Acetaminophen Overdose Research Articles

Characteristics of adverse drug reactions to N-acetylcysteine for paracetamol overdose in a tertiary Institution in Singapore

Characteristics of adverse drug reactions to N-acetylcysteine for paracetamol overdose in a tertiary Institution in Singapore

Protective effect of nanocurcumin on acetaminophen-induced hepatic and renal toxicities in pigeons.

In this study, the effects of nanocurcumin on acetaminophen-induced acute hepatorenal toxicity in domestic pigeons (Columba livia) were investigated. Fifteen pigeons were randomly assigned into three groups. Group I was served as a negative control group and received tap water as a placebo. Pigeons in groups II and III were administered acetaminophen at the beginning of the experiment (hr 0). Group III was further treated with nanocurcumin, at 12 hr after acetaminophen administration, being continued every 12 hr for two days. The birds were observed for clinical signs of acute drug toxicity. Blood samples were collected from the pigeons at hr 0, 12, 24 and 48 of the experiment for biochemical analysis of the serum. The results showed that acetaminophen toxicity increased the serum levels of aspartate aminotransferase, alanine aminotransferase, urea and uric acid in the pigeons. Nanocurcumin treatment of acetaminophen intoxicated pigeons attenuated increases in biomarkers of the liver and kidney functions towards control levels. Also, the consumption of nanocurcumin minimized histopathological changes in the liver and kidney. A mortality of 60.00% was seen in the acetaminophen-induced toxicity group; while, none of the birds treated with nanocurcumin died. It can be concluded that nanocurcumin alleviates the acetaminophen-induced acute toxic liver and kidney damages, which can lead to pigeon mortality.

Predicting serum acetaminophen concentrations in acute poisoning for safe termination of N-acetylcysteine in a resource-limited environment

Purpose: The Prescott nomogram has been utilized to forecast hepatotoxicity from acute acetaminophen poisoning. In developing countries, emergency medical centers lack the resources to report acetaminophen concentrations; thus, the commencement and cessation of treatment are based on the reported dose. This study investigated risk factors that can predict acetaminophen detection after 15 hours for safe treatment termination.Methods: Data were collected from an urban emergency medical center from 2010 to 2020. The study included patients ≥14 years of age with acute acetaminophen poisoning within 15 hours. The correlation between risk factors and detection of acetaminophen 15 hours after ingestion was evaluated using logistic regression, and the area under the curve (AUC) was calculated.Results: In total, 181 patients were included in the primary analysis; the median dose was 150.9 mg/kg and 35 patients (19.3%) had acetaminophen detected 15 hours after ingestion. The dose per weight and the time to visit were significant predictors for acetaminophen detection after 15 hours (odds ratio, 1.020 and 1.030, respectively). The AUCs were 0.628 for a 135 mg/kg cut-off value and 0.658 for a cut-off 450 minutes, and that of the combined model was 0.714 (sensitivity: 45.7%, specificity: 91.8%).Conclusion: Where acetaminophen concentrations are not reported during treatment following the UK guidelines, it is safe to start N-acetylcysteine immediately for patients who are ≥14 years old, visit within 15 hours after acute poisoning, and report having ingested ≥135 mg/kg. Additional N-acetylcysteine doses should be considered for patients visiting after 8 hours.

Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.

N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg-1 ). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.

