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Introduction: Paracetamol (acetaminophen)-induced acute liver failure (ALF) with severe hyperammonemia (ammonia >100 µmol⋅L−1) is a life-threatening condition. A strategy based on high-intensity continuous renal replacement therapy (CRRT) without early (up to day seven) transplantation may enable clinicians to safely identify which patients can recover and survive and which patients require transplantation. Methods: We conducted a single-center, retrospective cohort study of patients with severely hyperammonemic paracetamol-induced ALF. The primary outcome was early transplant-free survival. Results: We studied 84 patients (median age: 38; female sex: 79 [85%]) over a 12-year period (median ammonia level at ICU admission: 153 µmol⋅L−1; median peak aspartate aminotransferase (AST): 10,029 U⋅L−1; median lactate: 5.0 mmol⋅L−1; and median INR: 4.4) and 55 (65%) with King’s College criteria for transplantation. Overall, 87% received high-intensity CRRT (92% in 2020–2023). Median CRRT intensity was 54 mL⋅kg−1⋅hr−1 within the first 48 h and increased by 1.8 mL⋅kg−1⋅hr−1 per year during the study period (p = 0.002). Transplant-free survival to day 7 was 86% in 2011–2023 and 96% in 2020–2023. Overall, only 4 patients were transplanted and only 1 (4%) in 2020–2023. On multivariable Cox analysis, factors independently associated with failure to achieve day seven transplant-free survival were higher APACHE III score (HR = 1.05, 95% CI: 1.02–1.08), higher lactate (HR = 1.27, 95% CI: 1.12–1.44), and lower platelet count at ICU admission (HR = 0.85, 95% CI: 0.78–0.93) and the median effluent dose applied within the first 48 h of ICU admission (HR = 0.67, 95% CI: 0.46–0.98). Conclusions: Early transplant-free survival is achievable in most patients with paracetamol-induced ALF and severe hyperammonemia with a treatment based on high-intensity CRRT. Such transplant-free survival increased over time together with increased CRRT dose. [ABSTRACT FROM AUTHOR]

Abstract Background Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen. Case presentation We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48 h after she had taken 10 g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20 mg/dL on admission, with a peak at 3.67 mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose. Conclusion This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose.

Background: Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen. Case presentation: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48 h after she had taken 10 g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20 mg/dL on admission, with a peak at 3.67 mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose. Conclusion: This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose. [ABSTRACT FROM AUTHOR]

Background and Aim: 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. Methods: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/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 2 mmol/L within 12 h post ingestion. Results: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 μg/L [interquartile range, IQR, 533–1644] vs 270 μg/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 (3028 μg/L [IQR 1399–3556] vs 574 μg/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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized. Paracetamol overdose can have severe and life-threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK,1 Correct and early management is crucial and will be discussed within this article. [ABSTRACT FROM AUTHOR]

Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol. [ABSTRACT FROM AUTHOR]

We report a case of an unusual polypharmacy overdose including warfarin in a patient with a metallic heart valve, complicated by the history that he had ceased taking anticoagulation in the preceding few months, that placed him in an initial prothrombotic phase during his presentation. Our case highlights the importance of elucidating all relevant clinical details in a polypharmacy overdose, as clearly and rapidly as feasible, to enable appropriate management., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Moorthy et al.)

INTRODUCTION Paracetamol is one of the most widely used analgesics and antipyretics in the world. An overdose of this drug can occur after a single ingestion of a large amount of paracetamol or after repeated ingestion of smaller amounts that eventually exceed the recommended total dose and can result in liver damage. It is believed that the maximum daily dose of paracetamol for an adult is 4g. MATERIALS AND METHOD Patient information was collected from hospital records available in the clinical toxicology department. In addition, we conducted a literature review on paracetamol using PubMed. CASE REPORT A patient, 16 years old, was admitted from a district hospital to the Clinical Toxicology and Cardiology Department in Lublin for paracetamol intoxication and suspected intoxication with a psychoactive substance. The patient's history revealed that he had taken a total of 20 paracetamol 500mg (10g) tablets in short intervals of 2 h for abdominal pain. The patient was treated with a full dose of antidote (ACC), and the drug infusion was continued at a maintenance dose. Despite the treatment administered, increasing features of liver damage were observed (INR 2.78, AST 6273 U/l, ALT 8854 U/l, bilirubin 3.83 mg/dl).The patient was consulted to qualify for a possible liver transplant. With intensive treatment maintained, a downward trend in liver damage parameters was achieved. The patient was discharged from the Department in good general condition, without complaints. CONCLUSION Due to the increasing number of paracetamol overdoses (intentional or accidental), strategies should be implemented to raise awareness and prevent this-educating patients, encouraging label/leaflet reading, reducing the amount of paracetamol in packages, more visible warnings on packages.

