Hepatotoxicity Research Articles

Advanced In Vitro Models for Preclinical Drug Safety: Recent Progress and Prospects

The majority of drugs are typically orally administered. The journey from drug discovery to approval is often long and expensive, involving multiple stages. A major challenge in the drug development process is drug-induced liver injury (DILI), a condition that affects the liver, the organ responsible for metabolizing most drugs. Traditionally, identifying DILI risk has been difficult due to the poor correlation between preclinical animal models and in vitro systems. Differences in physiology between humans and animals or cell lines contribute to the failure of many drug programs during clinical trials. The use of advanced in vitro systems that closely mimic human physiology, such as organ-on-a-chip models like gut–liver-on-a-chip, can be crucial in improving drug efficacy while minimizing toxicity. Additionally, the adaptation of these technologies has the potential to significantly reduce both the time and cost associated with obtaining safe drug approvals, all while adhering to the 3Rs principle (replacement, reduction, refinement). In this review, we discuss the significance, current status, and future prospects of advanced platforms, specifically organ-on-a-chip models, in supporting preclinical drug discovery.

Acute Liver Failure: A Review of Indian Literature

Acute liver failure (ALF) is a rare, life-threatening condition marked by the sudden loss of liver function in individuals without prior liver disease. It presents with hepatic encephalopathy, coagulopathy, jaundice, and often multiorgan failure. The most common causes in India include viral hepatitis, drug-induced liver injury (especially antitubercular drugs) contrary to western world where drugs induced ALF (especially acetaminophen) and metabolic disorders are common. Early diagnosis is vital, relying on clinical evaluation, laboratory tests, and imaging studies. Management is complex and multidisciplinary, focusing on stabilizing the patient, preventing complications, and treating the underlying cause. Intensive care is essential for monitoring and managing complications such as cerebral edema, renal dysfunction, and sepsis. Specific treatments include N-acetylcysteine for acetaminophen toxicity, antivirals for hepatitis, or plasmapheresis in autoimmune cases. Liver transplantation is the definitive treatment for those who do not recover spontaneously, guided by prognostic tools like the King’s College Criteria. Despite advancements in care, ALF remains associated with high mortality, emphasizing the need for timely intervention and continued research into new therapies.

Evaluation of Rheum Aqueous Extract Effects on Inflammatory Biomarkers in Valproic Acid-Induced Hepatotoxicity in Rat Model

Background: Valproic acid (VPA) is a widely used anticonvulsant and mood stabilizer, but its clinical utility is often limited by hepatotoxicity. Rheum species, commonly known as rhubarb, have demonstrated hepatoprotective and anti-inflammatory properties, but their effects on inflammatory biomarkers in VPA-induced hepatotoxicity remain unclear. Objective: To evaluate the impact of Rheum aqueous extract on IL-6 and TNF-α levels in a rat model of VPA-induced hepatotoxicity, focusing on its potential hepatoprotective mechanisms. Methods: Thirty male albino rats were divided into five groups: Control, VPA-induced hepatotoxicity, L-carnitine, Rheum aqueous extract, and a combination of L-carnitine and Rheum extract. VPA was administered orally at 250 mg/kg/day for 20 days to induce hepatotoxicity. Treatments with L-carnitine (250 mg/kg/day) and Rheum extract (80 mg/kg/day) were initiated post-induction for 15 days. IL-6 and TNF-α levels were measured to assess inflammatory responses. Results: VPA treatment significantly increased IL-6 and TNF-α levels, indicating heightened inflammation. Both L-carnitine and Rheum extract independently reduced these inflammatory markers, with L-carnitine demonstrating a slightly stronger effect. However, combination therapy showed mixed outcomes: IL-6 levels were reduced, but TNF-α levels were unexpectedly elevated compared to the VPA group. Conclusion: L-carnitine and Rheum extract exhibit significant anti-inflammatory effects individually, reducing IL-6 and TNF-α levels in VPA-induced hepatotoxicity. However, their combination revealed potential adverse interactions, emphasizing the need for further research into their combined therapeutic application. These findings contribute to the understanding of natural and synthetic interventions for mitigating drug-induced liver injury.

