Acetaminophen Overdose Research Articles

Distinct Subtypes of Hepatorenal Syndrome and Associated Outcomes as Identified by Machine Learning Consensus Clustering

The utilization of multi-dimensional patient data to subtype hepatorenal syndrome (HRS) can individualize patient care. Machine learning (ML) consensus clustering may identify HRS subgroups with unique clinical profiles. In this study, we aim to identify clinically meaningful clusters of hospitalized patients for HRS using an unsupervised ML clustering approach. Consensus clustering analysis was performed based on patient characteristics in 5564 patients primarily admitted for HRS in the National Inpatient Sample from 2003-2014 to identify clinically distinct HRS subgroups. We applied standardized mean difference to evaluate key subgroup features, and compared in-hospital mortality between assigned clusters. The algorithm revealed four best distinct HRS subgroups based on patient characteristics. Cluster 1 patients (n = 1617) were older, and more likely to have non-alcoholic fatty liver disease, cardiovascular comorbidities, hypertension, and diabetes. Cluster 2 patients (n = 1577) were younger and more likely to have hepatitis C, and less likely to have acute liver failure. Cluster 3 patients (n = 642) were younger, and more likely to have non-elective admission, acetaminophen overdose, acute liver failure, to develop in-hospital medical complications and organ system failure, and to require supporting therapies, including renal replacement therapy, and mechanical ventilation. Cluster 4 patients (n = 1728) were younger, and more likely to have alcoholic cirrhosis and to smoke. Thirty-three percent of patients died in hospital. In-hospital mortality was higher in cluster 1 (OR 1.53; 95% CI 1.31-1.79) and cluster 3 (OR 7.03; 95% CI 5.73-8.62), compared to cluster 2, while cluster 4 had comparable in-hospital mortality (OR 1.13; 95% CI 0.97-1.32). Consensus clustering analysis provides the pattern of clinical characteristics and clinically distinct HRS phenotypes with different outcomes.

Gut inflammation and adaptive immunity amplify acetaminophen toxicity in bowel and liver.

Prevention of liver failure arising from accidental or deliberate paracetamol (acetaminophen [APAP]) overdose remains a vexed health problem despite well-publicized guidelines for its early detection and treatment. It is recognized that the gut may aggravate liver pathology, via the gut-liver axis. The main aim of this study was to assess the role of the colon in APAP-induced liver toxicity. Liver necrosis and colitis were studied following sublethal doses of APAP administered intraperitoneally to C57Bl/6 wild-type (WT) mice, as well as to C57Bl/6 Winnie mice, which develop a spontaneous colitis caused by a SNP in Muc2, and WT mice with acute DSS-induced colitis. Repeated APAP exposure was studied in WT and Rag1 ko mice that lack mature T and B lymphocytes. APAP overdose resulted in significant colonic injury in WT mice (P<0.05), which resolved by 24h. Underlying colitis was not associated with liver necrosis, but colitis exacerbated APAP-induced liver injury and extended APAP-colonic injury. Prior APAP exposure exacerbated both APAP-liver and APAP-colonic injury more so in WT than Rag1 ko mice. APAP impaired barrier function with increased intestinal permeability and associated bacterial translocation to the liver and spleen in mice with the Winnie phenotype. This study identifies novel roles for APAP in causing colitis, the amplification of APAP-liver toxicity where there is underlying colitis, and involvement of immune memory in APAP-toxicity. The latter could be key for decoding the poorly understood but important clinical entity of chronic APAP liver failure.

C-Jun-N Terminal Kinase-Mediated Degradation of γ-Glutamylcysteine Ligase Catalytic Subunit Inhibits GSH Recovery After Acetaminophen Treatment: Role in Sustaining JNK Activation and Liver Injury.