Abstract Background Tampering of psychoactive medicines presents challenges to regulation and public health. However, little is currently known about what influences the decisions to treat codeine-containing medicines (CCM) with cold water extraction (CWE) from the perspective of individuals employing these techniques. The article identifies factors influencing utilisation of CWE to separate codeine from compounded analgesics, such as paracetamol and ibuprofen, found in CCM. Methods Purposive sampling of 27 participants residing in England who took part in a qualitative interview. Of these, 14 individuals (11 males and 3 females) reported tampering of psychoactive medicines, and the relevant transcripts were included in the analyses for the study. Participants were recruited from one addiction treatment service and from an online survey. The mean age of the participants was 31.5 years (range = 18–42 years). Qualitative data analysis followed the processes of iterative categorization (IC). The codes ‘harm reduction’, ‘information sources’ and ‘changes on the drug markets’ were grouped and summarised. The coding of the data was done in a Microsoft® Word document. Results Two groups of participants were identified in the data analysis: (i) individuals who used CCM (n = 5), and (ii) individuals who used CCM and heroin (n = 9). Participants in both groups used CWE due to concerns of paracetamol overdose from the use of excessive dosages of CCM. For both of them, information obtained from the internet encouraged the use of CWE. Participants using CCM described how the many steps involved in conducting CWE, including sourcing codeine boxes from pharmacies (over the counter), presented a barrier against using CWE. Participants using CCM and heroin explained how reduced availability in the local heroin supply influenced utilisation of CWE techniques to maintain their use of opioids and avoid withdrawal. Withdrawal symptoms and cravings outweighed the concerns about the quality of the extracted codeine mixtures in this participant group, especially the ability of CWE to remove paracetamol and tablet fillers. Conclusions Utilisation of CWE of codeine was influenced by several factors including drug market supply, the availability of detailed information on the internet about CWE and restrictions on codeine sourcing in pharmacies. Risks identified with CWE include consumption of unknown doses of paracetamol if the CWE techniques are not used correctly. Attempts at extracting codeine from CCM should be considered in risk assessments of opioid medicines.

Introduction: Deliberate self-harm, including intentional self-poisoning, remains a major health concern in South Africa. Increasing number of cases place a significant burden on our Emergency Centres (EC's). Paracetamol remains the most frequent drug ingested in intentional self-poisoning. As an antidote, N-acetylcysteine (NAC) is very effective in the management of acute cases of paracetamol overdose. However, it shows less efficacy in cases of delayed presentation, where both liver transplant and mortality rates are significantly higher. Case report: We present a case of delayed presentation paracetamol overdose. The patient presented in fulminant hepatic failure with encephalopathy, but made a full recovery after being treated with NAC. Discussion: This case report highlighted NAC's potential effectiveness in delayed presentations of paracetamol overdose, irrespective of associated fulminant hepatic failure. The effectiveness of NAC in delayed presentations of paracetamol overdose should therefore not be underestimated, and warrants further research.