Click chemistry-based dual nanosystem for microRNA-122 detection with single-base specificity from tumour cells

MicroRNAs (miRNAs) have been recognised as potential biomarkers due to their specific expression patterns in different biological tissues and their changes in expression under pathological conditions. MicroRNA-122 (miR-122) is a vertebrate-specific miRNA that is predominantly expressed in the liver and plays an important role in liver metabolism and development. Dysregulation of miR-122 expression is associated with several liver-related diseases, including hepatocellular carcinoma and drug-induced liver injury (DILI). Given the potential of miR-122 as a biomarker, its effective detection is important for accurate diagnosis. However, miRNA detection methods still face challenges, particularly in terms of accurately identifying miRNA isoforms that may differ by only a single base. Here, with the aim of advancing accessible methods for the detection of miRNAs with single-base specificity, we have developed a robust dual nanosystem that leverages the simplicity of click chemistry reactions. Using the dual nanosystem, we successfully detected miR-122 at single-base resolution using flow cytometry and analysed its expression in various tumour cell lines with high specificity and strong correlation with TaqMan assay results. We also detected miR-122 in serum and identified four single nucleotide variations in its sequence. The chemistry employed in this dual nanosystem is highly versatile and offers a promising opportunity to develop nanoparticle-based strategies that incorporate click chemistry and bioorthogonal chemistry for the detection of miRNAs and their isoforms.Graphical

A new human autologous hepatocyte/macrophage co-culture system that mimics drug-induced liver injury-like inflammation.

The development of in vitro hepatocyte cell culture systems is crucial for investigating drug-induced liver injury (DILI). One prerequisite for monitoring DILI related immunologic reactions is the extension of primary human hepatocyte (PHH) cultures towards the inclusion of macrophages. Therefore, we developed and characterized an autologous co-culture system of PHH and primary human hepatic macrophages (hepM) (CoC1). We compared CoC1 with a co-culture of the same PHH batch + M0 macrophages derived from THP1 cells (CoC2) in order to represent a donor independent macrophage reaction. Then, we treated the mono- and co-cultures with drugs that cause DILI-menadione (MEN, 1 or 10µM, 3h), diclofenac (DIC, 0.5 or 5mM, 6h), or acetaminophen (APAP, 0.5 or 5mM, 6h)-and assessed culture stability, cell activity, macrophage differentiation, cytokine production and cell viability. Without drug treatment, CoC1 was the most stable over a culture time of up to 60h. Cytokine array analysis revealed a proinflammatory profile of PHH mono-cultures due to isolation stress but showed different influences of hepM and M0 on the cytokine profile in the co-cultures. MEN, DIC and APAP treatment led to donor-dependent signs of cell stress and toxicity. HepM can either promote or reduce the DILI effects donor dependently in CoC1. CoC2 are slightly less sensitive than CoC1 in representing DILI. In summary, we present a new autologous co-culture system that can mimic DILI in a donor-dependent manner. This cellular system could be useful for new drug testing strategies and reducing animal testing.

Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances.

Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.

A real-world disproportionality analysis of the US Food and Drug Administration (FDA) adverse event reporting system (FAERS) events for Durvalumab