Aims: Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States. Liver glutathione (GSH) depletion and sustained P-JNK (c-Jun-N-terminal kinase) activation are key modulators in the mechanism leading to hepatic necrosis. GSH depletion is directly related to the consumption of GSH by APAP metabolites N-acetyl-p-benzoquinone imine (NAPQI). We previously noticed that the glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH synthesis, rapidly decreased at the same time P-JNK increased. Our aims were to determine if JNK was directly responsible for decreased GCLC causing impaired recovery of GSH and if this was an important factor in determining APAP hepatotoxicity. Results: Immunoprecipitation of JNK after APAP identified binding to GCLC. Expression of a site-directed mutated canonical JNK docking site in GCLC was resistant to degradation and led to rapid restoration of GSH and inhibited sustained JNK activation. The JNK-resistant GCLC markedly protected against necrosis and alanine aminotransferase (ALT) elevation. The proteolytic loss of GCLC was abrogated by inhibition of the proteasome, ubiquitination, or calpain. Innovation: Using mutated-GCLC resistant to JNK-induced degradation, the results allowed us to identify impaired GSH recovery as an important contributor to early progression of APAP toxicity after the metabolism of APAP and initial GSH depletion had occurred. Conclusion: Activated JNK interacts directly with GCLC and leads to proteolytic degradation of GCLC. Degradation of GCLC impairs GSH recovery after APAP allowing the continued activation of JNK. Conversely, rapid recovery of GSH inhibits the sustained activation of the mitogen-activated protein (MAP) kinase cascade and dampens APAP toxicity by suppressing the continued activation of JNK. Antioxid. Redox Signal. 38, 1071-1081.

Glycogen-Endoplasmic Reticulum Connection in the Liver.

Glycogen, the branched polymer of glucose is found mainly in the liver and muscle in mammals. Along with several other proteins, glycogen forms separate cellular organelles, and particles in cells. Glycogen particles in the liver have a special metabolic and also regulatory connection to the intracellular endomembrane system, particularly the endoplasmic reticulum. This connection is part of the organelle homeostasis in hepatocytes and forms a "glycogenoreticular system". The actual size of hepatic glycogen stores and the rate of glycogenolysis determines several essential liver-specific metabolic processes, such as glucose secretion for the maintenance of blood glucose levels or the glucuronidation of certain vital endo-, and xenobiotics, and are also related to liver antioxidant defense. In starvation, and in certain physiological and pathological states, where glycogen stores are depleted, functions of the glycogenoreticular system are altered. The starvation-induced depletion of hepatic glycogen content changes the biotransformation of various endo- and xenobiotics. This can be observed especially in acute DILI (drug-induced liver injury) due to paracetamol overdose, which is the most common cause of acute liver failure in the West.

Assessing Paracetamol Overdose in Children: Acceptability and Potential Market for a Non-Invasive Testing Device.

Assessment of paracetamol overdose in children and teenagers in the emergency department (ED) requires blood, taken 4 hours post ingestion. A commercial partner developed transdermal paracetamol measuring technology. This work aims to understand the acceptability of such a device, and potential market size. A questionnaire study was undertaken with children and parents attending Alder Hey Children's Hospital, and healthcare professionals (HCP) involved in their care. A retrospective audit of paracetamol ingestion presenting to a paediatric ED was undertaken. One hundred forty-three questionnaires were distributed, and 139 returned (response rate 97.2%), comprising 55 children, 52 parents and 32 HCP (recruited between August-October 2019). Overall device acceptability, assessed by favourability of appearance and willingness to wear was high, at 60.0% and 81.5% respectively. Concerns raised included bulky size and weight, and concern regarding the duration younger children would tolerate wearing the device. All groups, including children, ranked accuracy of results as the most important device feature and device comfort the least important. Parents prioritised avoidance of blood tests more than children. One hundred twenty-seven children presented to ED with paracetamol ingestion (September 2017-August 2018), with 57 (44.9%) categorised as accidental overdose. Overall, 106 (83.4%) required paracetamol concentration measuring, and 25 (19.7%) of these required treatment with N-acetylcysteine. Extrapolating nationally, over 7000 children will present with accidental overdose per annum in the UK. Acceptability of a non-invasive paracetamol sensor was high in all groups, provided accuracy could be assured.

Effects of acute and chronic disease on cell junctions in mouse liver.

