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1.
Dan Med J ; 71(5)2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38704838

ABSTRACT

INTRODUCTION: To assess the effect of long-term isolation on the mental state of Danish youth. This study aimed to investigate trends in paracetamol overdoses among people under 18 years of age in Denmark during Covid-19 restrictions as an indicator of mental health. METHODS: All patients under the age of 18 years presenting with paracetamol overdose at one of the 18 paediatric departments in Denmark from 2016 to 2021 were included. They were identified in all Danish hospital databases using specific diagnostic codes. RESULTS: From 2016 to 2021, a total of 3,217 people under 18 years of age were admitted for paracetamol overdose. Among these, 86% (n = 2,755) were girls and 14% (n = 462) were boys. During 2020, a slight (7%) decrease in admissions was observed among both boys and girls compared with the preceding four-year mean value. In 2021, the number of overdoses among girls exceeded by 35% the former all-time high from 2016. Furthermore, the number of overdoses among girls exceeded the pre-four-year period mean value by 43%. Among boys, an 8% increase was seen from the highest ever previous value recorded in 2019 and a 23% increase compared with the previous four-year mean value. CONCLUSIONS: During the first year of restrictions, a slight decrease in paracetamol overdoses was observed, possibly associated with limited accessibility. The second year showed a considerable increase in paracetamol overdoses, which may imply an affected mental state among youth during the prolonged lockdown restrictions as seen in previous epidemics. Therefore, further studies are warranted to develop a pandemic preparedness plan to protect general mental health. FUNDING: None. TRIAL REGISTRATION: Not relevant.


Subject(s)
Acetaminophen , Analgesics, Non-Narcotic , COVID-19 , Drug Overdose , Humans , Drug Overdose/epidemiology , COVID-19/epidemiology , Acetaminophen/poisoning , Adolescent , Female , Denmark/epidemiology , Male , Child , Analgesics, Non-Narcotic/poisoning , Child, Preschool , SARS-CoV-2 , Infant
3.
Clin Toxicol (Phila) ; 62(3): 164-167, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38525861

ABSTRACT

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


Subject(s)
Acetaminophen , Acetylcysteine , Drug Overdose , Tertiary Care Centers , Humans , Acetaminophen/poisoning , Retrospective Studies , Drug Overdose/therapy , Drug Overdose/drug therapy , Female , Male , Adult , Acetylcysteine/therapeutic use , Middle Aged , Analgesics, Non-Narcotic/poisoning , Antidotes/therapeutic use , Toxicology/methods , Young Adult
4.
J Gastroenterol Hepatol ; 39(5): 920-926, 2024 May.
Article in English | MEDLINE | ID: mdl-38149309

ABSTRACT

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.


Subject(s)
Acetaminophen , Biomarkers , Drug Overdose , MicroRNAs , Acetaminophen/poisoning , Acetaminophen/blood , Humans , Male , Female , Adult , Biomarkers/blood , MicroRNAs/blood , Fatty Acid-Binding Proteins/blood , Middle Aged , Analgesics, Non-Narcotic/poisoning , Analgesics, Non-Narcotic/blood , Hyperlactatemia/chemically induced , Hyperlactatemia/blood , Prospective Studies , Lactic Acid/blood , Young Adult , Enterocytes/metabolism
5.
West J Emerg Med ; 24(6): 1131-1145, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38165196