BackgroundIn the past few years, an increasing number of research studies have documented the utilization of durvalumab in the field of immunotherapy for cancerous tumors. However, there remains insufficient documentation regarding its associated adverse event (AEs). In order to enhance our comprehension of its toxicological profile, this investigation retrospectively examined the AEs linked to durvalumab using data from the US Food and Drug Administration adverse event reporting system (FAERS).MethodsUsing data from FAERS for the period 2004 to 2024, the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and mu-item gamma Poisson shrinker (MGPS) four algorithms were used to quantify durvalumab related AEs. SAS 9.4 was used for statistical analysis.ResultsWe collected nonduplicated reported 17,629,340 patients from the FAERS database and 19,709 AEs cases in the target population with durvalumab as the primary drug of suspicion. There were 6 significantly disproportionate preferred terms (PTs) that fit all four algorithms simultaneously. The AEs commonly reported include death, radiation pneumonitis, pneumonitis, and lung disorders. Furthermore, durvalumab has been associated with additional AEs, such as metastases to the central nervous system and drug-induced liver injury.ConclusionsThe study revealed that durvalumab immunotherapy is associated with AEs including death, radiation pneumonitis, pneumonitis, metastases to the central nervous system, lung disorder and drug-induced liver injury. In clinical practice, it is crucial to be vigilant and prevent the occurrence of these AEs.

Prediction of bioactive compounds hepatotoxicity using in silico and in vitro analysis

The leading safety issue and side effect associated with natural herb products is drug-induced liver injury (DILI) caused by bioactive compounds derived from the herb products. Herein, in silico and in vitro analyses were compared to determine the hepatotoxicity of compounds. The results of in silico analyses, which included an integrated database and an interpretable DILI prediction model, identified calycosin, biochanin_A, xanthatin, piperine, and atractyloside as potential hepatotoxic compounds and tenuifolin as a non-hepatotoxic compound. To evaluate the viability of HepG2 cells exposed to the selected compounds, we determined the IC50 and IC20 values of viability using MTT assays. For in-depth screening, we performed hematoxylin and eosin-stained morphological screens, JC-1 mitochondrial assays, and mRNA microarrays. The results indicated that calycosin, biochanin_A, xanthatin, piperine, and atractyloside were potential hepatotoxicants that caused decreased viability and an apoptotic phase in morphology, while these effects were not observed for tenuifolin, a non-hepatotoxicant. In the JC-1 assay, apoptosis was induced by all the predicted hepatotoxicants except atractyloside. According to transcriptomic analysis, all the compounds predicted to induce DILI showed hepatotoxic effects. These results highlighted the importance of using in vitro assays to validate predictive in silico models and determine the potential of bioactive compounds to induce hepatotoxicity in humans.

Establishing reference ranges for circulating biomarkers of drug-induced liver injury in healthy human volunteers.

The potential of mechanistic biomarkers to improve prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation. Serum samples from 227 healthy volunteers were recruited as part of a cross-sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony-Stimulating Factor-1 (CSF-1) were assayed. Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra-individual variability was found to be non-significant, and there was no significant impact of diurnal variation. Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.

Dietary modulation of gut microbiota affects susceptibility to drug-induced liver injury

ABSTRACT The rising incidence of drug-induced liver injury (DILI) parallels contemporary dietary shifts that have transformed the composition of human gut microbiota. The relationship between these phenomena remains unknown. Here, it is unveiled that a high fiber diet (HFiD) provides substantial protection against DILI, whereas a western style diet (WSD) significantly exacerbates DILI. Gut microbiota transplantation further confirms these differing outcomes are mediated by diet-induced variations in gut microbiota. Mechanistically, Lactobacillus acidophilus, enriched by HFiD, alleviates DILI through its metabolite indole-3-lactic acid (ILA), which activates the AhR/Nrf2 signaling pathway, thus enhancing hepatocellular antioxidant defenses and detoxification capacity. In the clinical intervention of subjects with prediabetes (N = 330), dietary fiber intervention enriches intestinal L. acidophilus, elevates serum ILA levels, and improves liver function. Conversely, WSD induces disturbance in bile acid metabolism and dysbiosis in gut microbiota, which impairs the intestinal barrier and facilitates the translocation of lipopolysaccharides (LPS) to the liver, thus triggering inflammatory responses and exacerbating DILI. These results demonstrate that dietary patterns significantly influence the onset of DILI by modulating gut microbiota. This novel insight expands the understanding of DILI risk factors and highlights the potential of dietary modifications as a preventive strategy against DILI.

