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1.
Isr Med Assoc J ; 9(22): 481-485, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954693

RESUMO

BACKGROUND: Acetaminophen is the most common drug involved in pediatric poisonings, both intentionally and accidentally, and is the leading cause of acute liver failure among all age groups. OBJECTIVES: To define the characteristics of patients admitted to a pediatric emergency department (ED) where serum acetaminophen concentrations were measured, and to determine which variables are associated with significant risk of acetaminophen toxicity. METHODS: Acetaminophen serum concentrations were measured, in a retrospective case series, of patients younger than 18 years who had been admitted to the ED at Shamir Medical Center between 1 January 2008 and 31 December 2015. RESULTS: During the study period 180,174 children were admitted to the ED. Acetaminophen serum concentrations were measured in 209 (0.12%) patients. Mean age was 12.4 ± 5.9 years. Elevated liver enzymes were found in 12 patients, 5 of whom had documented acute liver injury. All five were older than 11years.Two cases of acute liver injury were attributable to acetaminophen ingestion. In both cases the cause was intentional overdose. Univariate analysis showed a significant (P < 0.05) correlation between detectable acetaminophen blood level and a positive history of drug or acetaminophen ingestion, and suicide attempt. Not all children with non-severe acetaminophen poisoning had been diagnosed during the study period. A positive history of acetaminophen ingestion was associated with a 28-fold higher risk for detectable acetaminophen blood level. CONCLUSIONS: In the absence of a positive history of acetaminophen ingestion and in young children with accidental intoxication, the risk of hepatotoxicity is relatively low.


Assuntos
Acetaminofen/envenenamento , Analgésicos não Entorpecentes/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Overdose de Drogas/epidemiologia , Serviço Hospitalar de Emergência , Acetaminofen/sangue , Adolescente , Analgésicos não Entorpecentes/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Israel , Masculino , Estudos Retrospectivos , Tentativa de Suicídio/estatística & dados numéricos
2.
Forensic Sci Int ; 310: 110258, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229318

RESUMO

Acetaminophen is the leading cause of acute liver failure worldwide following massive ingestion. We present here a fatal acute liver failure after repeated administration of four therapeutic doses of acetaminophen at 4-h intervals in a previously healthy 9-year-old female who presented dental pain after a facial trauma during sport practice. A diagnosis of paracetamol-induced hepatitis was deduced from the clinical picture of fulminant hepatitis and tubular necrosis, the encephalopathy with oedema and without signs of trauma. Liver biopsy showed typical acetaminophen-induced necrosis and a microvesicular steatosis in periportal hepatocytes. These injuries might have been favored by pre-existing mitochondrial dysfunction related, for instance, to a deficiency in an enzyme of the mitochondrial ß-oxidation pathway, or the respiratory chain. The observation of microvesicular steatosis in the periportal areas suggests an increased vulnerability via pre-existing mitochondrial dysfunction. As the liver status of patients is mostly unknown, the frequency of administration (every six hours) must be respected and the use of pharmaceutical forms allowing to adjust the dose as closely as possible to the child's weight should be promoted.


Assuntos
Acetaminofen/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/patologia , Criança , Diagnóstico Diferencial , Feminino , Patologia Legal , Humanos , Envenenamento/patologia
3.
Am J Case Rep ; 21: e919289, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32086430

RESUMO

BACKGROUND Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction of the outcome of the acetaminophen overdose are needed. Recently, using next-generation sequencing analysis of serum from human study participants we uncovered injury-specific signatures of circulating microRNAs (miRNAs) that represented underlying molecular mechanisms of toxicity. This case study is first to show the application of miRNA profiling to assess prognosis of acetaminophen poisoning. CASE REPORT The patient was admitted to the hospital following supra therapeutic acetaminophen ingestion. The patient showed elevated levels of biomarkers of hepatocellular injury alanine aminotransferase, aspartate transaminase, and glutamate dehydrogenase. Even though treatment with N-acetyl cysteine was initiated 24 hours post-ingestion, levels of alanine-aminotransferase and aspartate transaminase peaked at about 40 hours post ingestion of acetaminophen. We analyzed global circulating miRNA levels from 24 consecutive serum samples from this study participant covering the period from admission to time of death. CONCLUSIONS The resulting global miRNA profiles were compared with profiles from study participants with non-lethal acetaminophen poisoning and healthy controls. At the admission, the miRNA profiles of both lethal and non-lethal acetaminophen poisoning showed induction of cellular stress and oxidative damage. Later, the miRNA profiles of the lethal poisoning featured fibrosis and coagulation pathways while profiles of non-lethal cases resembled those of healthy study participants. Although additional confirmatory studies are needed, our case study is first to indicate that global miRNA profiles to be used as liquid biopsies have potential to facilitate the assessment of acetaminophen poisoning.