Cell junctions, including anchoring, occluding and communicating junctions, play an indispensable role in tissue architecture and homeostasis. Consequently, malfunctioning of cell junctions is linked with a wide range of disorders, including in liver. The present study was set up to investigate the effects of acute and chronic disease induced by chemical compounds on hepatic cell junctions in mice. Mice were either overdosed with paracetamol or repeatedly administered carbon tetrachloride followed by sampling at 24 hours or 8 weeks, respectively. mRNA and protein expression levels of adherens, gap and tight junction components were measured in liver using reverse transcription quantitative real-time polymerase chain reaction analysis and immunoblot techniques, respectively. It was found that protein levels of the adherens junction building blocks β-catenin and γ-catenin, the gap junction components Cx26 and Cx32, and the tight junction constituent zonula occludens 2 were decreased, while mRNA levels of the adherens junction building block E-cadherin, and the tight junction constituent zonula occludens 2 and claudin 1 were upregulated following paracetamol overdosing. Repeated administration of carbon tetrachloride increased protein levels of E-cadherin, β-catenin, Cx26, Cx32, Cx43 and claudin 1. The latter was reflected at the mRNA level. In conclusion, acute and chronic liver disease have different effects on cell junctions in liver.

Emergency diagnosis made easy: matrix removal and analyte enrichment from raw saliva using paper-arrow mass spectrometry.

Paracetamol overdose is a leading cause of acute liver failure that can prove fatal. Establishing paracetamol concentration accurately and quickly is critical. Current detection methods are invasive, time-consuming and/or expensive. Non-invasive, rapid and cost-effective techniques are urgently required. To address this challenge, a novel approach, called Paper-Arrow Mass Spectrometry (PA-MS) has been developed. This technique combines sample collection, extraction, enrichment, separation and ionisation onto a single paper strip, and the entire analysis process, from sample to result, can be carried out in less than 10 min requiring only 2 μL of raw human saliva. PA-MS achieved a LOQ of 185 ng mL-1, mean recovery of 107 ± 7%, mean accuracy of 11 ± 8% and precision ≤5% using four concentrations, and had excellent linearity (r2 = 0.9988) in the range of 0.2-200 μg mL-1 covering the treatment concentration range, surpassing the best-in-class methods currently available for paracetamol analysis. Furthermore, from a panel of human saliva samples, inter-individual variability was found to be <10% using this approach. This technique represents a promising tool for rapid and accurate emergency diagnosis.

Fluorine-thiol displacement probes for acetaminophen's hepatotoxicity.

Chemicals possessing reactive electrophiles can denature innate proteins leading to undesired toxicity, and the overdose-induced liver injury by drugs containing electrophiles has been one of the major causes of non-approval and withdraw by the US Food and Drug Administration (FDA). Elucidating the associated proteins could guide the future development of therapeutics to circumvent these drugs' toxicities, but was largely limited by the current probing tools due to the steric hindrance of chemical tags including the common "click chemistry" labels. Taking the widely used non-steroidal anti-inflammatory drug acetaminophen (APAP) as an example, we hereby designed and synthesized an APAP analogue using fluorine as a steric-free label. Cell toxicity studies indicated our analogue has similar activity to the parent drug. This analogue was applied to the mouse hepatocellular proteome together with the corresponding desthiobiotin-SH probe for subsequent fluorine-thiol displacement reactions (FTDRs). This set of probes has enabled the labeling and pull-down of hepatocellular target proteins of the APAP metabolite as validated by Western blotting. Our preliminary validation results supported the interaction of APAP with the thioredoxin protein, which is an important redox protein for normal liver function. These results demonstrated that our probes confer minimal steric perturbation and mimic the compounds of interest, allowing for global profiling of interacting proteins. The fluorine-thiol displacement probing system could emerge as a powerful tool to enable the investigation of drug-protein interactions in complex biological environments.

THE ACTIVITY OF HEME OXYGENASE AND δ-AMINOLEVULINATE SYNTHASE IN THE RAT KIDNEY UNDER CONDITIONS OF TOXIC INJURY WITH ACETAMINOPHEN