Drug-induced liver injury related to avacopan therapy.

The efficacy of avacopan as remission induction therapy for Anti-Neutrophil Cytoplasmic Autoantibody (ANCA)-associated vasculitis (AAV) is well-established. However, concerns regarding liver injury post-avacopan treatment remain, especially in Japan. Therefore, this study aimed to investigate drug-induced liver injury (DILI) associated with avacopan treatment. This study included 22 patients with AAV who were treated with avacopan at multiple centers in Japan between September 2021 and March 2024. DILI was assessed by the Japanese version of a revised electronic causality assessment method (RECAM-J 2023). Among the 22 patients treated with avacopan, DILI was observed in nine cases (40.9%): six with microscopic polyangiitis and three with granulomatosis with polyangiitis. Severe DILI with elevated total bilirubin (T-Bil) was observed in four of the nine patients (44.4%), a few weeks after the initiation of avacopan therapy. Eight of the nine patients (88.9%) with DILI improved after discontinuation of avacopan and other medications, and one patient developed vanishing bile duct syndrome (VBDS) leading to death. Avacopan-induced DILI was classified into three patterns: 1, short-term injury without T-Bil elevation; 2, transient cholestatic liver injury with T-Bil elevation; 3, decompensated liver injury with marked T-Bil elevation (VBDS). The risk factors for severe DILI with T-Bil elevation in Japanese patients included older age, lower body mass index, and early onset DILI following the initiation of avacopan treatment. Avacopan-induced DILI is relatively common in Japan and could be lethal. Frequent laboratory follow-ups should be considered, especially for elderly and low-body-weight patients.

Deep Learning Prediction of Drug-Induced Liver Toxicity by Manifold Embedding of Quantum Information of Drug Molecules.

Drug-induced liver injury, or DILI, affects numerous patients and also presents significant challenges in drug development. It has been attempted to predict DILI of a chemical by in silico approaches, including data-driven machine learning models. Herein, we report a recent DILI deep-learning effort that utilized our molecular representation concept by manifold embedding electronic attributes on a molecular surface. Local electronic attributes on a molecular surface were mapped to a lower-dimensional embedding of the surface manifold. Such an embedding was featurized in a matrix form and used in a deep-learning model as molecular input. The model was trained by a well-curated dataset and tested through cross-validations. Our DILI prediction yielded superior results to the literature-reported efforts, suggesting that manifold embedding of electronic quantities on a molecular surface enables machine learning of molecular properties, including DILI. The concept encodes the quantum information of a molecule that governs intermolecular interactions, potentially facilitating the deep-learning model development and training.

Secondary sclerosing cholangitis due to drug-induced liver injury: a retrospective cohort study.

The main objective of our study was to assess the frequency of drug-induced liver injury (DILI) patients with coexisting secondary sclerosing cholangitis (SSC) within our center and then analyze clinical features of these patients. SSC has received limited attention in the context of DILI. These changes can be observed on magnetic resonance cholangiopancreatography (MRCP). We conducted a single-center retrospective cohort study involving 185 consecutive patients diagnosed with DILI between January 2020 and August 2024. We reviewed MRCP images of 81 available patients. Among the 185 patients, 81 underwent MRCP and 14 patients (17.3%) were diagnosed with SSC. Nine (64.3%) of 14 were diagnosed with biliary strictures in extrahepatic bile ducts, and 11 of 14 patients (78.6%) displayed segmental distribution. The SSC group showed higher peak alkaline phosphatase (ALP) values (660 vs. 290 U/l, P = 0.015), longer resolution time (114 vs. 61 days, P = 0.038), and a higher frequency of chronic injury (35.7% vs. 10.4%, P = 0.016). Multivariate logistic regression analysis identified peak ALP values as a risk factor for SSC [odds ratio = 1.002 (1.000-1.005), P = 0.030]. The prevalence of drug-related SSC has noticeably increased in recent years. The higher peak ALP values potentially associated with an increased risk of drug-related SSC onset.