Evaluation of the Acute Toxicity of Acetaminophen in Mice

Acetaminophen (N-acetyl-para-aminophenol, APAP), widely used for pain relief across specie, poses significant toxicity risks. This study ‎aimed to assess the acute toxicity profile of APAP by determining the median toxic dose ‎‎(TD50) in a ‎‎murine model. Sixty male Balb/c mice, aged 8 weeks and weighing 20-30 ‎g, were randomized into six equal groups. Five groups received single oral doses of APAP (150, 200, 300, 500, and 700 mg/kg BW), while the control group received distilled water. The TD50 was ‎computed utilizing the probit method. Animals were ‎‎monitored for 24 h for ‎any sign indicative of clinical toxicity. Post-exposure, liver and kidney necropsies were conducted for histopathological analysis. Predominant symptoms of toxicity included prostration, hematuria, heightened agitation, lacrimation, cyanosis, and recumbency across doses from 150 to 700 mg/kg BW. The TD50 for APAP was estimated to be 732 ‎mg/kg BW. The liver histopathological examination of mice treated ‎‎with 700 mg/kg BW APAP ‎revealed severe multifocal hyper eosinophilic hepatocytes, indicating areas of centrilobular ‎necrosis, disorganized ‎‎hepatic cords, and multiple hemorrhage regions. The kidney ‎examination exhibited no pathological changes in treated mice with 700 mg/kg BW ‎‎APAP. In ‎conclusion this investigation provides critical insights into the acute toxicity profile of APAP. The findings not only highlight the ‎‎potential risk associated with APAP usage but also the ‎necessity of strict monitoring for stringent dosage control. Further research is also ‎‎needed to ‎understand the underlying mechanism of APAP-induced toxicity and pave the way for the ‎development of efficacious therapeutic ‎strategies to counter APAP overdose‎‎‎‎.

Intestinal injury in paracetamol overdose (ATOM-8).

Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. Serial samples of 30 patients with acute paracetamol overdose (>10g or 200mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2mmol/L within 12h post ingestion. In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720μg/L [interquartile range, IQR, 533-1644] vs 270μg/L [IQR 153-558], P<0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028μg/L [IQR 1399-3556] vs 574μg/L [IQR 526-943], P=0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P=0.019 and P=0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r=0.55) and lactate (r=0.60). Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Translocation of Adenosine A2B Receptor to Mitochondria Influences Cytochrome P450 2E1 Activity after Acetaminophen Overdose.

The adenosine A2B receptor (A2BAR) is a member of a family of G-protein coupled receptors (GPCRs), which has a low affinity for adenosine and is now implicated in several pathophysiological conditions. We have demonstrated the beneficial effects of A2BAR activation in enhancing recovery after acute liver injury induced by an acetaminophen (APAP) overdose. While receptor trafficking within the cell is recognized to play a role in GPCR signaling, its role in the mediation of A2BAR effects in the context of APAP-induced liver injury is not well understood. This was investigated here, where C57BL/6J mice were subjected to an APAP overdose (300 mg/kg), and the temporal course of A2BAR intracellular localization was examined. The impact of A2BAR activation or inhibition on trafficking was examined by utilizing the A2BAR agonist BAY 60-6583 or antagonist PSB 603. The modulation of A2BAR trafficking via APAP-induced cell signaling was explored by using 4-methylpyrazole (4MP), an inhibitor of Cyp2E1 and JNK activation. Our results indicate that APAP overdose induced the translocation of A2BAR to mitochondria, which was prevented via 4MP treatment. Furthermore, we demonstrated that A2BAR is localized on the mitochondrial outer membrane and interacts with progesterone receptor membrane component 1 (PGRMC1). While the activation of A2BAR enhanced mitochondrial localization, its inhibition decreased PGRMC1 mitochondria levels and blunted mitochondrial Cyp2E1 activity. Thus, our data reveal a hitherto unrecognized consequence of A2BAR trafficking to mitochondria and its interaction with PGRMC1, which regulates mitochondrial Cyp2E1 activity and modulates APAP-induced liver injury.