The aim of this work was to study the activity of δ-aminolevulinate synthase, heme oxygenase and the content of mitochondrial cytochromes in the rat kidney conditions of toxic damage with acetaminophen against the background of protein deficiency. δ-Aminolevulinate synthase activity was determined spectrophotometrically taking into account the molar extinction coefficient of 0.023·103 mol-1·cm-1, heme oxygenase activity – by the amount of bilirubin formed and expressed in nanomoles per 1 mg of protein per 1 minute. The determination of the contents of cytochromes a+a3, b, c and c1 in the suspension of isolated mitochondria was carried out by the difference spectra between the reduced and oxidized states in the region of their spectral maxima. The study was conducted on 4 groups of animals: Group I - control animals (K); II – rats kept on a low-protein diet (LPD); ІІІ – animals with acetaminophen-induced liver injury receiving complete ration (AII); IV – animals with acetaminophen-induced liver injury that were previously maintained on semi-synthetic low-protein ration (LPD/AII). It was established that under the conditions of consumption of a low-protein diet, there are no significant changes in the activities of heme oxygenase and δ-aminolevulinate synthase, but a decrease in the content of mitochondrial cytochromes a+a3, b, c, c1 is observed, which probably indicates the critical role of providing protein in the diet for the synthesis of cytochromes. At the same time, under the conditions of toxic damage by acetaminophen, regardless of whether the ration is provided with protein, there is a decrease in the activity of δ-aminolevulinate synthase by an average of 1.6 times with a simultaneous increase in the activity of heme oxygenase by approximately 1.5 times compared to the control values, which indicates an increase in the processes of heme catabolism on against the background of slowing down of its synthesis under the studied conditions. The increase in the activity of heme oxygenase against the background of the decrease in the activity of δ-aminolevulinate synthase can be considered as one of the possible mechanisms of the established decrease in the content of mitochondrial cytochromes under the conditions of acetaminophen intoxication, which in turn may further lead to a violation of the activity of the enzymes of the cytochrome part of the respiratory chain. The obtained results regarding the content of cytochromes, the activities of key enzymes of heme metabolism in the kidneys can be considered as prerequisites for deepening the energy imbalance under the conditions of toxic damage to the kidneys by acetaminophen.

Titanate nanotubes as an efficient oral detoxifying agent against drug overdose: application in rat acetaminophen poisoning.

Voluntary drug intoxication is mainly due to drug overdose or the interaction of several drugs. Coma and its associated complications such as hypoventilation, aspiration pneumopathy, and heart rhythm disorders are the main hallmarks of drug intoxication. Conventional detoxification treatments, including gastric lavage or vomiting, administration of ipecac or activated charcoal (CH), and the use of antidotes, have proven to be inefficient and are generally associated with severe adverse effects. To overcome these limitations, titanate nanotubes (TiNTs) are proposed as an efficient emerging detoxifying agent because of their tubular shape and high adsorption capacity. In the present study, the detoxifying ability of TiNTs was evaluated on paracetamol (PR)-intoxicated rats. Results indicate that the loading ability of PR into TiNTs (70%) was significantly higher than that recorded for CH (38.6%). In simulated intestinal medium, TiNTs showed a controlled drug release of less than 10% after 72 h of incubation. In PR-intoxicated rats, TiNTs treatment resulted in a 64% decrease of PR after 4 h of poisoning versus 40% for CH. Concomitantly, TiNTs efficiently reduced PR absorption by 90% after 24 h of poisoning, attenuated the elevated levels of biochemical markers (i.e., alanine aminotransferase, aspartate aminotransferase, creatinine, and TNF-α) and mitigated oxidative stress by increasing the activity of superoxide dismutase and reducing the oxidized glutathione/total glutathione ratio, suggesting a histoprotective effect of TiNTs against paracetamol-induced toxicity in rats. In addition to their safety and high stability in the entire gastro-intestinal tract, biodistribution analysis revealed that TiNTs exhibited low intestinal absorption owing to their large cluster size of compact aggregate nanomaterials across the intestinal villi hindering the absorption of paracetamol. Collectively, these data provide a new and promising solution for in vivo detoxification. TiNTs are expected to have great potential for the treatment of voluntary and accidental intoxication in emergency care.