CYP3A4-Mediated Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor JNJ-54861911 Results in Redox-Neutral Addition of Glutathione via Catalysis by Glutathione S-Transferase α1, Identified as the Major Target Protein in Human Hepatocytes.

The β-amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor JNJ-54861911, a candidate for the treatment of Alzheimer's disease, was withdrawn from clinical trials due to drug-induced liver injury (DILI). This paper describes our investigation of the metabolism of JNJ-54861911 to understand the potential contribution to the observed DILI. In human hepatocytes, JNJ-54861911 is metabolized by CYP450 3A4 to a reactive intermediate (RI), which undergoes glutathione (GSH) addition at C6 of the 2-amino-4-methyl-1,3-thiazin-4-yl moiety via glutathione S-transferase α1 (GSTA1) catalysis. Despite the preponderant role of CYP3A4 as an enabler, the adduct has the same level of oxidation as that of JNJ-54861911. The exact mechanism of RI formation might involve a sulfoxide (with further reduction) or tautomeric forms of JNJ-54861911 bearing a reactive thiazinium cation activating both the C2 and C6 positions. The cell pellet from the human hepatocyte incubated with 14C-JNJ-54861911 was analyzed via gel electrophoresis, resulting in the identification of a major protein adduct on GSTA1, a cross-link resulting from the addition of GSH and lysine 120 to JNJ-54861911, most likely on position C6 and on the nitrile, respectively. Ultimately, this major adduct might only account for 15-25% of the total covalent binding (CVB). Other important contributors to CVB might exist, like the bioactivation of the major diaminothiazine metabolite (DIAT). The level of covalent binding (CVB) burden (fraction of the dose resulting in CVB) is clearly below 1 mg/day, with a low daily dose of 25 mg. Despite this limited magnitude of CVB, it could still contribute to the liver enzyme elevations observed in approximately 20% of the patients and to the few cases of severe immune-mediated DILI. The latter could occur through a haptenization phenomenon and/or by inducing stress in hepatocytes. Such stress may activate an innate immune response, which, in turn, promotes the adaptive immune response.

Drug-induced Liver Injury Due to Medications for Alcohol Use Disorder: Results From the DILIN Prospective Study.

Concerns about drug-induced liver injury (DILI) may deter physicians from prescribing medications for alcohol use disorder (MAUD). We aim to explore DILI due to MAUD in Drug-Induced Liver Injury Network (DILIN) prospective study. High-confidence DILI cases (ie, definite, highly likely, or probable) due to MAUD in DILIN prospective study (2004-2024) were included. Demographic, clinical, laboratory data, and 6-month outcomes were analyzed. HLA allele frequency (AF) of disulfiram cases was compared to matched controls with DILI due to non-MAUD (DILI controls). Among 1975 high-confidence cases, 13 were attributed to MAUD (11 disulfiram; 1 naltrexone and 1 baclofen; and none from acamprosate). Median age was 45 years, with 77% female and 85% White. All had hepatocellular injury. In disulfiram group, the median time for DILI occurrence was 34 days. Eight patients developed jaundice, with 3 fatal or near-fatal cases (2 liver transplantation and 1 liver-related death). Five (71%) patients with severe or fatal disulfiram DILI had underlying liver disease. AF for HLA-C*01:02 (OR, 6.29; P = 0.02) and DRB1*09:01 (OR, 10.16; P = 0.02) were significantly higher in disulfiram cases than in DILI controls. DILI from baclofen and naltrexone was mild and self-limited with no chronic DILI. Disulfiram is the leading cause of DILI among MAUD and is most common in women. Disulfiram can cause severe DILI and is associated with HLA-C*01:02 and DRB1*09:01. Baclofen and naltrexone can cause mild to moderate self-limited DILI. There were no cases of acamprosate. These findings suggest DILI due to MAUD are less frequent.