ABSTRACT

Introduction: Acetaminophen poisoning is commonly treated by emergency physicians. First-line therapy is N-acetylcysteine (NAC), traditionally administered intravenously via a US Food and Drug Administration (FDA)-approved three-bag protocol in which each bag has a unique concentration and infusion duration. Recently, simplified, off-label two-bag NAC infusion protocols have become more common. The purpose of this review is to summarize the effectiveness and safety of two-bag NAC. Methods: We undertook a comprehensive search of PubMed, EMBASE, and MEDLINE from inception to December 13, 2022, for articles describing human acetaminophen poisonings treated with two-bag NAC, defined as any regimen involving two discrete infusions in two separate bags. Outcomes included effectiveness (measured by incidence of liver injury); incidence of non-allergic anaphylactoid reactions (NAAR); gastrointestinal, cutaneous, and systemic reactions; treatments for NAARs; incidence of NAC-related medication errors; and delays or interruptions in NAC administration. Results: Twelve articles met final inclusion, 10 of which compared two-bag NAC to the three-bag regimen. Nine articles evaluated the two-bag/20-hour regimen, a simplified version of the FDA-approved three-bag regimen in which the traditional first and second bags are combined into a single four-hour infusion. Nine articles assessed comparative effectiveness of two-bag NAC in terms of liver injury, most commonly assessed for by incidence of hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >1,000 international units per liter). No difference in liver injury was observed between two-bag and three-bag regimens. Of nine articles comparing incidence of NAARs, eight demonstrated statistically fewer NAARs with two-bag regimens, and one showed no difference. In seven articles evaluating treatment for NAARs (antihistamines, corticosteroids, epinephrine), all showed that patients received fewer medications for NAARs with two-bag NAC. Three articles evaluated NAC-related medication errors; two demonstrated no difference, while one study evaluating only children showed fewer errors with two-bag NAC. Two studies evaluated delays and/or interruptions in NAC infusions; both favored two-bag NAC. Conclusion: For patients with acetaminophen poisoning, two-bag NAC regimens appear to have similar outcomes to the traditional three-bag regimen in terms of liver injury. Two-bag NAC regimens are associated with fewer adverse events and fewer treatments for those events than the three-bag regimen and fewer interruptions in antidotal therapy.


Subject(s)
Acetaminophen , Acetylcysteine , Drug Overdose , Drug-Related Side Effects and Adverse Reactions , Child , Humans , Acetaminophen/poisoning , Acetylcysteine/therapeutic use , Acetylcysteine/adverse effects , Analgesics, Non-Narcotic/therapeutic use , Antidotes/therapeutic use , Drug Overdose/drug therapy , Infusions, Intravenous
6.
Arch. pediatr. Urug ; 94(2): e309, 2023. graf
Article in Spanish | LILACS, UY-BNMED, BNUY | ID: biblio-1520108

ABSTRACT

La intoxicación por paracetamol de causa no intencional en niños pequeños, e intencional en adolescentes es un motivo de consulta cada vez más frecuente en los servicios de urgencia. La gravedad y el pronóstico de esta intoxicación están dados por el riesgo de falla hepática. Ante la sospecha de ingesta de paracetamol, se debe conocer el tiempo transcurrido, la cantidad de ingesta del fármaco, estimar la toxicidad de la dosis ingerida para predecir hepatotoxicidad, determinar las medidas de contaminación necesarias, dosificar paracetamol en sangre y evaluar la necesidad de administración de antídoto. Se describe el caso de una adolescente que con intención suicida presentó una intoxicación aguda por paracetamol con riesgo de daño hepático requiriendo decontaminación digestiva, administración de antídoto y abordaje interdisciplinario de sus problemas psicoemocionales.


Paracetamol intoxication due to an unintentional cause in young children, and intentional in adolescents, is an increasingly frequent cause for consultation in emergency services. The severity and prognosis of this poisoning is due to the risk of liver failure. Given the suspicion of paracetamol ingestion, the time passed since the ingestion, the amount of paracetamol ingested, the estimate of the dose ingested to predict hepatotoxicity, we must determine the necessary decontamination measures and the paracetamol dose in blood and evaluate the need to administer a paracetamol antidote. We describe the case of an adolescent who presented acute paracetamol poisoning with risk of liver damage resulting from a suicide attempt and who required digestive decontamination, antidote administration and an interdisciplinary approach to her psychological and emotional problems.


A intoxicação não intencional por paracetamol em crianças pequenas e a intoxicação intencional em adolescentes é um motivo cada vez mais comum de consulta em serviços de emergência. A gravidade e o prognóstico desse envenenamento são dados pelo risco de insuficiência hepática. Quando há suspeita de ingestão de paracetamol, o tempo decorrido desde que é ingerido, a quantidade de paracetamol ingerida, a estimação da dose ingerida para predizer hepatotoxicidade, utilizamse para determinar as medidas de contaminação necessárias, dosar paracetamol no sangue e avaliar a ne- cessidade de administração de antídoto. Descrevemos o caso de uma adolescente com intenção suicida que apresentou intoxicação aguda por paracetamol com risco de lesão hepática com necessidade de descontaminação digestiva, administração de antídoto e abordagem interdisciplinar de seus problemas psicoemocionais.