Background and Aim: Though rodenticidal hepatotoxicity is reported from India, there is no systematic study to assess its magnitude. This study aimed to assess exposure to rodenticide as a risk factor for acute hepatotoxicity in Tamil Nadu, India. Methods: We retrospectively analyzed acute hepatotoxicity caused by ingestion of hepatotoxin or potentially hepatotoxic drug overdose across 15 hospitals in 6 districts of Tamil Nadu from 1 January 2019 to 30 June 2019. Study exclusion criteria were idiosyncratic drug-induced liver injury and chronic liver diseases. Results: Of the 702 patients, 685 gave history of consuming rodenticide; hepatotoxicity in the other patients resulted from paracetamol overdose (n=10) and due to other drugs (n=7); 97% patients had a suicidal intent. Of 671 patients with complete data, ratio of number of patients with hepatotoxicity due to rodenticide to paracetamol overdose was 450:6 (i.e. 75:1). The 451 rodenticidal hepatotoxicity patients (255 males, 75% were 15–34 years old) underwent conservative management (n=396), plasma exchange (n=54) and plasma exchange followed by liver transplant (n=1); 159 patients (35%) had poor outcome (131 died, 28 discharged in moribund state). Based on our observations, we estimate a case burden of 1584 rodenticidal hepatotoxicity patients (95% CI: 265–6119) with poor outcome in 554 patients in Tamil Nadu from January 2019 to June 2019. Population attributable risk for rodenticide as cause of hepatotoxicity was 22.7%. Conclusion: Rodenticide ingestion was an important cause of acute hepatotoxicity in Tamil Nadu. Most patients were young and one-third had poor outcome. Public health interventions are needed to address this. [ABSTRACT FROM AUTHOR]

Paracetamol‐induced hepatotoxicity is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. Among the three dominant paracetamol metabolism pathways (i.e. glucuronidation, sulfation and oxidation), the importance of sulfation is often underestimated because of the general thinking that the sulfation pathway is saturated at therapeutic doses and ultimately accounts for a limited proportion of the fate of a paracetamol dose. We illustrate that insufficient sulfation leads to a shift in biotransformation of paracetamol to toxic oxidation pathways and patients with low sulfate reserves are at higher risk of paracetamol toxicity. Here, we propose that sulfation is of critical importance in understanding the risk of liver toxicity secondary to paracetamol overdose. Serum inorganic sulfate, a measurable substrate on the causal path of paracetamol‐induced liver toxicity, should be considered a biomarker for potential toxicity as well as a target for treatment. [ABSTRACT FROM AUTHOR]

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized. Paracetamol overdose can have severe and life threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK, 1 Correct and early management is crucial and will be discussed within this article. [ABSTRACT FROM AUTHOR]

Paracetamol is the most common drug taken in overdose in the UK, and this is recognised as a major cause of acute liver failure. However, death rates from acute liver failure have fallen, due to the rapid availability and accessibility of the antidote, N-acetylcysteine (NAC). This article critically evaluates the literature on the assessment and management of patients presenting with paracetamol overdose, in order to promote best practice within their clinical team. It includes discussion of presentation, risk factors and complications, as well as treatment and referral to specialist centres for liver transplantation. [ABSTRACT FROM AUTHOR]

James G Cowman, Manuel Bakheet Royal College of Surgeons in Ireland – Medical University of Bahrain, Manama, Bahrain Background: A student-selected component (SSC) of the medical curriculum requires the student to be self-directed in locating and undertaking a placement in a clinical specialty of their choosing and completing a project. The clinical area for experience was an accident and emergency department, and our topic was a focused audit on the investigations and referral for paracetamol overdose. The purpose of this paper is twofold: to reflect on the education value to medical students of an SSC in a medical curriculum, and to highlight learning and understanding through completion of an audit.Materials and methods: An audit approach was applied. The aim of the project study was to investigate the level of compliance with best-practice guidelines for investigations and psychiatric referral in paracetamol overdose.Results: A total of 40 cases meeting the inclusion criteria were randomly selected. The sample had a mean age of 27 years, of whom 70.5% were female, and the ingested dose of paracetamol ranged from 0.864 to 80 g. Paracetamol abuse may present as intentional and unintentional overdose. In our study, 85% of cases were identified as intentional overdose and 76% had a history of psychiatric illness. Generally, medical management was compliant with guidelines, with some minor irregularities. The international normalized ratio was the most underperformed test.Conclusion: Our choice of topic, paracetamol overdose, contributed to our understanding of the breadth of factors to be considered in the emergency medical management of a patient. In this regard, we had the benefit of understanding how the diagnostic and therapeutic factors, when applied in accordance with best-practice guidelines, work very effectively. The SSC impacted positively on our cognitive, personal, and professional development. In facilitating the student with choice, the SSC encouraged self-direction and proactivity. We gained experience in the discipline of research and acquired some skills in independent thinking and analysis. Keywords: self-directed learning, medical curriculum, student-selected component, paracetamol overdose, investigations, psychiatric referral

