugs evaluated by transcriptomics. During transport in the bloodstream, the drug binds to bovine serum albumin (BSA) by hydrogen bonding and has only one binding site. Hydrogen bonds were formed between O (2) of CYA and ARG208, O (3) of CYA and LEU480, VAL481. The secondary protein conformation of BSA changed after binding with an increase in α-helix and a decrease in β-strand. After a single oral administration of [3H]-CYA, it was excreted rapidly within 7days, with 34.81% from the urine and 60.25% from the feces. Higher and sustained levels of radioactivity were detected in the liver during the post-dose period, suggesting that the drug may concentrate in the liver. The transcriptomic data indicates that CYA exhibits low hepatotoxicity. However, there are indications that it may have an impact on steroid biosynthesis. This study could serve as a basis for conducting further studies on the use of CYA in food animals and improving the pharmacologic, pharmacokinetic, and toxicologic effects of CYA on food animals.

Advanced Liver-on-a-Chip Model for Evaluating Drug Metabolism and Hepatotoxicity.

The liver has many important functions, including the biotransformation of drugs and detoxification of the human organism. As such, it is also exposed to many harmful substances, which leads to disorders and diseases such as cirrhosis. For these reasons, it seems important to consider liver metabolism and the direct effects on the liver when evaluating the efficacy of new drugs. Accordingly, we have developed an advanced in vitro liver model using an organ-on-a-chip approach that replicates many of the morphological and functional features of the liver in vivo. The model we created can metabolize drugs, which we demonstrated using two widely used anticancer drugs, 5-fluorouracil (5FU) and capecitabine (CAP). In addition, to the best of our knowledge, we are the first who evaluate the direct effects of these drugs not only on the viability of liver model-building cells but on their functions, such as cytochrome P450 activity and albumin production. Our study brings new hope to properly evaluating drug efficacy at the in vitro level.

Novel reduced heteropolyacid nanoparticles for effective treatment of drug-induced liver injury by manipulating reactive oxygen and nitrogen species and inflammatory signals

With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun-N-terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N-acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function.

Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults

Use of herbal and dietary supplements (HDSs) accounts for an increasing proportion of drug hepatotoxicity cases. Turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha are the most frequently reported hepatoxic botanicals, but their prevalence and reasons for use in the general population are unknown. To assess the prevalence and clinical characteristics of adult consumers of 6 potentially hepatoxic botanicals. This survey study analyzed nationally representative data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative, cross-sectional survey of the general US population. Prescription drug and HDS exposure data in the past 30 days were analyzed, and 2020 US Census data were used for population estimates. Data were analyzed July 1, 2023, to February 1, 2024. Adult NHANES participants enrolled between January 2017 and March 2020. Baseline weighted characteristics of HDS users and users of 6 potentially hepatotoxic botanical products were compared with non-HDS users. Multivariable analysis was undertaken to identify factors associated with HDS use or at-risk botanical use. Among 9685 adults enrolled in this NHANES cohort, the mean (SE) age was 47.5 (0.5) years, and 51.8% (95% CI, 50.2%-53.4%) were female. The overall prevalence of HDS product use was 57.6% (95% CI, 55.9%-59.4%), while the prevalence of using the 6 botanicals of interest was 4.7% (95% CI, 3.9%-5.7%). Turmeric-containing botanicals were most commonly used (n = 236), followed by products containing green tea (n = 92), ashwagandha (n = 28), Garcinia cambogia (n = 20), red yeast rice (n = 20), and black cohosh (n = 19). Consumers of these 6 botanicals were significantly older (adjusted odds ratio [AOR], 2.36 [95% CI, 1.06-5.25]; P = .04 for 40-59 years of age and AOR, 3.96 [95% CI, 1.93-8.11]; P = .001 for ≥60 years of age), had a higher educational level (AOR, 4.78 [95% CI, 2.62-8.75]; P < .001), and were more likely to have arthritis (AOR, 2.27 [95% CI, 1.62-3.29]; P < .001) compared with non-HDS users. An estimated 15 584 599 (95% CI, 13 047 571-18 648 801) US adults used at least 1 of the 6 botanical products within the past 30 days, which was similar to the estimated number of patients prescribed potentially hepatotoxic drugs, including simvastatin (14 036 024 [95% CI, 11 202 460-17 594 452]) and nonsteroidal anti-inflammatory drugs (14 793 837 [95% CI, 13 014 623-16 671 897]). The most common reason for consuming turmeric and green tea was to improve or maintain health. In this survey study, an estimated 15.6 million US adults consumed at least 1 botanical product with liver liability within the past 30 days, comparable with the number of people who consumed nonsteroidal anti-inflammatory drugs and a commonly prescribed hypolipidemic drug. Given a lack of regulatory oversight on the manufacturing and testing of botanical products, clinicians should be aware of possible adverse events from consumption of these largely unregulated products.