Subject(s)
Humans , Female , Child , Poisoning/drug therapy , Charcoal/therapeutic use , Acetaminophen/poisoning
7.
Toxicol Sci ; 189(2): 175-185, 2022 09 24.
Article in English | MEDLINE | ID: mdl-35944217

ABSTRACT

Larval zebrafish is emerging as a new model organism for studying drug-induced liver injury (DILI) with superiorities in visual assessment, genetic engineering as well as high throughput. Metabolic bioactivation to form reactive intermediates is a common event that triggers DILI. This study first addressed the correlation between acetaminophen metabolism and hepatotoxicity in zebrafish larvae (3-day postfertilization) and demonstrated the occurrence of cytochrome P450 enzymes-mediated acetaminophen (APAP) bioactivation at early developmental stage through characterizing the dose-effect (0-1.6 mg/ml) and the time course (0-72 h) of liver injury and metabolism in the AB strain and LiPan transgenic line Tg(lfabp10a: DsRed; elaA:egfp) expressing the liver-specific fluorescent protein. APAP caused multiorgan developmental retardation and elicited dose- and time-dependent hepatotoxicity. Liver imaging revealed significant changes earlier than histological and biochemical measurements. APAP bioactivation in larval zebrafish was first confirmed by the detection of the glutathione conjugate of the reactive intermediate NAPQI (NAPQI-GSH) and subsequent mercapturate derivatives NAPQI-cysteine and NAPQI-N-acetylcysteine after even short (0.5-h postexposure) or low (0.2 mg/ml) APAP exposure. APAP overdose impaired metabolic function, in particular sulfation, whereas facilitated GSH depletion and APAP sulfate excretion. Meanwhile, APAP displayed triphasic accumulation in the larvae, agreeing with fluctuating metabolic capabilities with sulfation dominating the early larval developmental stage. Most importantly, the dose-response effects and time course of APAP accumulation and metabolism agree well with those of the liver injury development. Overall, larval zebrafish has developed mammalian-like metabolic function, enabling it an ideal model organism for high-throughput screening hepatotoxicity and mechanistic study of bioactivation-based DILI.


Subject(s)
Acetaminophen , Chemical and Drug Induced Liver Injury , Acetaminophen/poisoning , Acetylcysteine/pharmacology , Animals , Benzoquinones , Chemical and Drug Induced Liver Injury/metabolism , Cytochrome P-450 Enzyme System/metabolism , Glutathione/metabolism , Imines , Larva/metabolism , Liver , Mammals/metabolism , Sulfates/metabolism , Sulfates/pharmacology , Zebrafish/metabolism
8.
Sci Signal ; 15(740): eabn4395, 2022 06 28.
Article in English | MEDLINE | ID: mdl-35763560

ABSTRACT

Ligands of the transforming growth factor-ß (TGF-ß) superfamily, including TGF-ßs, activins, and bone morphogenetic proteins (BMPs), have been implicated in hepatic development, homeostasis, and pathophysiology. We explored the mechanisms by which hepatocytes decode and integrate injury-induced signaling from TGF-ßs and activins (TGF-ß/Activin) and BMPs. We mapped the spatiotemporal patterns of pathway activation during liver injury induced by acetaminophen (APAP) in dual reporter mice carrying a fluorescent reporter of TGF-ß/Activin signaling and a fluorescent reporter of BMP signaling. APAP intoxication induced the expression of both reporters in a zone of cells near areas of tissue damage, which showed an increase in autophagy and demarcated the borders between healthy and injured tissues. Inhibition of TGF-ß superfamily signaling by overexpressing the inhibitor Smad7 exacerbated acute liver histopathology but eventually accelerated tissue recovery. Transcriptomic analysis identified autophagy as a process stimulated by TGF-ß1 and BMP4 in hepatocytes, with Trp53inp2, which encodes a rate-limiting factor for autophagy initiation, as the most highly induced autophagy-related gene. Collectively, these findings illustrate the functional interconnectivity of the TGF-ß superfamily signaling system, implicate the coordinated activation of TGF-ß/Activin and BMP pathways in balancing tissue reparatory and regenerative processes upon APAP-induced hepatotoxicity, and highlight opportunities and potential risks associated with targeting this signaling system for treating hepatic diseases.