Up-to-date treatment of acetaminophen poisoning

N-Acetylcysteine (NAC) is the standard antidote treatment for preventing hepatotoxicity caused by acetaminophen (AAP) poisoning. This review summarizes the recent evidence for the treatment of AAP poisoning. Several alternative intravenous regimens of NAC have been suggested to improve patient safety by reducing adverse drug reactions and medication errors. A two-bag NAC infusion regimen (200 mg/kg over 4 h, followed by 100 mg/kg over 16 h) is reported to have similar efficacy with significantly reduced adverse reactions compared to the traditional 3-bag regimen. Massive AAP poisoning due to high concentrations (more than 300-lines in the nomogram) needs to be managed with an increased maintenance dose of NAC. In addition to NAC, the combination therapy of hemodialysis and fomepizole is advocated for severe AAP poisoning cases. In the case of a patient presenting with an altered mental status, metabolic acidosis, elevated lactate, and an AAP concentration greater than 900 mg/L, hemodialysis is recommended even if NAC is used. Fomepizole decreases the generation of toxic metabolites by inhibiting CYP2E1 and may be considered an off-label use by experienced clinicians. Since the nomogram cannot be applied to sustained-release AAP formulations, all potentially toxic sustained-release AAP overdoses should receive a full course of NAC regimen. In case of ingesting less than the toxic dose, the AAP concentration is tested twice at an interval of 4 h or more; NAC should be administered if either value is above the 150-line of the nomogram.

The Prophylactic Anti-Inflammatory Effect of Omega-7 Against Paracetamol-Induced Liver Injury in Rats

&#x0D; &#x0D; &#x0D; &#x0D; Paracetamol poisoning, whether intentionally or accidentally, is one of the main public health problems since the prevalence of its toxicity increased significantly in many countries. Currently, paracetamol is one of the primary causes of acute liver failure worldwide. The aim of this study was to investigate the potential prophylactic effect of omega-7 fatty acid in protecting male rats' livers from paracetamol-induced liver damage. Thirty albino male rats were divided randomly and equally into five groups and then treated as follows: Group 1 (negative control) rats were orally given liquid paraffin for seven consecutive days. Group 2 (positive control) rats were orally given liquid paraffin for seven consecutive days and a single injection of paracetamol (500 mg/kg) intraperitoneally on day eight of the experiment. Group 3 rats were orally given omega-7 (300 mg/kg) for seven consecutive days. Group 4 rats were orally given a single dose of omega-7 (100 mg/kg/day) for 7 days and a single injection of paracetamol (500 mg/kg) intraperitoneally on day eight of the experiment. Group 5 rats were orally given a single dose of omega-7 (300 mg/kg/day) for 7 days and a single injection of paracetamol (500 mg/kg) intraperitoneally on day eight of the experiment. After 24 h of the endpoint of treatment (on day 9), blood samples were collected, and serum was prepared for the evaluation of tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10). This study found that rats given paracetamol had a significant (P&lt;0.05) increase in serum levels of TNF-α and IL-10, whereas rats previously given oral administration of omega-7 fatty acid before injection of paracetamol resulted in a significant decrease (P&lt;0.05) of these cytokines. Oral omega-7 fatty acid supplementation may help to prevent liver damage caused by paracetamol.&#x0D; &#x0D; &#x0D; &#x0D;

Modification of antidote therapy for poisoning due to massive admission of paracetamol

Background. Paracetamol poisoning is common all over the world, including in Russia. In 20–25% of cases, a massive dose of the drug is observed: more than 30–40 g of paracetamol at a time.The aim of the study was to demonstrate the efficacy of using an increased doses of acetylcysteine in the treatment of a massive paracetamol admission.Results. Patient G., 22 years old, took 70 tablets (35 g) of paracetamol for suicide 3 hours before admission to the hospital. The blood level of paracetamol 4 hours after taking it was 694.94 µg/mL. Upon admission to the hospital, acetylcysteine administering was started according to a 12-hour scheme. Subsequently, the administration of acetylcysteine was continued according to a 20-hour regimen with an increased dosage at the 2nd stage. Laboratory parameters, including aspartate aminotransferase and alanine aminotransferase, remained within the reference values during hospital stay. Conclusion. The case report we have presented shows the efficacy and expediency of using an increased doses of acetylcysteine in case of massive admission of paracetamol, which contributes to the prevention of the development of severe complications and a favorable course and outcome of the disease.