Proteome profiling, biochemical and histological analysis of diclofenac-induced liver toxicity in Yersinia enterocolitica and Lactobacillus fermentum fed rat model: a comparative analysis.

Diclofenac is a hepatotoxic non-steroidal anti-inflammatory drug (NSAID) that affects liver histology and its protein expression levels. Here, we studied the effect of diclofenac on rat liver when co-administrated with either Yersinia enterocolitica strain 8081 serotype O:8 biovar 1B (D*Y) or Lactobacillus fermentum strain 9338 (D*L). Spectroscopic analysis of stool samples showed biotransformation of diclofenac. When compared with each other, D*Y rats lack peaks at 1709 and 1198cm-1, while D*L rats lack peaks at 1411cm-1. However, when compared to control, both groups lack peaks at 1379 and 1170cm-1. Assessment of serum biomarkers of hepatotoxicity indicated significantly altered activities of AST (D*Y: 185.65 ± 8.575 vs Control: 61.9 ± 2.607, D*L: 247.5 ± 5.717 vs Control: 61.9 ± 2.607), ALT (D*Y: 229.8 ± 6.920 vs Control: 70.7 ± 3.109, D*L: 123.75 ± 6.068 vs Control: 70.7 ± 3.109), and ALP (D*Y: 276.4 ± 18.154 vs Control: 320.6 ± 9.829, D*L: 298.5 ± 12.336 vs Control: 320.6 ± 9.829) in IU/L. The analysis of histological alterations showed hepatic sinusoidal dilation with vein congestion and cell infiltration exclusively in D*Y rats along with other histological changes that are common to both test groups, thereby suggesting more pronounced alterations in D*Y rats. Further, LC-MS/MS based label-free quantitation of proteins from liver tissues revealed 74.75% up-regulated, 25.25% down-regulated in D*Y rats and 51.16% up-regulated, 48.84% down-regulated in D*L experiments. The proteomics-identified proteins majorly belonged to metabolism, apoptosis, stress response and redox homeostasis, and detoxification and antioxidant defence that demonstrated the potential damage of rat liver, more pronounced in D*Y rats. Altogether the results are in favor that the administration of lactobacilli somewhat protected the rat hepatic cells against the diclofenac-induced toxicity.

Hepatotoxicity Patterns of Anidulafungin and Fluconazole in the Management of Candida Infections: A Comparative Study among Hospitalized Patients

Hepatotoxicity can potentially arise in hospitalized patients with Candida infections due to antifungal medications. Ongoing research has focused on the hepatotoxicity profiles of fluconazole and anidulafungin. Nevertheless, a limited number of studies have directly compared the hepatotoxicity of these two antifungals. This study compares the hepatotoxic effects of anidulafungin and fluconazole in patients hospitalized with Candida infections. This retrospective study was conducted at the Prince Mohamed Bin Abdelaziz Hospital in Saudi Arabia to compare the hepatotoxicity of fluconazole and anidulafungin in patients with Candida infection. The liver function test results were analyzed using linear mixed models, with adjustments made for confounding factors. The investigation comprised 202 cases, of which 85 (42%) were treated with fluconazole and 117 (58%) was treated with anidulafungin—mortality and prevalence of candidemia and septic shock in the Anidulafungin group (p 0.001). There was no significant difference between the two groups regarding age, gender, duration of treatment, or concomitant use of hepatotoxic drugs. Analyses utilizing Linear Mixed-Effects Models revealed higher alanine aminotransferase (ALT) (p = 0.001) and aspartate aminotransferase (AST) (p = 0.001) levels in the Anidulafungin group initially; however, after adjusting for covariates, these differences were no longer statistically significant. The levels of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GTT) did not differ significantly between groups after controlling for confounding variables. However, the Anidulafungin group had substantially higher bilirubin levels than the Fluconazole group, and this difference remained significant after adjusting for potential confounding variables (p = 0.022). In summary, this study contributes to understanding the relative hepatotoxicity of anidulafungin and fluconazole. After controlling for confounding variables, it was found that there were no significant differences in liver enzyme levels between the two groups. When assessing the hepatotoxicity of these antifungal agents, it is imperative to consider the individual patient characteristics, underlying health conditions, and concurrent administration of other hepatotoxic medications.