Subject(s)
Acetaminophen , Bone Morphogenetic Proteins , Chemical and Drug Induced Liver Injury , Transforming Growth Factor beta , Acetaminophen/poisoning , Activins/metabolism , Animals , Autophagy , Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/metabolism , Liver/drug effects , Liver/metabolism , Mice , Signal Transduction/drug effects , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism
9.
Pharmacol Res Perspect ; 10(1): e00920, 2022 02.
Article in English | MEDLINE | ID: mdl-35106928

ABSTRACT

Timely assessment of acetaminophen concentration in overdose situations is not always available in resource-poor settings. The 150 mg/kg dose-estimate for acetaminophen is widely considered as criterion for acetaminophen overdose. Its sensitivity and specificity when compared to the 150 mg/L treatment line on the Rumack-Matthew Nomogram (150-treatment line) has rarely been evaluated. This is a retrospective chart review of acute acetaminophen overdose patients. We evaluated the sensitivity and specificity of the 150, 200 mg/kg and 8- and 10-g dose-estimates by plotting the serum acetaminophen levels and using 150-treatment line on the Nomogram as the treatment cut-off. A comparison of medical care costs was performed. We enrolled 784 cases for analysis. Median (IQR) age was 23 (20-28) years (81.9% female). There were 545 cases (69.5%) where the estimated ingested acetaminophen dose were ≥150 mg/kg and 406 cases (51.8%) with concentrations ≥150-treatment line. Hepatotoxicity and acute liver injury (ALI) occurred in 7.3% and 23.9%, respectively. The sensitivity and specificity of 150 mg/kg dose-estimate for the 150-treatment line were 92.6% (95% CI 89.6, 94.8) and 55.3% (95% CI 50.3, 60.2). Among patients with dose-estimate below150 mg/kg, none developed hepatotoxicity and 17 (7.1%) develop ALI. The administration of activated charcoal significantly decreased the risk of being above the 150-treatment line by half. In resource-poor setings, the use of 150 mg/kg dose-estimate as a stand-alone criteria for initiation of N-acetylcysteine therapy is satisfactory, especially when combined with decontamination with activated charcoal and follow up of aminotransferase at 24 h.


Subject(s)
Acetaminophen/poisoning , Antidotes/administration & dosage , Chemical and Drug Induced Liver Injury/etiology , Nomograms , Acetaminophen/administration & dosage , Acetylcysteine/administration & dosage , Adolescent , Adult , Aged , Charcoal/administration & dosage , Dose-Response Relationship, Drug , Drug Overdose , Female , Humans , Male , Middle Aged , Retrospective Studies , Sensitivity and Specificity , Young Adult
10.
Arch Toxicol ; 96(2): 453-465, 2022 02.
Article in English | MEDLINE | ID: mdl-34978586

ABSTRACT

Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.


Subject(s)
Acetaminophen/poisoning , Antidotes/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Acetylcysteine/pharmacology , Analgesics, Non-Narcotic/poisoning , Animals , Chemical and Drug Induced Liver Injury/etiology , Drug Overdose , Fomepizole/pharmacology , Hepatocytes/drug effects , Hepatocytes/pathology , Humans , Mice
11.
Clin Toxicol (Phila) ; 60(2): 221-230, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34047639

ABSTRACT

BACKGROUND: Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases. METHODS: This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L (n = 25) vs. no increase (n = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t-tests with false discovery rate correction, chi square, and partial least squares discriminant analyses. RESULTS: Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group (p = .032). Baseline ALT (p = .011) and alkaline phosphatase (p = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI. CONCLUSIONS: Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.


Subject(s)
Acetaminophen , Chemical and Drug Induced Liver Injury , Acetaminophen/poisoning , Alanine Transaminase , Biomarkers , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/etiology , Drug Overdose , Humans , Liver/metabolism
12.
Basic Clin Pharmacol Toxicol ; 130(1): 191-199, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34649297

ABSTRACT

Acetaminophen is one of the most commonly used analgesic drugs in the United States. However, the outcomes of acute acetaminophen overdose might be very serious in some cases. Therefore, prediction of the outcomes of acute acetaminophen exposure is crucial. This study is a 6-year retrospective cohort study using National Poison Data System (NPDS) data. A decision tree algorithm was used to determine the risk predictors of acetaminophen exposure. The decision tree model had an accuracy of 0.839, an accuracy of 0.836, a recall of 0.72, a specificity of 0.86 and an F1_score of 0.76 for the test group and an accuracy of 0.848, a recall of 0.85, a recall of 0.74, a specificity of 0.87 and an F1_score of 0.78 for the training group. Our results showed that elevated serum levels of liver enzymes, other liver function test abnormality, anorexia, acidosis, electrolyte abnormality, increased bilirubin, coagulopathy, abdominal pain, coma, increased anion gap, tachycardia and hypotension were the most important factors in determining the outcome of acute acetaminophen exposure. Therefore, the decision tree model is a reliable approach in determining the prognosis of acetaminophen exposure cases and can be used in an emergency room or during hospitalization.