Assuntos
Acetaminofen/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/sangue , Overdose de Drogas/sangue , Biópsia Líquida , MicroRNAs/sangue , Adulto , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Overdose de Drogas/diagnóstico , Evolução Fatal , Feminino , Humanos
4.
Dtsch Med Wochenschr ; 145(3): 161-165, 2020 02.
Artigo em Alemão | MEDLINE | ID: mdl-32018289

RESUMO

While monitoring and symptomatic care is sufficient for most intoxicated patients, some develop life threatening symptoms. We present recent changes in the recommendations of the treatment in patients with calcium channel blocker, beta blocker and high dose paracetamol intoxications. Additionally, new insights in the efficacy and safety of the use of physostigmine in anticholinergic patients and beta blockers in cocaine intoxication are discussed as well as the specific considerations in the resuscitation of intoxicated patients.


Assuntos
Cuidados Críticos , Envenenamento/tratamento farmacológico , Acetaminofen/envenenamento , Antagonistas Adrenérgicos beta/envenenamento , Bloqueadores dos Canais de Cálcio/envenenamento , Carbono/uso terapêutico , Humanos , Fisostigmina/efeitos adversos , Fisostigmina/uso terapêutico
5.
Med J Aust ; 212(4): 175-183, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31786822

RESUMO

INTRODUCTION: Paracetamol is a common agent taken in deliberate self-poisoning and in accidental overdose in adults and children. Paracetamol poisoning is the commonest cause of severe acute liver injury. Since the publication of the previous guidelines in 2015, several studies have changed practice. A working group of experts in the area, with representation from all Poisons Information Centres of Australia and New Zealand, were brought together to produce an updated evidence-based guidance. MAIN RECOMMENDATIONS (UNCHANGED FROM PREVIOUS GUIDELINES): The optimal management of most patients with paracetamol overdose is usually straightforward. Patients who present early should be given activated charcoal. Patients at risk of hepatotoxicity should receive intravenous acetylcysteine. The paracetamol nomogram is used to assess the need for treatment in acute immediate release paracetamol ingestions with a known time of ingestion. Cases that require different management include modified release paracetamol overdoses, large or massive overdoses, accidental liquid ingestion in children, and repeated supratherapeutic ingestions. MAJOR CHANGES IN MANAGEMENT IN THE GUIDELINES: The new guidelines recommend a two-bag acetylcysteine infusion regimen (200 mg/kg over 4 h, then 100 mg/kg over 16 h). This has similar efficacy but significantly reduced adverse reactions compared with the previous three-bag regimen. Massive paracetamol overdoses that result in high paracetamol concentrations more than double the nomogram line should be managed with an increased dose of acetylcysteine. All potentially toxic modified release paracetamol ingestions (≥ 10 g or ≥ 200 mg/kg, whichever is less) should receive a full course of acetylcysteine. Patients ingesting ≥ 30 g or ≥ 500 mg/kg should receive increased doses of acetylcysteine.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Analgésicos não Entorpecentes/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Overdose de Drogas/terapia , Administração Intravenosa , Antídotos/uso terapêutico , Austrália , Carvão Vegetal/uso terapêutico , Humanos , Nova Zelândia , Guias de Prática Clínica como Assunto
6.
Biomed Pharmacother ; 123: 109783, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31855737

