Acetaminophen Overdose Research Articles

The p21+ perinecrotic hepatocytes produce the chemokine CXCL14 after a severe acetaminophen overdose promoting hepatocyte injury and delaying regeneration

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.

Sex differences in glutathione metabolism and acetaminophen toxicity

Aims: Clinical and experimental evidence has shown that females in humans and other mammals have higher glutathione (GSH) levels than males, which are caused by higher levels of estradiol. Understanding how hepatic GSH level and synthesis velocity depend on the sex hormones is an extremely important question since oxidative stress contributes to the risk for heart disease and cancer, and oxidative stress is reduced by GSH. Our aim is to develop a systems approach to understanding GSH metabolism and use this to explain the causes of GSH differences in males and females, how GSH changes during the menstrual cycle, and why women may be less susceptible to acetaminophen toxicity. Methods: We use mathematical models for hepatic glutathione metabolism, including one-carbon metabolism and acetaminophen detoxification, to investigate how the activation of certain enzymes by estradiol leads to dramatic changes in reaction velocities and metabolite concentrations. Results: The models explain why women of childbearing age have higher glutathione than men, and that this is caused by the balance of activation of glutamyl cysteine synthetase (GCL) and glutathione peroxidase (GPX) by estradiol. The steady-state concentration of glutathione in women depends on the strength of the activation of GCL and GPX and is quite homeostatic over a wide range of activations. Conclusions: During the menstrual cycle, the GSH concentration changes daily but over a relatively narrow range. We explain how this dynamic homeostasis depends on the biochemical network that produces GSH. The model is also consistent with published results that show that female mice are less susceptible than males to hepatotoxicity due to acetaminophen overdose and suggests that this might also be true for humans, though the human epidemiological data are contradictory.

Indole-3-carboxaldehyde alleviates acetaminophen-induced liver injury via inhibition of oxidative stress and apoptosis

Drug-induced liver injury (DILI) occurs frequently and can be life-threatening. Increasing researches suggest that acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury. Indole-3-carboxaldehyde (I3A) alleviates hepatic inflammation, fibrosis and atherosclerosis, suggesting a potential role in different disease development. However, the question of whether and how I3A protects against acetaminophen-induced liver injury remains unanswered. In this study, we demonstrated that I3A treatment effectively mitigates acetaminophen-induced liver injury. Serum alanine/aspartate aminotransferases (ALT/AST), liver malondialdehyde (MDA) activity, liver glutathione (GSH), and superoxide dismutase (SOD) levels confirmed the protective effect of I3A against APAP-induced liver injury. Liver histological examination provided further evidence of I3A-induced protection. Mechanistically, I3A reduced the expression of apoptosis-related factors and oxidative stress, alleviating disease symptoms. Finally, I3A treatment improved survival in mice receiving a lethal dose of APAP. In conclusion, our study demonstrates that I3A modulates hepatotoxicity and can be used as a potential therapeutic agent for DILI.

Protective effects of jervine purified from Veratrum album on paracetamol-induced liver toxicity in rats

Purpose: Since paracetamol toxicity is a very common type of poisoning, we planned to investigate whether Jervine has an effect on paracetamol toxicity by utilizing its anti-inflammatory effect.
 Materials and Methods: In our study, 42 Sprague Dawley rats of 8 weeks of age were used. Seven groups were formed with 6 animals in each group. At the 24th hour of the study, all groups underwent laparotomy under anesthesia, and liver dissection was performed. Hematoxylin and Eosin (H&E) staining was performed to evaluate liver histopathology. SOD, CAT, GSH, and MDA levels were analyzed biochemically.
 Results: Histopathological, while liver tissues were normal in the control group, we observed degeneration areas, inflammation, and hemorrhage in the paracetamol group. Jervine reduced the severity of paracetamol toxicity and prevented liver damage. Jervine significantly increased SOD levels. Paracetamol administration significantly decreased CAT levels. Paracetamol significantly decreased GSH levels compared to the control group. 
 Conclusion: Jervine reduced the adverse effects of paracetamol toxicity on liver tissue, such as degeneration, inflammation, and hemorrhage. Jervine increased antioxidant activity and reduced the harmful effects of NAPQI, the toxic metabolite of paracetamol, on liver tissue.