Subject(s)
Acetaminophen/poisoning , Analgesics, Non-Narcotic/poisoning , Chemical and Drug Induced Liver Injury/epidemiology , Poison Control Centers/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Algorithms , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/physiopathology , Child , Child, Preschool , Cohort Studies , Databases, Factual/statistics & numerical data , Decision Trees , Drug Overdose , Female , Humans , Infant , Male , Middle Aged , Prognosis , Reproducibility of Results , Retrospective Studies , United States/epidemiology , Young Adult
17.
Pharm Biol ; 59(1): 1378-1387, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34629029

ABSTRACT

CONTEXT: Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury. Bianliang ziyu, a variety of Chrysanthemum morifolium Ramat. (Asteraceae), has potential hepatoprotective effect. However, the mechanism is not clear yet. OBJECTIVE: To investigate the hepatoprotective activity and mechanism of Bianliang ziyu flower ethanol extract (BZE) on APAP-induced rats based on network pharmacology. MATERIALS AND METHODS: Potential pathways of BZE were predicted by network pharmacology. Male Sprague-Dawley rats were pre-treated with BZE (110, 220 and 440 mg/kg, i.g.) for eight days, and then APAP (800 mg/kg, i.g.) was used to induce liver injury. After 24 h, serum and liver were collected for biochemical detection and western blot measurement. RESULTS: Network pharmacology indicated that liver-protective effect of BZE was associated with its antioxidant and anti-apoptotic efficacy. APAP-induced liver pathological change was alleviated, and elevated serum AST and ALT were reduced by BZE (440 mg/kg) (from 66.45 to 22.64 U/L and from 59.59 to 17.49 U/L, respectively). BZE (440 mg/kg) reduced the ROS to 65.50%, and upregulated SOD and GSH by 212.92% and 175.38%, respectively. In addition, BZE (440 mg/kg) increased levels of p-AMPK, p-GSK3ß, HO-1 and NQO1, ranging from 1.66- to 10.29-fold compared to APAP group, and promoted nuclear translocation of Nrf2. BZE also inhibited apoptosis induced by APAP through the PI3K-Akt pathway and restored the ability of mitochondrial biogenesis. DISCUSSION AND CONCLUSIONS: Our study demonstrated that BZE protected rats from APAP-induced liver injury through antioxidant and anti-apoptotic pathways, suggesting BZE could be further developed as a potential liver-protecting agent.


Subject(s)
Acetaminophen/poisoning , Chemical and Drug Induced Liver Injury/prevention & control , Chrysanthemum/chemistry , Plant Extracts/pharmacology , Animals , Antioxidants/administration & dosage , Antioxidants/isolation & purification , Antioxidants/pharmacology , Apoptosis/drug effects , Chemical and Drug Induced Liver Injury/etiology , Dose-Response Relationship, Drug , Drug Overdose , Flowers , Male , Network Pharmacology , Oxidative Stress/drug effects , Plant Extracts/administration & dosage , Rats , Rats, Sprague-Dawley
18.
Arch Toxicol ; 95(10): 3377-3391, 2021 10.
Article in English | MEDLINE | ID: mdl-34420083

ABSTRACT

N-acetylcysteine (NAC) is the only clinically approved antidote against acetaminophen (APAP) hepatotoxicity. Despite its efficacy in patients treated early after APAP overdose, NAC has been implicated in impairing liver recovery in mice. More recently, 4-methylpyrazole (4MP, Fomepizole) emerged as a potential antidote in the mouse APAP hepatotoxicity model. The objective of this manuscript was to verify the detrimental effect of NAC and its potential mechanism and assess whether 4MP has the same liability. C57BL/6J mice were treated with 300 mg/kg APAP; 9 h after APAP and every 12 h after that, the animals received either 100 mg/kg NAC or 184.5 mg/kg 4MP. At 24 or 48 h after APAP, parameters of liver injury, mitochondrial biogenesis and cell proliferation were evaluated. Delayed NAC treatment had no effect on APAP-induced liver injury at 24 h but reduced the decline of plasma ALT activities and prevented the shrinkage of the areas of necrosis at 48 h. This effect correlated with down-regulation of key activators of mitochondrial biogenesis (AMPK, PGC-1α, Nrf1/2, TFAM) and reduced expression of Tom 20 (mitochondrial mass) and PCNA (cell proliferation). In contrast, 4MP attenuated liver injury at 24 h and promoted recovery at 48 h, which correlated with enhanced mitochondrial biogenesis and hepatocyte proliferation. In human hepatocytes, 4MP demonstrated higher efficacy in preventing cell death compared to NAC when treated at 18 h after APAP. Thus, due to the wider treatment window and lack of detrimental effects on recovery, it appears that at least in preclinical models, 4MP is superior to NAC as an antidote against APAP overdose.