RESUMO

Acetaminophen (APAP) overdose has become the most common cause of drug-induced acute liver failure. Angiogenesis and redox homeostasis play an important role in liver protection and repair of APAP-induced acute liver injury (AILI). Hypoxia inducible factor-1 (HIF-1) is a transcription factor that plays a crucial role in regulating the expression of genes associated with angiogenesis, redox homeostasis and energy balance. Prolyl hydroxylase 2 (PHD2) predominantly hydroxylates proline residues in HIF-1α to promote its degradation. In our previous study, we reported an intrabody against PHD2 (ER-INP) that enhances angiogenesis by blocking PHD2 activity to increase HIF-1α abundance and activity. The present study was designed to explore the role and possible mechanisms of ER-INP in AILI in mice. Mice were pretreated intravenously with ER-INP before intraperitoneal injection of APAP to induce AILI. The results showed that pretreatment with ER-INP dramatically decreased the high ALT and AST activities and significantly ameliorated the centrilobular necrosis induced by APAP administration. ER-INP expression promoted angiogenesis in vivo by upregulating the mRNA and protein levels of HIF-1α target genes. Meanwhile, ER-INP pretreatment restored redox homeostasis, verified by reinforcement of PRDX4 activity and suppression of GSH depletion. This study demonstrated that ER-INP protects against AILI in part by increasing angiogenesis and maintaining redox homeostasis. These results indicate that ER-INP may provide a potential liver protection strategy against AILI in the future.


Assuntos
Acetaminofen/envenenamento , Anticorpos/imunologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Prolina Dioxigenases do Fator Induzível por Hipóxia/imunologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Células HEK293 , Homeostase/imunologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Fisiológica/imunologia , Oxirredução/efeitos dos fármacos , Células RAW 264.7
8.
Clin Toxicol (Phila) ; 58(1): 62-64, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050299

RESUMO

Introduction: Several reports describe high anion gap metabolic acidosis with 5-oxoproline (5-OP) after acetaminophen exposure, including therapeutic use of acetaminophen. The mechanism may involve disordered glutathione metabolism. It is unknown whether acute acetaminophen overdose consistently causes elevations in 5-oxoproline concentration.Methods: We enrolled 23 consecutive adult and adolescent patients with measureable plasma APAP after acute APAP overdose. We used plasma left over in the laboratory after blood tests obtained in clinical care of the patients. We measured plasma [5-OP] by GC/MS. We compared the [5-OP] to laboratory results obtained in the care of these patients to search for correlations. The study had IRB approval.Results: Eighteen patients had non-detectable or normal (<100 µmol/L) 5-oxoproline concentrations. Six more patients had concentrations between 100 µmol/L and 300 µmol/L. There was no significant correlation of 5-OP with APAP, AST, ALT, creatinine, anion gap, INR, or total bilirubin.Discussion: Limitations of the study include small sample size and treatment with IV N-acetylcysteine for all patients with APAP concentrations above the 150 line of the Rumack Matthew nomogram or with hepatotoxicity. We believe that inherited enzyme deficiencies more likely explain cases of 5-oxoprolinemia.Conclusion: Acetaminophen overdose generally results in normal 5-oxoproline concentrations with some patients having slightly elevated 5-oxoproline concentrations.


Assuntos
Acetaminofen/envenenamento , Overdose de Drogas/sangue , Ácido Pirrolidonocarboxílico/sangue , Acetaminofen/sangue , Acetaminofen/metabolismo , Adolescente , Adulto , Idoso , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Pessoa de Meia-Idade , Adulto Jovem
9.
Daru ; 27(2): 839-851, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713183

RESUMO

PURPOSE: Acetaminophen (Paracetamol, APAP) poisoning is frequently implicated in self-harm. Cases of acetaminophen-associated cardiotoxicity are rare in relation to the number of patients with acetaminophen poisoning. A review of acetaminophen cardiotoxicity in 1996 concluded that there was no decisive evidence demonstrating that acetaminophen overdose has a cardiotoxic effect. This review study aimed to determine whether acetaminophen could induce heart injury. METHODS: We searched for keywords of acetaminophen, paracetamol, cardiotoxicity, heart injury, heart damage, myocarditis, pericarditis, myocardial infarction, and myocardial ischemia in Web of Science, PubMed, Scopus, Embase, Google Scholar, and Persian databases. The search included articles published from January 1950 to October 2018 with no language restrictions. RESULTS: The search yielded 64 citations in English; 36 of the articles were excluded as they were not relevant; 5 articles were excluded since they were duplicates, leaving 23 articles. Full-text articles of the 23 citations were obtained and reviewed. Myocardial infarction, heart dysfunction and failure, cardiac arrhythmias, pericarditis, heart cell necrosis, and sudden cardiac death were reported in acetaminophen overdose. CONCLUSIONS: Ddysrhythmias, heart failure, and various other cardiac effects could occur following acetaminophen induced hepatic failure. However, the evidence for direct injury on cardiac tissue is weak. Graphical abstract Potential mechanisms for cardiotoxicity of acetaminophen.