Drug-induced hepatitis B virus reactivation: insights from FAERS database analysis

ABSTRACT Background Reactivation of the hepatitis B virus (HBV) induced by drugs is a commonly overlooked but clinically significant complication, posing risks of treatment interruptions, hepatitis exacerbation, liver failure, and even mortality. Methods Disproportionality analyses were conducted on the Food and Drug Administration Adverse Event Reporting System (FAERS) database data spanning from January 2017 to December 2023 to detect drugs posing a risk of HBV reactivation (HBV-R). HBV-R cases were identified using the Medical Dictionary for Regulatory Activities (MedDRA), and drug generic names were ascertained from the DrugBank database. Results A total of 2596 adverse event reports (AERs) were found to be related to drug-induced HBV-R.According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were daklinza, vocabria, doxorubicin, sovaldi, and ribavirin. The top 40 drugs causing drug-induced HBV-R can be roughly divided into three categories: anti-tumor drugs, immunosuppressive drugs, and antiviral drugs. Among them, 23 drugs do not explicitly mention the risk of HBV-R in their drug instructions. Conclusions It was observed that some pharmaceuticals do not adequately address the risk of HBV-R in their drug documentation. These findings could assist healthcare providers in promptly recognizing drug-induced HBV-R.

Pentoxifylline ameliorates carbamazepine-induced hepatotoxicity via down expression of CYP3A4 and NF-kB gene expression in the rat: in vivo study

Drug-induced liver injury (DILI) is a serious complication of many drugs, including carbamazepine; this study investigates the protective effect of pentoxifylline (PTX) against DILI induced by carbamazepine in rat models by attenuating CYP3A4 and NF-κB gene expression. Forty rats were divided into five groups: the control group received no treatment, the induction group received 50 mg/kg carbamazepine orally for 28 days, and three groups received PTX (100, 200, and 300 mg/kg) once daily for one hour before carbamazepine induction for 28 days. Then, the rats were euthanized, and blood and liver tissue were collected for biochemical, gene expression, and histopathology. PTX attenuates the carbamazepine-induced increased CYP3A4 and NF-κB gene expression, with the highest dose showing the best result. PTX also reduced aspartate aminotransferase, alanine aminotransferase, and malondialdehyde, while glutathione levels increased. In conclusion, PTX is highly efficacious in preventing and restoring the liver cells’ normal morphology and cellular function caused by carbamazepine hepatotoxicity. A possible mechanism of the PTC effect is hindering oxidative stress by scavenging free radicals and enhancing the body’s natural defense antioxidant system. Additionally, it exerts an anti-inflammatory impact by modulating NF-κB gene expression.

Risk factors for viral hepatitis in pulmonary tuberculosis patients undergoing treatment: A systematic review and meta-analysis

Liver injury in tuberculosis patients, associated with noncompliance with treatment, is further exacerbated by viral hepatitis, which not only directly harms the liver but also increases susceptibility to drug-induced liver injury. The aim of this study was to analyze the associated risk factors for viral hepatitis in tuberculosis patients. This systematic review and meta-analysis adhere to the PRISMA 2020 statement, and the protocol has been registered with PROSPERO (CRD42023477241). Screening and selection of articles were carried out according to predetermined inclusion and exclusion criteria, utilizing four databases: Embase, Medline, Scopus, and ProQuest. Baseline characteristics and patient-related risk factors from each included study were extracted, followed by a meta-analysis of factors that potentially had significance, with the heterogeneities also being analyzed. Of the 21 included studies out of 6,415 identified records, 12 potential risk factors for hepatitis B and 15 for hepatitis C were subjected to meta-analysis. Some key risk factors included for hepatitis B and C were HIV infection (OR: 3.42; 95%CI: 2.19–5.34 and OR: 6.99; 95%CI: 5.09–9.61, respectively), smoking (OR: 1.55; 95%CI: 1.19–2.02 and OR: 3.06; 95%CI: 1.63–5.75, respectively) and alcohol consumption (OR: 2.38; 95%CI: 1.06–5.37 and OR: 4.32; 95%CI: 2.76–6.78, respectively). Furthermore, meta-analysis indicated that other significant risk factors for hepatitis B and/or C include injecting and non-injecting drug use, multiple sexual partners, tattooing, ear-nose piercing, blood transfusion, dental interventions, homelessness, incarceration, living with prisoners, sexually transmitted diseases, and diabetes mellitus. In conclusion, patients with tuberculosis who have risk factors such as smoking, HIV, or alcohol consumption should be screened for hepatitis B and C to prevent liver injury.