Background: Knowledge about patients with acute liver failure (ALF) in Australia and New Zealand (ANZ) is lacking. Aims: To evaluate whether the pattern of ALF would be similar to previous studies and whether, despite potentially low transplantation rates, mortality would be comparable. Methods: We obtained data from the ANZ Intensive Care Society Adult Patient Database and the ANZ Liver Transplant Registry for 10 years commencing 2005 and analysed for patient outcomes. Results: During the study period, 1 022 698 adults were admitted to intensive care units across ANZ, of which 723 had ALF. The estimated annual incidence of ALF over this period was 3.4/million people and increased over time (P = 0.001). ALF patients had high illness severity (Acute Physiology And Chronic Health Evaluation III 79.8 vs 50.1 in non‐ALF patients; P < 0.0001) and were more likely to be younger, female, pregnant and immunosuppressed. ALF was an independent predictor of mortality (odds ratio 1.5 (1.26–1.79); P < 0.0001). At less than 23%, the use of liver transplantation was low, but the mortality of 39% was similar to previous studies. Conclusions: ALF is a rare but increasing diagnosis in ANZ intensive care units. Low transplantation rates in ANZ for ALF do not appear to be associated with higher mortality rates than reported in the literature. [ABSTRACT FROM AUTHOR]

Deliberate self-harm, including intentional self-poisoning, remains a major health concern in South Africa. Increasing number of cases place a significant burden on our Emergency Centres (EC's). Paracetamol remains the most frequent drug ingested in intentional self-poisoning. As an antidote, N-acetylcysteine (NAC) is very effective in the management of acute cases of paracetamol overdose. However, it shows less efficacy in cases of delayed presentation, where both liver transplant and mortality rates are significantly higher. We present a case of delayed presentation paracetamol overdose. The patient presented in fulminant hepatic failure with encephalopathy, but made a full recovery after being treated with NAC. This case report highlighted NAC's potential effectiveness in delayed presentations of paracetamol overdose, irrespective of associated fulminant hepatic failure. The effectiveness of NAC in delayed presentations of paracetamol overdose should therefore not be underestimated, and warrants further research. [ABSTRACT FROM AUTHOR]

Context: The intravenous (IV) N-acetylcysteine (NAC) regimen used worldwide in paracetamol overdose is complex with three separate weight-based doses and is associated with a high incidence of adverse events including non-allergic anaphylactoid reactions (NAARs). In 2012, Denmark adopted the two-bag IV NAC regimen which combined the first two infusions of the three-bag regimen and kept the third infusion unchanged. We compared the safety and efficacy of the two-bag IV NAC regimen with the traditional Danish three-bag regimen. Methods: A medical chart review was conducted in three Danish medical centers from January 2012 through December 2014. Safety and efficacy data were compared for patients who received the traditional infusion protocol in Denmark or the 20-h two-bag IV regimen. Results: Four hundred and ninety-three cases received the two-bag regimen and 274 received the three-bag regimen. The overall incidence of NAARs was 9% with all being mild to moderate in intensity. Fewer subjects in the two-bag group (4%) developed NAARs compared to 17% in the three-bag group (p < .001). Overall, 31 patients (4%) developed hepatotoxicity. There was no apparent difference in hepatotoxicity rates between the groups and no deaths or liver transplants. Patients receiving the two-bag regimen had fewer interruptions or delays (5%) compared to the three-bag regimen cohort (12%). Overall, there were very few medication errors reported (1%). Conclusions: The incidence of NAARs was lower in patients receiving acetylcysteine in a two-bag regimen compared to the traditional Danish three-bag regimen without an apparent reduction in efficacy. [ABSTRACT FROM AUTHOR]