Subject(s)
Acetaminophen/poisoning , Acetylcysteine/pharmacology , Antidotes/pharmacology , Chemical and Drug Induced Liver Injury/drug therapy , Fomepizole/pharmacology , Acetylcysteine/administration & dosage , Animals , Antidotes/administration & dosage , Cell Proliferation/drug effects , Chemical and Drug Induced Liver Injury/etiology , Drug Overdose/drug therapy , Fomepizole/administration & dosage , Hepatocytes/drug effects , Hepatocytes/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Time Factors
19.
Expert Rev Clin Pharmacol ; 14(10): 1267-1278, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34187297

ABSTRACT

INTRODUCTION: Acetylcysteine is the standard treatment for preventing hepatotoxicity caused by acetaminophen overdose. Several novel approaches to the management of acetaminophen overdose have been suggested to improve patient safety by reducing adverse drug reactions and dosing errors. This article reviews these alternative treatment regimens and intends to offer a detailed assessment of the available options to assist providers in managing cases of acetaminophen overdose. AREAS COVERED: This review article covers observational and experimental studies that assessed the efficacy and safety of alternative intravenous acetylcysteine regimens for acetaminophen overdose. A literature search was conducted using PubMed, ProQuest, and Scopus to identify the studies, which included results through April 2021. The assessment of alternative regimens consists of a discussion on the limitations and benefits, barriers to implementation, and important considerations for each regimen. EXPERT OPINION: Several alternative regimens have been studied and implemented in various institutions. Many of these dosing regimens have supporting safety data but most lack robust data. A reduction in infusion-related side effects is an important outcome, but established efficacy, local poison center familiarity with the regimen, institutional resources, and patient-specific factors should be equally considered when deciding on implementing and using an alternative dosing strategy.


Subject(s)
Acetaminophen/poisoning , Acetylcysteine/administration & dosage , Antidotes/administration & dosage , Acetylcysteine/adverse effects , Administration, Intravenous , Analgesics, Non-Narcotic/poisoning , Antidotes/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/prevention & control , Drug Overdose/drug therapy , Humans
20.
Dtsch Med Wochenschr ; 146(12): 818-820, 2021 06.
Article in German | MEDLINE | ID: mdl-34130324

ABSTRACT

INTRODUCTION: Procalcitonin (PCT) is an established marker for bacterial infection. Elevation of PCT can occur due to various reasons and is not specific, as we outline in the following case report. HISTORY: We report on a 29 year old patient, who was presented by the psychiatric department because of obscure abdominal pain, nausea and vomiting since two days. Taking the patients history did not result in conclusive findings at first. FINDINGS AND DIAGNOSIS: The clinical examination did not result in conclusive findings. The patient was afebrile. Blood work showed an elevation of transaminases and a massive elevation of PCT. In ultrasound no abnormalities were shown, serological investigations for viral hepatitis were negative. Blood cultures remained sterile, the search for an infectious focus remained unremarkable. THERAPY AND COURSE: In the course of the in-patient stay the patient reported the ingestion of approximately 40 g of acetaminophen in suicidal intention two days before. Therapy with N-acetylcysteine (NAC) was initiated. The transaminases and PCT were regressive the next day. Antibiotic therapy was foregone. CONCLUSIONS: This case illustrates that PCT-elevation is not specific for a bacterial infection and must be seen in correlation to patient's history and clinical findings.


Subject(s)
Acetaminophen/poisoning , Poisoning , Procalcitonin/blood , Suicide, Attempted , Abdominal Pain/etiology , Acetylcysteine/therapeutic use , Adult , Diagnosis, Differential , Female , Humans , Nausea/etiology , Poisoning/diagnosis , Poisoning/drug therapy , Poisoning/psychology
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