Retrospective evaluation of medical information for predicting tazobactam/piperacillin-induced liver injury.

Tazobactam/piperacillin is a first-line treatment option for hospital-acquired pneumonia; however, drug-induced liver injury (DILI) is relatively frequently observed with tazobactam/piperacillin in clinical practice. This study aimed to verify the usefulness of available patient data for predicting DILI prior to tazobactam/piperacillin administration. Tazobactam/piperacillin-treated patients were retrospectively selected and divided into patients with and without DILI. Comparative analysis was performed regarding age, gender, dose, duration of treatment, clinical laboratory values prior to treatment initiation, and the types of organ-specific infections in both groups. Multiple logistic regression analyses indicated that elevated C-reactive protein (odds ratio (OR), 1.284; 95% confidence interval (CI), 1.172 - 1.406; p < 0.001) and high hemoglobin (OR, 1.697; 95% CI, 1.259 - 2.286; p < 0.001) levels prior to the administration of tazobactam/piperacillin were risk factors for DILI in males who received a 4.5-g dose. A predictive model for DILI risk was constructed by combining these test values and analyzed using receiver operating characteristic curves, obtaining 0.910 for the model construction set and 0.845 for the validation set. The development of DILI was predicted with good accuracy in males who received a 4.5-g dose with elevated C-reactive protein and hemoglobin.

Safety evaluation of ceftazidime/avibactam based on FAERS database.

To explore adverse event (AE) signals of Ceftazidime/avibactam (CZA) based on the FDA Adverse Event Reporting System (FAERS) database. AE reports primarily associated with CZA were retrieved from the FAERS database from the second quarter of 2015 to the second quarter of 2023. Signal detection was conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) methods. A total of 750 AEs reports with CZA as the preferred suspected drug were obtained, identifying 66 preferred terms (PTs) involving 24 system organ classes (SOCs). Besides, the AEs already mentioned in the drug label, this study also revealed some new, clinically valuable potential AEsignals, such as Cholestasis (n = 14, ROR 29.39, PRR 29.15, IC 3.34, EBGM 29.11), Drug-induced liver injury (n = 8, ROR 9.05, PRR 9.01, IC 2.25, EBGM 9.01), Hepatocellular injury (n = 7, ROR 13.90, PRR 13.84, IC 2.41, EBGM 13.63), Haemolytic anaemia (n = 5, ROR 24.29, PRR 24.22, IC 2.42, EBGM 40.53), etc. Additionally, AE signals with higher intensity were identified, such as Hypernatraemia (n = 5, ROR 40.73, PRR 40.61, IC 2.31, EBGM 24.19), Toxic epidermal necrolysis (n = 4, ROR 11.58, PRR 11.55, IC 1.89, EBGM 11.54). Therefore, special vigilance for these potential AEs is warranted when using CZA clinically. This study highlights the potential AEs and risks associated with the clinical use of CZA, particularly the risks related to Cholestasis, Drug-induced liver injury, Haemolytic anaemia, Hypernatraemia, and Toxic epidermal necrolysis.