Objective: Acetylcysteine (NAC), an effective antidote for paracetamol poisoning, is commonly associated with adverse reactions. This has been postulated to be related to the rapid initial infusion rate (150 mg/kg over 1 h) of the traditional three-bag protocol. We hypothesized that a slower rate would result in fewer adverse reactions. Our institution in Western Sydney moved to a modified two-bag protocol in February 2015 - first bag: 200 mg/kg over 4 h (50 mg/kg/h) and second bag: (100 mg/kg over 16 h). Methods: Data was extracted from our database on paracetamol overdoses treated with NAC from August 2010 to September 2016. We compared adverse reactions in patients receiving the modified two-bag protocol with a historical control (traditional three-bag regimen with initial bolus of 150 mg/kg/h). Results: Over the study period 1011 paracetamol poisonings presented to our toxicology service, of which 476 required NAC (three-bag = 313, two-bag = 163). Demographic characteristics of the two groups were similar. Fewer anaphylactoid reactions (itch, rash, and swelling) occurred using the two-bag regimen (14% versus 5%, p = .002), a relative reduction of 66%. Similarly, there were fewer prescriptions of anti-allergy medications in the two-bag group (11% versus 4%, p = .01). There was no difference in incidence of hepatotoxicity. Conclusions: Adverse reactions to NAC were less common with the two-bag regimen. These results add to the accumulating evidence that reducing the initial NAC infusion rate reduces the risk of adverse reactions. [ABSTRACT FROM AUTHOR]

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure, drug choice and dosing regime will need to be rationalized. Paracetamol overdose can have severe and life-threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK. Correct and early management is crucial and will be discussed within this article. [ABSTRACT FROM AUTHOR]

Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)-induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty-seven compounds were identified, with monoterpene hydrocarbons being abundant class. d-Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d-limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2-12.27, 1.79-5.91, and 235.05-585.28 μM Trolox eq/mg oil for 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic (ABTS), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo, citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d-limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of -6.17, -4.51, and -5.61 kcal/mol, respectively., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Background The licensed intravenous acetylcysteine regimen for treating paracetamol overdose in most countries uses three separate infusions over 21 h. This complex regimen, requiring different infusion concentrations and rates, has been associated with administration errors. The aim of the present study was to assess the extent of administration delays occurring during this acetylcysteine regimen. Method A 6-month retrospective observational study was conducted at three English teaching hospitals with clinical toxicology services from October 2014. Patients aged 16 years and over, treated with intravenous acetylcysteine for paracetamol overdose, were included. The start times for infusions were recorded and the delays compared with the prescribed infusion times were calculated. Anaphylactoid reactions, intravenous cannula problems, overdose intent and smoking status were recorded to assess their contribution to delays. Results From 263 cases identified, 198 met the study inclusion criteria. The median time between the start of infusions 1 and 3 was delayed from the intended 5 h by a median (interquartile range) of 90 (50-163) min, with 135 (68%) cases delayed by more than 1 h. Significantly longer delays were observed in patients with anaphylactoid reactions [median delay 267 (217-413) min, n = 8] and accidental/supratherapeutic overdose [median delay 170 (95-260) min, n = 29]. There were no significant differences between smokers and nonsmokers, or for patients with intravenous cannula problems. Conclusion Long delays were identified during the three-infusion acetylcysteine regimen for the treatment of paracetamol overdose. These were of clinical significance and could lead to periods of subtherapeutic plasma acetylcysteine concentrations and potentially avoidable hepatotoxicity, as well as delaying hospital discharge. [ABSTRACT FROM AUTHOR]