Investigation of the Effects of Resveratrol on Paracetamol Toxicity Established in Hep3B Cells

Aim: We therefore wanted to investigate acetaminophen hepatotoxicity by using Hep3B human hepatoma cells exposed to acetaminophen and resveratrol, used as a protective agent. Specifically, we studied the role of some proinflammatory markers and oxidative damage as possible mechanisms of acetaminophen-associated cytotoxicity.&#x0D; Materials and Method: The Hep3B human hepatoma cell line was used for this study. In vitro studies (GSH, SOD, CAT, AST, ALT, TNF-alpha, IL-6 and cell viability) were performed by using different methods such as Biochemical analyzer, RT-PCR, ELISA and MTT. Acetaminophen and resveratrol were applied to cells in a different time and doses.&#x0D; Results: Only acetaminophen treatment decreased SOD, CAT and GSH levels in Hep3B cells whereas acetaminophen and resveratrol co-treatment increased these enzymes levels. On the other hand, acetaminophen and resveratrol co-treatment (especially 160 µM dose of resveratrol) lead a severe increase in TNF-alpha and IL-6 levels.&#x0D; Conclusion: It is shown that acetaminophen has caused hepatotoxicity but interestingly but resveratrol treatment effects the related parameters mentioned above. Only, acetaminophen administration may cause abnormal decreases and/or increases in antioxidant enzymes and proinflammatory cytokines levels. Additionally, acetaminophen and high dose resveratrol co-treatment triggered the inflammation and oxidative stress. These results showed that resveratrol have a potential to be an effective agent on the treatment and protection of hepatic damage.

Study protective role Camellia sinensis L. (black tea) and silver, Zn oxide nanoparticles on antioxidant-oxidant enzymes and biochemical level against paracetamol overdose in adult male rats

This study aims to measure the preventive effect of the silver, Zn oxide nanoparticles, and Camellia sinensis L. (black tea) on liver toxicity caused by the paracetamol drug. The Nanomaterials, with a practical size range of 33–40nm, black tea was extracted by Soxhlet apparatus using methanol alcohol at a concentration (80%); design in this study, 60 adult male rats weighing between 195 and 330 g and aged 11 to 14 weeks were used. They were kept in a relatively regulated setting with a temperature of 25Co at the University of Karbala’s animal facility. They received food. There were eight rat group divisions. G1: just received saline solution (0,85%) as the control. G2: 250 milligrams of black tea and 250 milligrams of paracetamol per kilogram of body weight. G3: 400 milligrams of C. sinensis L. and 250 milligrams of paracetamol per kilogram of body weight. G4: injection of 0.3 milligrams of zinc nanoparticles and 250 milligrams of paracetamol per kilogram of body weight. G5: injection of 0.5 milligrams of zinc nanoparticles and 250 milligrams of paracetamol per kilogram of body weight. G6: injection of 0.3 milligrams of silver nanoparticles and 250 milligrams of paracetamol per kilogram of body G7: injection of 0.5 milligrams of silver nanoparticles and 250 milligrams of paracetamol per kilogram of body, G8: 250 milligrams of paracetamol per kilogram of body administered intravenously, the blood bled for 30 days after receiving all dosages orally once daily for 21 days. When rats were given injections of 0.5 mg of nanoparticles and when injections of 250 mg of a black tee., it was discovered that the concentration of Malondialdehyde MDA, Lipid Peroxidation LPO, Triacylglycerid, cholesterol levels, and glucose decreased significantly. In contrast, Glutathione peroxidase GPX and protein levels are increased considerably. This was due to the injections’ preventive and antioxidant action against the oxidative stress brought on by the paracetamol height dose. Keywords: silver nanoparticles, Zn oxide nanoparticles, Camellia sinensis L., paracetamol.