Assessment of the Role of Keratin 18 and High Mobility Group Box 1 Biomarkers for Early Prediction of Drugs and Chemicals Induced Hepatotoxicity A Prospective Study in the Poison Control Center of Ain Shams University Hospitals (PCC-ASUH)

Abstract Background Drug-induced hepatotoxicity represents a major clinical problem worldwide. Hepatotoxicity may be caused by drugs, chemicals used in laboratories and industries or natural products and rodenticides such as metal phosphides. Early identification of hepatotoxicity would facilitate patient- individualized treatment strategies. New biomarkers (HMGB1and K18) used to identify subsequent acute liver injury (ALI) in patients on admission to the hospital. Objectives This study aims to assess the role of keratin 18 and high mobility group box 1 biomarkers in early prediction of drugs and chemicals induced hepatotoxicity for better outcome and to compare these new liver biomarkers with the currently used parameters (ALT &amp; AST) in the early prediction of drugs and chemicals induced hepatotoxicity. Methods This prospective study was conducted on 50 adult patients of both sex presented to the PCC- ASUH with acute intoxication of hepatotoxic drugs or chemicals. For all patients, we measured high mobility group box-1 (HMGB1), keratin-18 (K18), AST and ALT on admission then patients were followed- up for development of liver injury . Subjects were classified into group I (control group), group II (no liver affection) and group III (with liver affection). Receiver operator characteristic (ROC) curve was used to compare sensitivity and specificity to report liver injury versus alanine transaminase (ALT) and aspartate transaminase (AST). Results This study showed that HMGB1 and K18 were much more elevated in patients who developed liver injury in the first hospital presentation when ALT and AST were within normal ranges with a highly significant difference between the hepatotoxic and non-hepatotoxic group. ROC analysis showed that HMGB1 and K18 were more sensitive than ALT and AST and more specific than AST in predicting ALI. Conclusion Elevations in plasma HMGB1, and K18 identified subsequent ALI development in patients on admission to the hospital, soon after drug and chemical overdose, and in patients with ALT and AST in the normal range.

A Impact Of Potentially Hepatotoxic Drug Use On Clinical Outcomes In Patients With Liver Cirrhosis

Liver cirrhosis is a pathological liver disease characterized by the formation of fibrous tissue and regenerative nodules in liver cells. The potential for hepatotoxicity due to the use of hepatotoxic drugs leads to worsening of the liver disease suffered by these patients. This study aims to assess the impact of using potentially hepatotoxic drugs on patients' clinical outcomes. This study was an observational study with a cross-sectional design. Data were collected retrospectively through the medical records of patients with liver cirrhosis hospitalized in 2021. The clinical outcomes studied were SGOT, SGPT, albumin, total bilirubin and length of hospitalization. The results obtained were tested using the Kruskal-Wallis statistical test. A total of 62 patients with liver cirrhosis met the inclusion criteria as the study sample. The number of potentially hepatotoxic drug prescriptions received by patients based on Likelihood scores with categories A, B, C, D and E was 368 drugs out of 776 total drug prescriptions (47.4%). The most commonly prescribed potentially hepatotoxic drugs were paracetamol, ceftriaxon, and levofloxacin. It can be concluded that potentially hepatotoxic drugs are still prescribed to patients with liver cirrhosis. Age, gender, child pugh-score, number of drugs, and number of potentially hepatotoxic drugs had no significant effect (p&gt;0.1) on SGOT, SGPT, albumin and total bilirubin. However, patients who received more drugs would have a higher.