Analisis Studi Biofarmasetika dan Farmakokinetika tentang Pengeluaran Parasetamol Melalui Urin dan Saliva

The purpose of this study was to determine that Paracetamol, also known as acetaminophen, is a commonly used analgesic and antipyretic drug to relieve pain and reduce fever. The process of metabolism and elimination of paracetamol from the body is important to understand, especially in the context of the safe use of this drug. This study aims to analyze the biopharmaceutics and pharmacokinetics studies of paracetamol excretion through urine and saliva as important indicators in understanding the metabolic and elimination processes of this drug. Paracetamol is rapidly and efficiently absorbed through the gastrointestinal tract, reaches the highest concentration in plasma in a short time, and is dispersed throughout the body fluids. The metabolic process of paracetamol mainly occurs in the liver, through two main phases: oxidation and conjugation with glucuronic and sulfuric acids. Excretion of drugs and their metabolites can occur through urine and saliva, with the kidney as the main organ in the excretion process. Qualitative analytical methods were used in this study to identify paracetamol metabolite compounds in urine and saliva samples and to evaluate the metabolic pathways involved. Glucoronide, sulfate, and phenol conjugate assays were used to detect the presence of paracetamol metabolites in the samples. The assay results showed that urine was more effective in excreting paracetamol compared to saliva. In conclusion, this study provides a better understanding of the metabolic process and elimination of paracetamol from the human body through the analysis of biopharmaceutics and pharmacokinetics studies. These results are important for understanding the therapeutic effects and toxicity of paracetamol as well as for developing more effective and safe drug use management strategies.

Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose

BackgroundMacrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug’s mode of inhibition has not been fully investigated.MethodsWe conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose.ResultsKinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion.ConclusionsT-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.

Has the rescheduling of modified-release paracetamol in Australia affected the frequency of overdoses?

In June 2020, modified-release paracetamol (paracetamol-MR) preparations were up-scheduled from schedule-2 (available in pharmacy) to schedule-3 (available by request to a pharmacist only). The present study aims to ascertain whether up-scheduling affected the frequency of paracetamol-MR overdoses. This is a retrospective cohort study of two data sets from 1 June 2017 to 31 May 2022. Monash Health data were extracted using the diagnosis of paracetamol overdose coding and electronic medical records data. Calls regarding paracetamol-MR overdoses to Victorian Poisons Information Centre (VPIC) were extracted from the Poisons centre call database. We used a quasi-experimental research design with interrupted time series analysis to evaluate the immediate impact and change in trend of poisoning-related calls and ED presentations before and after June 2020. The change in proportion of paracetamol-MR cases in both databases was analysed using the Χ2 test. The proportion of paracetamol-MR cases in both data sets did not change. From Monash Health, there was no level change in monthly paracetamol-MR overdose-related presentations following re-scheduling (rate ratio [RR] = 1.08, 95% confidence interval [CI] = 0.57-2.01). There was no change in monthly paracetamol-MR overdose-related calls to VPIC following re-scheduling (RR = 1.05, 95% CI = 0.96-1.14). The proportion of paracetamol-MR overdoses did not decrease after the up-scheduling to S3. Similarly, the frequency of overdoses by month remained similar. Further limitations on access to paracetamol products may need to be considered.

Extra-corporeal non-liver transplant therapies for acute liver failure: Focus on plasma exchange and continuous renal replacement therapy.

The acute inflammatory milieu in patients with acute liver failure (ALF) results in 'toxic' blood in these patients. In vitro experiments have shown that the plasma obtained from ALF patients is toxic to rabbit hepatocytes and inhibits regeneration of rat hepatocytes. Treatments such as plasma exchange and continuous renal replacement therapy to cleanse the blood have improved survival in ALF patients. In the liver microcirculation, the exchange of fluid across fenestrae in liver sinusoidal endothelial cells (LSECs) is vital for proper functioning of hepatocytes. Clogging of the liver filter bed by inflammatory debris and cells ('traffic jam hypothesis') impeding blood flow in sinusoids may in turn reduce the exchange of fluid across LSEC fenestrae and cause dysfunction and necrosis of hepatocytes in ALF patients. In mouse model of paracetamol overdose, disturbances in microcirculation in the liver preceded the development of injury and necrosis of hepatocytes. This may represent a reversible pathophysiological mechanism in ALF which may be improved by the anti-inflammatory effect of plasma exchange. Wider access to urgent plasma exchange is a major advantage compared to urgent liver transplantation to treat ALF patients worldwide, especially so in resource constrained settings. Continuous hemo-filtration or dialysis is used toreduce ammonia levels and treat cerebral edema in ALF patients. In this review, we discuss the different modalities to cleanse the blood in ALF patients, with an emphasis on plasma exchange, from a hepatology perspective.

Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker substudy).

Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.

Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.

Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents. At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results. A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate. The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.

The Use and Potential Benefits of N-Acetylcysteine in Non-Acetaminophen Acute Liver Failure: An Etiology-Based Review.

Acute liver failure represents a life-threatening organ dysfunction with high mortality rates and an urgent need for liver transplantation. The etiology of the disease varies widely depending on various socio-economic factors and is represented mainly by paracetamol overdose and other drug-induced forms of liver dysfunction in the developed world and by viral hepatitis and mushroom poisoning in less developed countries. Current medical care constitutes either specific antidotes or supportive measures to ensure spontaneous recovery. Although it has been proven to have beneficial effects in paracetamol-induced liver failure, N-acetylcysteine is widely used for all forms of acute liver failure. Despite this, few well-designed studies have been conducted on the assessment of the potential benefits, dose regimens, or route of administration of N-acetylcysteine in non-acetaminophen liver failure. This review aims to summarize the current evidence behind the use of this drug in different forms of liver failure.

Острое отравление парацетамолом у детей. Оказание неотложной помощи в реанимационном отделении многопрофильной больницы на примере клинических случаев

The article presents a three -year analysis of the structure of acute paracetamol poisoning in children. On the example of clinical cases, the tactics of treating patients with acute paracetamol poisoning are described.The effectiveness of the recommended doses and antidote therapy schemes is evaluated. The main factors contributing to the adverse outcome of the disease are indicated.

A novel HDAC6 inhibitor attenuate APAP-induced liver injury by regulating MDH1-mediated oxidative stress

Glutathione (GSH) depletion, mitochondrial damage, and oxidative stress have been implicated in the pathogenesis of acetaminophen (APAP) hepatotoxicity. Here, we demonstrated that the expression of histone deacetylase 6 (HDAC6) is highly elevated, whereas malate dehydrogenase 1 (MDH1) is downregulated in liver tissues and AML-12 cells induced by APAP. The therapeutic benefits of LT-630, a novel HDAC6 inhibitor on APAP-induced liver injury, were also substantiated. On this basis, we demonstrated that LT-630 improved the protein expression and acetylation level of MDH1. Furthermore, after overexpression of MDH1, an upregulated NADPH/NADP+ ratio and GSH level and decreased cell apoptosis were observed in APAP-stimulated AML-12 cells. Importantly, MDH1 siRNA clearly reversed the protection of LT-630 on APAP-stimulated AML-12 cells. In conclusion, LT-630 could ameliorate liver injury by modulating MDH1-mediated oxidative stress induced by APAP.

Perturbations in human bile acid profiles following drug-induced liver injury investigated using semitargeted high-resolution mass spectrometry.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in North America. To investigate the effect of drug-induced liver injury (DILI) on circulating bile acid (BA) profiles, serum from ALF patients and healthy controls were analyzed using a semitargeted high-resolution mass spectrometry approach to measure BAs in their unconjugated and amidated forms and their glucuronide and sulfate conjugates. Human serum samples from 20 healthy volunteers and 34 ALF patients were combined with deuterated BAs and extracted, prior to liquid chromatography high-resolution tandem mass spectrometry analysis. A mix of 46 standards helped assign 26 BAs in human serum by accurate mass and retention time matching. Moreover, other isomers of unconjugated and amidated BAs, as well as glucuronide and sulfate conjugates, were assigned by accurate mass filtering. In vitro incubations of standard BAs provided increased information for certain peaks of interest. A total of 275 BA metabolites, with confirmed or putative assignments, were measured in human serum samples. APAP overdose significantly influenced the levels of most BAs, promoting glycine conjugation, and, to a lesser extent, taurine conjugation. When patient outcome was considered, 11 BAs were altered significantly, including multiple sulfated species. Although many of the BAs measured did not have exact structures assigned, several putatively identified BAs of interest were further characterized using in vitro incubations. An optimized chromatographic separation tailored to BAs of ranging polarities was combined with accurate mass measurements to investigate the effect that DILI has on their complex profiles and metabolism to a much wider extent than previously possible. The analysis of complex BA profiles enabled in-depth analysis of the BA metabolism perturbations in ALF, including certain metabolites related to patient outcomes.