Protective and therapeutic effects of okra seed in acute nontraumatic brain injury

Aim The purpose of this study was to examine the protective and therapeutic effects of okra (Abelmoschus esculentus [AE]) seed extract, with its known antioxidant, immunomodulatory, and anti-inflammatory properties, in an acetaminophen (paracetamol, N-acetyl- para-aminophenol)-induced model of hepatotoxicity and subsequent acute non-traumatic brain damage. Material and Method Forty male Wistar rats were randomly divided into five equal groups, control, paracetamol (P), okra seed extract (AE), okra seed extract + paracetamol (P + AE), and okra seed extract + paracetamol + N-acetyl cysteine (NAC) (P + AE + N). AE was administered by oral gavage through a gastric tube at 600 mg/kg/day for seven days. On the eighth day of the procedure, a single 1 g/kg dose of paracetamol and 300 mg/kg NAC were injected via the intraperitoneal route 1.5 h after AE administration. Rat tissue specimens were subsequently subjected to biochemical and histopathological analyses. Levels of markers such as S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and matrix membrane metalloproteinase-9 (MMP-9) were investigated from rat serum specimens. Malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured to determine oxidant-antioxidant status. Results S100B, NSE, MMP-9, MDA levels, and SOD enzyme activities were examined using biochemical methods. MDA levels were significantly lower in the P + AE group and MMP-9 levels in the AE, P + AE, and P + AE + N groups compared to the P group. Histopathological examination results supported the biochemical findings Conclusion Okra seed extract exhibits a protective and therapeutic effect against non-traumatic brain damage resulting from acute paracetamol intoxication. We think that this benefit of AE derives from its antioxidant property.

N-Acetylcysteine and Atherosclerosis: Promises and Challenges.

Atherosclerosis remains a leading cause of cardiovascular diseases. Although the mechanism for atherosclerosis is complex and has not been fully understood, inflammation and oxidative stress play a critical role in the development and progression of atherosclerosis. N-acetylcysteine (NAC) has been used as a mucolytic agent and an antidote for acetaminophen overdose with a well-established safety profile. NAC has antioxidant and anti-inflammatory effects through multiple mechanisms, including an increase in the intracellular glutathione level and an attenuation of the nuclear factor kappa-B mediated production of inflammatory cytokines like tumor necrosis factor-alpha and interleukins. Numerous animal studies have demonstrated that NAC significantly decreases the development and progression of atherosclerosis. However, the data on the outcomes of clinical studies in patients with atherosclerosis have been limited and inconsistent. The purpose of this review is to summarize the data on the effect of NAC on atherosclerosis from both pre-clinical and clinical studies and discuss the potential mechanisms of action of NAC on atherosclerosis, as well as challenges in the field.

An intravenous paracetamol overdose in an eight-day-old neonate

An intravenous paracetamol overdose in an eight-day-old neonate

Good Cells Go Bad: Immune Dysregulation in the Transition from Acute Liver Injury to Liver Failure After Acetaminophen Overdose.

The role of inflammatory cells and other components of the immune system in acetaminophen (APAP)-induced liver injury and repair has been extensively investigated. Although this has resulted in a wealth of information regarding the function and regulation of immune cells in the liver after injury, apparent contradictions have fueled controversy around the central question of whether the immune system is beneficial or detrimental after APAP overdose. Ultimately, this may not be a simple assignment of "good" or "bad." Clinical studies have clearly demonstrated an association between immune dysregulation and a poor outcome in patients with severe liver damage/liver failure induced by APAP overdose. To date, studies in mice have not uniformly replicated this connection. The apparent disconnect between clinical and experimental studies has perhaps stymied progress and further complicated investigation of the immune system in APAP-induced liver injury. Mouse models are often dismissed as not recapitulating the clinical scenario. Moreover, clinical investigation is most often focused on the most severe APAP overdose patients, those with liver failure. Notably, recent studies have made it apparent that the functional role of the immune system in the pathogenesis of APAP-induced liver injury is highly context dependent and greatly influenced by the experimental conditions. In this review, we highlight some of these recent findings and suggest strategies seeking to resolve and build on existing disconnects in the literature. SIGNIFICANCE STATEMENT: Acetaminophen overdose is the most frequent cause of acute liver failure in the United States. Studies indicate that dysregulated innate immunity contributes to the transition from acute liver injury to acute liver failure. In this review, we discuss the evidence for this and the potential underlying causes.

Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine

Acetaminophen (APAP) overdose causes liver injury and acute liver failure, as well as acute kidney injury, which is not prevented by the clinical antidote N-acetyl-L-cysteine (NAC). The absence of therapeutics targeting APAP-induced nephrotoxicity is due to gaps in understanding the mechanisms of renal injury. APAP metabolism through Cyp2E1 drives cell death in both the liver and kidney. We demonstrate that Cyp2E1 is localized to the proximal tubular cells in mouse and human kidneys. Virtually all the Cyp2E1 in kidney cells is in the endoplasmic reticulum (ER), not in mitochondria. By contrast, hepatic Cyp2E1 is in both the ER and mitochondria of hepatocytes. Consistent with this subcellular localization, a dose of 600 mg/kg APAP in fasted C57BL/6J mice induced the formation of APAP protein adducts predominantly in mitochondria of hepatocytes, but the ER of the proximal tubular cells of the kidney. We found that reactive metabolite formation triggered ER stress-mediated activation of caspase-12 and apoptotic cell death in the kidney. While co-treatment with 4-methylpyrazole (4MP; fomepizole) or the caspase inhibitor Ac-DEVD-CHO prevented APAP-induced cleavage of procaspase-12 and apoptosis in the kidney, treatment with NAC had no effect. These mechanisms are clinically relevant because 4MP but not NAC also significantly attenuated APAP-induced apoptotic cell death in primary human kidney cells. We conclude that reactive metabolite formation by Cyp2E1 in the ER results in sustained ER stress that causes activation of procaspase-12, triggering apoptosis of proximal tubular cells, and that 4MP but not NAC may be an effective antidote against APAP-induced kidney injury.

Implications and future direction of the effect of reducing acetaminophen dosage in prescription combination drugs on mitigating hepatotoxicity

Dear editor, Acetaminophen is the most widely used pain relief medication around the globe. It is used as an antipyretic and treat various medical ailments, including mild to moderate pain [1]. However, studies have shown that acetaminophen is associated with several adverse consequences, among which hepatotoxicity is the most pronounced [2]. However, despite its well know side-effects and risk of hepatotoxicity, acetaminophen is widely prescribed and its overdosing is a serious issue. Moreover, many combination of medications prescribed for pain relief do contain acetaminophen as its component. Often a single dose of such combinations contains two or more drugs of which many recipient remain ignorant that they are ingesting acetaminophen in the prescribed combination of drugs. This ignorance can lead to overdosing of acetaminophen and subsequent risk of hepatotoxicity [3]. On January 13, 2011, the U.S FDA addressed this issue by asking manufacturers to limit acetaminophen dosage from 750 mg/tablet to 325 mg/tablet in combination acetaminophen and opioid medications. The U.S FDA also asked all its manufacturers to place a box warning on all the combination medications that contain acetaminophen as its component, stating its association with liver injury [4]. A recent study published in JAMA, March 2023, further authenticated this ruling [5]. The study assessed the impact of U.S FDA’s decision to limit the amount of acetaminophen dose to 325 mg/tablet in prescription combination opioid drugs on the incidence of subsequent hospitalization and acute liver failure. It was found that predicted incidence of hospitalization, a day prior to FDA announcement was 12.2 cases/ 100000 hospitalizations whereas in 2019 it was reduced to 4.4 cases/ 100000 hospitalizations. Prior to the announcement the percentage of acute liver failure caused by acetaminophen and opioid toxicity rose by 07% per year and it fell by 16% annually after the announcement. Hence, it was concluded that U.S FDA’s decision of limiting acetaminophen dosage to 325 mg/tablet in combination drugs helped in reducing the incidents of acetaminophen related hepatotoxicity [5]. The above stated study showed satisfying statistics regarding the decline hepatotoxicity with lower doses of acetaminophen in prescription combination drugs. However, the matter is still not totally resolved because the U.S FDA’s decision of reducing acetaminophen dosage was limited to the prescription combination medications and excluded the acetaminophen drugs available over-the-counter. ---Continue

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis

Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of Mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.