Purpose The management of paracetamol poisoning was revolutionized after use of acetylcysteine in the 1970s. The protocol used, 3 weight-related infusions, requires almost 24 hours in hospital. It is associated with adverse events in treated patients, particularly anaphylactoid reactions and vomiting. Present treatment nomograms were based on a small series of untreated patients: only 5 of 22 (23%) and 6 of 25 (24%) between the 100 to 200 mg/L and 200 to 300 mg/L nomogram lines, respectively, developed liver injury (alanine transaminase >1000 IU/L). Many patients treated today are unlikely to be at actual risk for major hepatotoxicity. This article discusses the background to future prospects in this area. Methods The history behind approaches to the use of acetylcysteine is presented briefly. The rationale for, and key findings of, a new 12-hour antidote regimen for paracetamol poisoning are detailed. Newer markers of hepatotoxicity, such as miR-122, HMGB1, and necrosis K18, which predict patients at risk more reliably and earlier than existing tests, are discussed. Findings A 2-phase 12-hour acetylcysteine infusion protocol (100 mg/kg over 2 hours: 200 mg/kg over 10 hours) was studied in a formal factorial design against the traditional 3-phase 20.25-hour infusion protocol, with and without pretreatment with ondansetron or placebo. The 12-hour regimen was associated with very significant reductions in anaphylactoid reactions (odds ratio = 0.23; 95% CI, 0.12−0.43; P < 0.0001) and vomiting (odds ratio = 0.37; 95% CI, 0.18−0.79; P = .003) compared with the 20.25-hour infusion protocol. There were few withdrawals from the clinical trial, indicating the feasibility of conducting such studies in Europe. Implications Novel proteomic markers are better than existing standard tests (alanine transaminase and international normalized ratio) early in the course of paracetamol poisoning. Together with these new biomarkers of hepatotoxicity, a 12-hour acetylcysteine protocol offers clinicians and patients the possibility for better targeting of therapy, fewer adverse effects, a simpler dosing regimen, and shorter hospital stay. [ABSTRACT FROM AUTHOR]

Aims Acute drug overdose, especially with paracetamol, may cause acute liver failure leading to registration for transplantation (ALFT). Population statistics and between-country differences for ALFT related to overdose have been poorly described. The aim of the present study was to evaluate overdose ALFT in the multi-country Study of Acute Liver Transplantation (SALT). Methods All adult overdose-related ALFT, with or without suicidal intent, in France, Greece, Ireland, Italy, the Netherlands, Portugal and the UK between 2005 and 2007 were identified from liver transplant registries and hospital records. These were compared with whole-country and per capita use of paracetamol. Results Six hundred cases of ALFT were identified in 52 of 57 eligible transplant centres, of which 114 involved overdose (72 intentional, 10 non-intentional, 32 uncertain). Overdose represented 20% of all-cause ALFT: Ireland 52%, UK 28%, France 18%, the Netherlands 8%, and Italy 1%. Overdose ALFT were mostly females (61%), mean age 33.6 ± 10.9 years. A total of 111 (97%) of the overdoses involved paracetamol. Event rates ranged from one ALFT for 20.7 tons of paracetamol in Ireland, to one for 1074 tons in Italy and one case in 60 million inhabitants over 3 years in Italy to one case in 286 000 inhabitants per year in Ireland. Per-country event rates for non-overdose ALFT exposed to paracetamol were between 2.5 and 4.0 per million treatment-years sold. Conclusions Paracetamol overdose was found to represent one-sixth of all-cause ALFT. There was a 50-fold difference in Europe in the rates of paracetamol overdose ALFT, and a 200-fold difference per million inhabitants. [ABSTRACT FROM AUTHOR]

The liver is a major organ with multiple functions. A number of drugs are metabolized by the liver during phase 1 and 2 reactions which include complex processes involving cytochrome P450 enzymes. Genetic and acquired variability in cytochrome P450 activity may have profound effects on pharmacokinetics. Additionally, drugs can also modify how the liver functions and cause dysfunction or even failure of the organ both by a direct effect on the liver or by alteration in liver blood flow. It is important to recognize the signs and symptoms of liver failure in patients and identify possible causes including drug interactions. Furthermore, once a patient has been recognized to be suffering with liver dysfunction or failure drug choice and dosing regime will need to be rationalized. Paracetamol overdose can have severe and life-threatening consequences for patients due to its effect on liver function. It is the leading cause of acute liver failure in the UK. Correct and early management is crucial and will be discussed within this article. [ABSTRACT FROM AUTHOR]