Tuberculosis in combination with HIV infection and viral hepatitis: clinical case

ABSTRACT. In recent years, there has been an increase in the number of cases of combined HIV/TB/VH (human immunodeficiency virus / tuberculosis / viral hepatitis) infection. Approaches to the treatment of these patients are changing with the advent of antiviral drugs for the treatment of hepatitis B and C. Treatment of VH in patients with TB increases the effectiveness of antituberculosis therapy by reducing the hepatotoxicity of antimycobacterial drugs. The interaction of antituberculosis, antiretroviral, and direct-acting antiviral drugs for the treatment of HCV was taken into account when managing a case of HIV/TB/HV. The article presents a case of effective treatment of a patient with combined HIV/TB/VH infection.

Construction of an explanatory model for predicting hepatotoxicity: a case study of the potentially hepatotoxic components of Gardenia jasminoides

It is well-known that the hepatotoxicity of drugs can significantly influence their clinical use. Despite their effective therapeutic efficacy, many drugs are severely limited in clinical applications due to significant hepatotoxicity. In response, researchers have created several machine learning-based hepatotoxicity prediction models for use in drug discovery and development. Researchers aim to predict the potential hepatotoxicity of drugs to enhance their utility. However, current hepatotoxicity prediction models often suffer from being unverified, and they fail to capture the detailed toxicological structures of predicted hepatotoxic compounds. Using the 56 chemical constituents of Gardenia jasminoides as examples, we validated the trained hepatotoxicity prediction model through literature reviews, principal component analysis (PCA), and structural comparison methods. Ultimately, we successfully developed a model with strong predictive performance and conducted visual validation. Interestingly, we discovered that the predicted hepatotoxic chemical constituents of Gardenia possess both toxic and therapeutic effects, which are likely dose-dependent. This discovery greatly contributes to our understanding of the dual nature of drug-induced hepatotoxicity.

HLA-DPB1*05:01 and HLA-A*11:01 Is Associated with Adverse Drug Reactions to Isoniazid and Rifampin for Treatment of Latent Tuberculosis Infection in South Korea.

Background: Screening and treating healthcare workers (HCWs) for latent tuberculosis infection (LTBI) are essential for tuberculosis (TB) infection control. Adverse drug reactions (ADRs) to anti-TB drugs present challenges to patient safety and treatment completion. Objective: This study investigated the association between human leukocyte antigen (HLA) alleles and the risk of ADRs, especially drug hypersensitivity (DHS) and hepatotoxicity, in HCWs with LTBI receiving isoniazid (INH) and rifampin (RIF) therapy. Methods: Korean HCWs with LTBI who received a 3 month INH and RIF regimen were included in this study. HLA genotyping was performed on HCWs who experienced ADRs during treatment, as well as the control group consisted of individuals who did not develop ADRs. Results: Of the 67 patients, 29 (43.2%) experienced ADRs during INH and RIF therapy. The HLA-A*11:01 allele was more frequent in patients with DHS without hepatotoxicity (DSH+/H-) compared to the control group (DHS-/H-) (4/9, 44.4% vs. 3/38, 7.9%; odd ratio [OR], 8.554; 95% confidence interval [CI], 1.415-59.869; p = 0.018). Conversely, HLA-DPB1*05:01 was associated with an increased risk of hepatotoxicity regardless of DHS (10/20, 50% vs. 5/38, 13.2%; OR, 5.323; 95% CI, 1.493-21.518; p = 0.011). In the DHS with hepatotoxicity group (DHS+/H+), HLA-DPB1*05:01 was present in a higher proportion (3/5, 60% vs. 5/38, 13.2%; OR, 8.912; 95% CI, 1.110-92.993; p = 0.037), whereas HLA-A*11:01 was not observed in this group. Conclusions: The HLA-A*11:01 allele was associated with an increased risk of DHS without hepatotoxicity, whereas the HLA-DPB1*05:01 allele was associated with an increased risk of hepatotoxicity.