Visualization of production and remediation of acetaminophen-induced liver injury by a carboxylesterase-2 enzyme-activatable near-infrared fluorescent probe

Acetaminophen (APAP) overdose, also known as APAP poisoning, may directly result in hepatic injury, acute liver failure and even death. Nowadays, APAP-induced liver injury (AILI) has become an urgent public health issue in the developing world so the early accurate diagnosis and the revelation of underlying molecular mechanism of AILI are of great significance. As a major detoxifying organ, liver is responsible for metabolizing chemical substances, in which human carboxylesterase-2 (CES2) is present. Hence, we chose CES2 as an effective biomarker for evaluating AILI. By developing a CES2-activatable and water-soluble fluorescent probe PFQ-E with superior affinity (Km = 5.9 μM), great sensitivity (limit of detection = 1.05 ng/mL), near-infrared emission (655 nm) and large Stokes shift (135 nm), activity and distribution of CES2 in cells were determined or imaged effectively. More importantly, the APAP-induced hepatotoxicity and the underlying molecular mechanism of pathogenesis of AILI were investigated by measuring the "light-up" response of PFQ-E towards endogenous CES2 in vivo for the first time. Based on the superior performance of the probe PFQ-E for sensing CES2, we believe that it has broad potential in clinical diagnosis and therapy response evaluation of AILI.

Protective effect of Tibetan medicine Qiwei Tiexie pills on liver injury induced by acetaminophen overdose: an integrated strategy of network pharmacology, metabolomics and transcriptomics

BackgroundDrug-induced liver injury, particularly from acetaminophen (APAP), has emerged as a significant public health concern. Unfortunately, there is currently no effective treatment strategy available. Qiwei Tiexie pills (QWTX), a traditional Tibetan medicine, have demonstrated considerable clinical efficacy in treating various liver diseases. Nevertheless, the protective effect of QWTX against drug-induced liver injury and its underlying mechanism remains poorly understood. PurposeThis study aimed to assess the therapeutic potential of QWTX, a Tibetan medicine, in an animal model of APAP-induced liver injury. Additionally, we sought to investigate the molecular mechanism through which QWTX exerts its effects. MethodsWe employed LC-MS and network pharmacology to predict the potential targets of QWTX in drug-induced liver injury. Subsequently, we employed HE staining, transcriptomics, metabolomics, and qRT-PCR to analyze the mechanism underlying QWTX treatment in drug-induced liver injury. ResultsNetwork pharmacology analysis revealed that the active components of QWTX are involved in inflammatory and drug metabolism-related pathways. In mouse models, pretreatment with QWTX effectively mitigated the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory factors (IL-1β, IL-6, and TNF-α) induced by APAP overdose. Moreover, APAP inhibited 1459 differentially expressed genes (DEGs) and 874 differential accumulation metabolites (DAMs), while QWTX promoted their expression. Conversely, APAP promoted 874 genes and 119 metabolites, which were inhibited by QWTX. Further analysis demonstrated that QWTX ameliorated the metabolic disorders induced by APAP overdose and potentially exerted a protective effect by inhibiting the expression of critical genes in crucial inflammatory pathways. QWTX also up-regulated antioxidant enzymes, thereby mitigating the oxidative stress resulting from APAP overdose. ConclusionQWTX treatment effectively protects against APAP-induced liver damage in mice. Transcriptomic and metabolomic analyses further revealed that QWTX ameliorated hepatic metabolic disorders induced by APAP overdose while significantly suppressing the inflammatory response and oxidative stress associated with drug-induced liver injury. This study provides a new insight into the treatment of drug-induced liver injury by the TCM system and provides a basis for the development of new therapies for drug-induced liver injury by QWTX and its active ingredients.