Fomepizole as an emerging adjunct in treating severe acetaminophen toxicity: a case report and a brief review

Fomepizole as an emerging adjunct in treating severe acetaminophen toxicity: a case report and a brief review

Jasminum elongatum Ameliorates Acetaminophen Induced Hepatotoxicity by Modulating Dysregulated Antioxidant Enzyme System

Objectives To evaluate the hepatoprotective activity of fractions of Jasminum elongatum methanolic extract against acetaminophen-induced hepatic damage. Materials and Methods Fractions obtained from methanolic extract of J. elongatum (petroleum ether, chloroform and hydroalcoholic) were investigated for hepatoprotective activity. Doses of 100 mg/kg and 200 mg/kg of different fractions were administered for 7 days, and acetaminophen toxicity was induced on the eighth day. After 24 hr of toxicity induction, biochemical markers and histological alterations were measured to determine the amount of hepatoprotection. Results The chloroform and hydroalcoholic fractions showed a significant decrease in biochemical parameters when compared to the toxic group, which was confirmed by histopathological changes and antioxidant parameters. Conclusion The results of this study revealed that the chloroform and hydroalcoholic fraction of J. elongatum have significant hepatoprotective activity against acetaminophen-induced toxicity.

Natural Product 2-Oxokolavenol Is a Novel FXR Agonist.

Acetaminophen (APAP) toxicity is a common cause of hepatic failure, and the development of effective therapy is still urgently needed. Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been identified as a master gene for regulating enterohepatic metabolic homeostasis and has proven to be a promising drug target for various liver diseases. Through high-throughput chemical screening, the natural product 2-oxokolavenol was identified as a novel and selective FXR agonist. Further investigations revealed that 2-oxokolavenol exerts therapeutic efficacy against APAP-induced hepatocyte damage in an FXR-dependent manner. Mechanistically, 2-oxokolavenol forms two hydrogen bonds with M265 and Y369 of human FXR to compatibly fit into the ligand binding pocket of FXR, which potently leads to the recruitment of multiple co-regulators and selectively induces the transcriptional activity of FXR. Our findings thus not only reveal the direct target of natural product 2-oxokolavenol, but also provide a promising hit compound for the design of new FXR modulators with potential clinical value.

1277: USE OF MOLECULAR ADSORBENT RECIRCULATING SYSTEM LEADING TO IMPROVED TRANSPLANT-FREE SURVIVAL

Introduction: Acute liver failure (ALF) has many different etiologies and carries significant morbidity and mortality. Hepatic encephalopathy (HE) is a main cause of mortality in these patients and is associated with cerebral edema and risk for progression to brainstem herniation. Albumin dialysis, mainly utilizing the Molecular Adsorbent Recirculating System (MARS) has been demonstrated in the past to improve HE, although data on mortality benefit has been inconsistent. The Children’s Hospital at Montefiore is a children’s hospital within a larger adult healthcare system. We report our single center experience utilizing extracorporeal liver support via the MARS device on pediatric and adult patients over our inaugural year. Methods: This is a retrospective report of all patients who underwent MARS therapy during the first year of our program. As per our institutional guidelines, all patients were eligible for MARS due to having grade 3+ HE or grade 2 HE with an additional failing organ system. All patients, despite their age, were treated by the pediatric MARS team. Results: Four pediatric and two adult patients underwent MARS therapy. The underlying etiologies of the acute liver failure were: acetaminophen overdose in one, indeterminate in three, disseminated varicella in one, and acute fatty liver of pregnancy with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome and atypical hemolytic uremic syndrome in one. Survival was 100%. Of the two adults, one had severe Grade 4 HE with loss of multiple brainstem reflexes upon initiation of MARS support. Her neurologic exam demonstrated improvement during her first MARS treatment cycle, and she was successfully transplanted later that night. The second adult, as well as all four pediatric patients were able to achieve full recovery of their native liver function without need for transplantation. Conclusions: The use of MARS therapy appears in this cohort to allow for liver recovery and improved transplant free survival.

Hepatoprotective effect of Thyme aqueous extract in Acetaminophen induces hepatotoxicity in male rats.