Acetaminophen overdose: analysis of 2018 US nationwide emergency database.

Recognized risk factors for acetaminophen overdose include alcohol, opioids, and mood disorders. The aim of this study is to assess additional risk factors for acetaminophen overdose evaluated in the emergency department (ED). A retrospective study was performed using the 2018 US Nationwide Emergency Department Sample (NEDS). All adult ED visits for acetaminophen overdose were included in the study group and those without it were taken as control. STATA, 16.1 was used to perform multivariable logistic regression analysis and adjusted odds ratios (ORadj) were reported. We identified 27,792 ED visits for acetaminophen overdose. Relative to non-acetaminophen ED visits, this group was younger (median age 32 vs 47years; p < 0.0001), more oftenfemale (66.1% vs 57.0%; p < 0.0001), had higher ED charges ($3,506 vs $2,714; p < 0.0001), higher proportion of alcohol-related disorders (15.8% vs 3.5%; p < 0.0001), anxiety disorders (30.2% vs 8.3%; p < 0.0001), cannabis use (8.7% vs 1.4%; p < 0.0001), hematology/oncology diagnoses (13.3% vs 10.9%; p < 0.0001), mood disorders (52.4% vs 7.9%; p < 0.0001), opioid-related disorders (4.1% vs 1.0%; p < 0.0001), and suicide attempt/ideation (12.2% vs 1.1%; p < 0.0001). Multivariable analysis showed alcohol-related disorders (ORadj 2.67), anxiety disorders (ORadj 1.24), cannabis (ORadj 1.63), females (ORadj 1.45), Income Q3 (ORadj 1.09), hematology/oncology diagnoses (ORadj 1.40), mood disorders (ORadj 10.07), opioid-related disorders(ORadj 1.20), and suicide attempt/ideation (ORadj 1.68) were associated with acetaminophen overdose. In addition to previously recognized risks, our study demonstrated thatcannabis use and hematologic/oncologic comorbidities were more common among acetaminophen-overdose ED visits. These newfindings are concerning because of rapid legalization of cannabis and the increasing incidence of cancerworldwide. Additionalinvestigation into these risksshould be a priorityfor clinicians, policymakers, and researchers.

PROTECTIVE EFFECTS OF VITAMIN C ON ACETAMINOPHEN-INDUCED LIVER AND KIDNEY TOXICITY IN MALE RATS

Acetaminophen (paracetamol) is a widely used over-the-counter analgesic and antipyretic medication known for its efficacy and safety when administered within recommended doses. However, overdose or prolonged use of acetaminophen can lead to severe hepatotoxicity and nephrotoxicity, posing a significant public health concern. This study aims to investigate the protective effects of vitamin C on acetaminophen-induced hepatotoxicity and nephrotoxicity in male Wistar rats. Six rats were randomly assigned to seven groups, with Group 1 designated as the control. Groups 2, 4, and 6 were given daily single oral doses of 100, 200, and 400 mg/kg of acetaminophen, respectively. Meanwhile, Groups 3, 5, and 7 received daily single oral doses of 100, 200, and 400 mg/kg of acetaminophen, followed by intraperitoneal administration of 100 mg/kg of vitamin C daily, for 14 days. Liver function markers (AST, ALT, total bilirubin, and total protein) and renal function indicators (urea and creatinine levels) were assessed, alongside antioxidant status in liver and kidney tissues through antioxidant assays (SOD, CAT, GSH, and MDA). The results demonstrated the protective influence of vitamin C on liver and kidney tissues, as indicated by the modulation of biochemical markers. These findings suggest that vitamin C may play a pivotal role in alleviating acetaminophen-induced liver and kidney damage across different dosage regimens, potentially serving as a therapeutic intervention for preventing or treating drug-induced organ injuries. Further investigations are essential to elucidate the underlying mechanisms and validate the translational potential of vitamin C as a protective agent against acetaminophen toxicity.