Antioxidative and Anti-Inflammatory Protective Effects of Fucoxanthin against Paracetamol-Induced Hepatotoxicity in Rats.

Paracetamol or acetaminophen (PAC) is a commonly used analgesic and antipyretic drug. It has been shown that overdoses beyond the therapeutic range can cause hepatotoxicity and acute liver injury. The most common cause of drug-induced liver injury (DILI) in Saudi Arabia and worldwide is paracetamol overdose. Fucoxanthin (FUC) is an allenic carotenoid that is found in edible brown seaweeds, and it has antioxidant and anti-inflammatory effects. Several studies have shown the potential therapeutic effects of FUC in diabetes, cancers, and inflammatory disorders. This study aims to investigate the protective effect of FUC against PAC-induced acute liver injury in rats. FUC was administered (100, 200, and 500 mg/kg, p.o.) for 7 days, and then the liver injury was induced by the administration of PAC (2000 mg/kg, oral). Blood and liver tissue samples were collected from PAC-positive untreated, treated, and negative control rats. Biochemical and inflammatory parameters in the blood were measured. In addition, RT-PCR, Western blotting, and immunohistochemistry were performed for liver tissue. The serum levels of liver biomarkers (ALT, AST, and ALP) increased after PAC-induced liver toxicity; FUC-treated rats showed lower levels compared to the positive control. There was an increase in the expression of TNF-α, IL-1, IL-6, NF-kB, INF-γ, and iNOS and a decrease in IL-10, IL-22, and IL-10R expression after the FUC treatment of injured liver rats. For the hepatic inflammation and PAC-toxicity-induced oxidative stress genes and proteins, FUC-treated rats (100, 200, and 500 mg/kg) showed a reduction in the expression of oxidative stress genes. These results showed that FUC protected the liver against PAC-induced injury through antioxidant and anti-inflammatory actions. However, further clinical studies are required to confirm the findings.

An international survey of the treatment of massive paracetamol overdose in 2023

Introduction Changes in the commercialization of nonprescription drugs have made large quantities of paracetamol available to individuals, resulting in larger overdoses than previously observed. Although most patients with paracetamol overdose can be managed with acetylcysteine, patients with a massive overdose may become critically ill earlier and fail standard antidotal therapy. Several strategies are proposed for the management of these patients, including using increased doses of acetylcysteine, extracorporeal removal, and fomepizole. However, the benefits of these strategies remain largely theoretical, with sparse evidence for efficacy in humans. Methods This cross-sectional study surveys international practice patterns of medical toxicology providers regarding the management of a hypothetical patient with a massive paracetamol overdose. Results A total of 342 responses from 31 different nations were obtained during the study period. Sixty-one percent of providers would have increased their acetylcysteine dosing when treating the hypothetical massive overdose. Thirty percent of respondents recommended an indefinite infusion of acetylcysteine at 12.5 mg/kg/hour after the bolus dose, whereas 20 percent recommended following the “Hendrickson” protocol, which advocates for a stepwise increase in acetylcysteine dosing to match high paracetamol concentrations at the 300 mg/L, 400 mg/L, and 600 mg/L lines on the Rumack-Matthew nomogram. Ten percent of respondents stated they would have given “double dose acetylcysteine” but did not specify what that entailed. Forty-seven percent of respondents indicated that they would have given fomepizole, and 28 percent of respondents recommended extracorporeal removal. Discussion Our survey study assessed the approach to a hypothetical patient with a massive paracetamol overdose and demonstrated that, at minimum, most respondents would increase the dose of acetylcysteine. Additionally, almost half would also include fomepizole, and nearly one-third would include extracorporeal removal. Conclusions There is considerable international variation for the treatment of both non-massive and massive paracetamol overdoses. Future research is needed to identify and standardize the most effective treatment for both non-massive and massive paracetamol overdoses.