Thyme vulgaris is effective in treating acetaminophen toxicity in clinical trials. The present study investigates Thyme aqueous extract's effect on rats poisoned with Acetaminophen. In this study, the data were obtained from male Wister rats. Animals were divided into three groups: distilled water, acetaminophen (1mg/ kg), and aqueous thyme extract (400 mg/kg). All animals were orally treated for seven days respectively. The animal was sacrificed on the eighth day. ALT, AST, GSH, TAC, and Caspase3 were all measured in plasma obtained from heart-derived blood samples centrifuged to determine plasma levels of these enzymes and other antioxidants, malondialdehyde precursors (MDA). Liver enzyme levels were reduced, total antioxidant levels were increased, and an aqueous extract of thyme compensated for glutathione levels. Caspase3 levels were also reduced. Acetaminophen-induced liver tissue damage and inflammatory cell damage were considerably lessened by Aqueous Thyme extract treatment. To protect the liver from Acetaminophen-induced hepatotoxicity, aqueous Thyme extract was found to be beneficial. Keywords: Acetaminophen, Hepatotoxicity, Thyme aqueous extract, Histopathology

Potential role of angiotensin converting enzyme/neprilysin pathway and protective effects of omapatrilat for paracetamol‑induced acute liver injury.

The renin-angiotensin-aldosterone system (RAAS) is an important pathway that contributes to the pathophysiology of acute liver injury due to paracetamol toxicity. Omapatrilat, a RAAS-acting agent, inhibits both angiotensin converting enzyme (ACE) and neprilysin/neutral endopeptidase (NEP). The aim of the present study was to investigate the hepatoprotective effects of omapatrilat and examine the role of ACE/NEP pathway on the physiopathology of paracetamol toxicity. A total of 56 BALB/c mice were separated into seven groups: Control, 40 mg/kg omapatrilat only, 400 mg/kg paracetamol only, paracetamol and 140 mg/kg N-acetylcysteine and three groups with paracetamol and 10-40 mg/kg omapatrilat. Blood and liver tissue samples were studied through histopathological imaging, alanine transaminase (ALT) and aspartate transaminase (AST) liver function tests and oxidant/antioxidant biomarker measurements including superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA). ACE and NEP activities were also measured. Histopathological analysis revealed that paracetamol toxicity resulted in a number of apoptotic and necrotic cells in liver tissue samples. By contrast, with 40 mg/kg omapatrilat administration in toxicity-induced mice, hepatocytes were significantly improved and exhibited similar appearance to the control group. Biochemical measurements also supported these histopathological results. Omapatrilat pretreatment provided a dose-dependent reduction in oxidative stress and reversed paracetamol toxicity indications by reducing ALT and AST activities, increasing SOD activity and GSH levels and reducing MDA levels. Dose-dependent increase of ACE and NEP enzymes in omapatrilat groups was also observed. The results demonstrated promotion of antioxidant activity by omapatrilat and suppression of oxidative stress associated with acute liver injury. These findings revealed the potential role of ACE/NEP pathway in paracetamol toxicity and hepatoprotective effects of omapatrilat against oxidative stress.

Sensitive electrochemical assay of acetaminophen based on 3D-hierarchical mesoporous carbon nanosheets

Acetaminophen plays a key role in first-line Covid-19 cure as a supportive therapy of fever and pain. However, overdose of acetaminophen may give rise to severe adverse events such as acute liver failure in individual. In this work, 3D-hierarchical mesoporous carbon nanosheet (hMCNS) microspheres with superior properties were fabricated using simple and quick strategy and applied for sensitive quantification of acetaminophen in pharmaceutical formulation and rat plasmas after administration. The hMCNS microspheres are prepared via chemical etching of zinc oxide (ZnO) nanoparticles from a zinc-gallic acid precursor composite (Zn-GA) synthesized by high-temperature anaerobic pyrolysis. The obtained hMCNS could enhance analytes accessibility and accelerate proton transfer in the interface, hence increasing the electrochemical performance. Under optimized experimental conditions, the proposed electrochemical sensor achieves a detection limit of 3.5 nM for acetaminophen. The prepared electrochemical sensor has been successfully applied for quantification of acetaminophen in pharmaceutical formulations and the rat plasma samples before and after administration. Meanwhile, this sensor is compared with high-performance liquid chromatography (HPLC) as a reference technology, showing an excellent accuracy. Such an electrochemical sensor has great potential and economic benefits for applications in the fields of pharmaceutical assay and therapeutic drug monitoring (TDM).