Assessing the impact of a new medical toxicology service on the treatment of paracetamol overdose at a large tertiary care hospital

Background Paracetamol overdose is the most common cause of acute liver failure in the United States. Administration of acetylcysteine is the standard of care for this intoxication. Laboratory values and clinical criteria are used to guide treatment duration, but decision-making is nuanced and often complex and difficult. The purpose of this study was to evaluate the effect of the introduction of a medical toxicology service on the rate of errors in the management of paracetamol overdose. Methods This was a single center, retrospective, cohort evaluation. Patients with suspected paracetamol overdose were divided into two groups: those attending in the 1 year period before and those in the 1 year after the introduction of the medical toxicology service. The primary outcome was the frequency of deviations from the established management of paracetamol intoxication, using international guidelines as a reference. Results Fifty-four patients were eligible for the study (20 pre-toxicology-service, 34 post-toxicology-service). The frequency of incorrect therapeutic decisions was significantly lower in the post-toxicology service implementation versus the pre-implementation group (P = 0.005). Discussion Our study suggests that a medical toxicology service reduces the incidence of management errors, including the number of missed acetylcysteine doses in patients with paracetamol overdose. The limitations include the retrospective study design and that the study was conducted at a single center, which may limit generalizability. Conclusions The implementation of a medical toxicology service was associated with a decrease in the number of errors in the management of paracetamol overdose.

A Comparison of the Protective Effect of Pyridoxine and N-Acetylcysteine in Paracetamol Induced Hepatotoxicity in Rats

Paracetamol is a common over the counter drug. Paracetamol-induced hepatotoxicity results in over 300,000 hospitalizations each year and accounts for up to 42% of all cases of acute liver failure. N-acetylcysteine (NAC) is a potential antidote to manage paracetamol toxicity. Objective: To investigate the effects of pyridoxine, alone and in combination with NAC in repairing paracetamol-induced liver damage in male Wister rats. Methods: A single oral dose of paracetamol (650 mg/kg) was administered to Wistar rats to induce hepatotoxicity. The hepato-protective effects of NAC at a dose 300 mg/kg, and pyridoxine (200 mg/kg) were evaluated using standard liver function tests and histopathological along with serum glutathione levels. Results: The administration of pyridoxine and NAC resulted in a significant decrease in AST, ALT, and total bilirubin levels and the reversal of histopathological changes. Conversely, administering NAC and pyridoxine in combination yielded significant changes except for the glutathione level. Conclusions: The study concluded that pyridoxine may be used as a potential hepatoprotective drug in paracetamol-induced hepatotoxicity. In combination with NAC, it showed protective effects in paracetamol-induced hepatoxicity.

Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

Hepatoprotective effect of amifostine and WR-1065 on acetaminophen-induced liver toxicity on Wistar rats.

The most important problem with acetaminophen is its hepatotoxicity. N-acetylcysteine (NAC) is used to treat the hepatotoxicity of acetaminophen. Due to the structural similarities of this compound with amifostine, we decided to test the effect of this substance and its metabolite, WR-1065, on the hepatotoxicity of acetaminophen. The single-dose method contained 1. Control; 2. Acetaminophen (1 g/kg, gavage); 3-5. Acetaminophen + amifostine (100, 200, 400 mg/kg, i.p.); 6-8. Acetaminophen + WR-1065 (50, 100, 200 mg/kg, i.p.); and 9. Acetaminophen + NAC (100, 200 mg/kg, i.p.). The multiple-dose method included the same groups: amifostine (50, 100, 200 mg/kg), WR-1065 (25, 50, 100 mg/kg), and NAC (100 mg/kg). Then, animals were sacrificed, and blood samples were collected for measuring ALT, AST, ALP, and T-Bil, liver tissue for histopathological examination, MDA, and GSH amounts. Acetaminophen increased the levels of MDA, T-Bil, ALT, AST, and ALP, decreased GSH levels, and augmented necrosis, neutrophils, lymphocytes, and macrophages in the port space in single-dose and multiple-dose studies. Amifostine and WR-1065 significantly reduced the levels of MDA, T-Bil, ALT, AST, ALP, increased GSH content, and ameliorated histopathological alterations in a single-dose and multiple-dose method compared to the acetaminophen group. Moreover, NAC caused a significant decrease in the levels of MDA, T-Bil, ALT, AST, and ALP, and reduced GSH amounts in single-dose and multiple-dose studies. Amifostine and WR-1065 as antioxidant and hepatoprotective compounds are effective in reducing acetaminophen-induced hepatotoxicity with a similar effect to NAC and can be administered as an adjunct in the treatment of acetaminophen overdose.