Assuntos
Acetaminofen/envenenamento , Traumatismos Cardíacos/epidemiologia , Overdose de Drogas/complicações , Feminino , Traumatismos Cardíacos/induzido quimicamente , Humanos , Masculino
10.
Lakartidningen ; 1162019 Nov 01.
Artigo em Sueco | MEDLINE | ID: mdl-31688944

RESUMO

Since the late 1970s N-acetylcystein has been used as an antidote after paracetamol intoxication. The treatment is traditionally given as three consecutive infusions for 20 hours and 15 minutes. The total dose given is 300 mg/kg. Half of this amount is given as a bolus during the first 15 minutes of treatment.  This regime has proven very efficient in avoiding liver injury. However, side effects, caused by histamine release, are common (10-15%). Symptoms as flush, urticaria and, in rare cases, bronchospasm, angioedema and circulatory shock typically appear during the bolus dose and may lead to interrupted and inadequate treatment. In addition, the regime is complicated leading to a risk of administration errors. During the last years several publications have described the use of a model with two infusions instead of three. The first and the second infusions are merged and given over four hours. The third infusion and the total dose are left unchanged. This modified regime has been shown to reduce side effects and seems not to increase the risk of liver injury. As of November 1, 2019, the Swedish Poisons Information Centre will change its recommendations to the new two-infusion protocol.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Antídotos/administração & dosagem , Overdose de Drogas/tratamento farmacológico , Envenenamento/tratamento farmacológico , Acetilcisteína/efeitos adversos , Acetilcisteína/uso terapêutico , Administração Intravenosa , Antídotos/efeitos adversos , Antídotos/uso terapêutico , Humanos , Centros de Controle de Intoxicações , Guias de Prática Clínica como Assunto
11.
Lancet ; 394(10201): 869-881, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31498101

RESUMO

Acute liver failure is a rare and severe consequence of abrupt hepatocyte injury, and can evolve over days or weeks to a lethal outcome. A variety of insults to liver cells result in a consistent pattern of rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation. The absence of existing liver disease distinguishes acute liver failure from decompensated cirrhosis or acute-on-chronic liver failure. Causes of acute liver failure include paracetamol toxicity, hepatic ischaemia, viral and autoimmune hepatitis, and drug-induced liver injury from prescription drugs, and herbal and dietary supplements. Diagnosis requires careful review of medications taken, and serological testing for possible viral exposure. Because of its rarity, acute liver failure has not been studied in large, randomised trials, and most treatment recommendations represent expert opinion. Improvements in management have resulted in lower mortality, although liver transplantation, used in nearly 30% of patients with acute liver failure, still provides a life-saving alternative to medical management.


Assuntos
Insuficiência Hepática Crônica Agudizada/etiologia , Acetaminofen/envenenamento , Insuficiência Hepática Crônica Agudizada/fisiopatologia , Insuficiência Hepática Crônica Agudizada/terapia , Adulto , Doença Hepática Crônica Induzida por Substâncias e Drogas/complicações , Feminino , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade
12.
Med J Aust ; 211(5): 218-223, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31389025

RESUMO

OBJECTIVES: To assess the numbers of paracetamol overdose-related hospital admissions and deaths in Australia since 2007-08, and the overdose size of intentional paracetamol overdoses since 2004. DESIGN, SETTING: Retrospective analysis of data on paracetamol-related exposures, hospital admissions, and deaths from the Australian Institute of Health and Welfare National Hospital Morbidity Database (NHMD; 2007-08 to 2016-17), the New South Wales Poisons Information Centre (NSWPIC; 2004-2017), and the National Coronial Information System (NCIS; 2007-08 to 2016-17). PARTICIPANTS: People who took overdoses of paracetamol in single ingredient preparations. MAIN OUTCOME MEASURES: Annual numbers of reported paracetamol-related poisonings, hospital admissions, and deaths; number of tablets taken in overdoses. RESULTS: The NHMD included 95 668 admissions with paracetamol poisoning diagnoses (2007-08 to 2016-17); the annual number of cases increased by 44.3% during the study period (3.8% per year; 95% CI, 3.2-4.6%). Toxic liver disease was documented for 1816 of these patients; the annual number increased by 108% during the study period (7.7% per year; 95% CI, 6.0-9.5%). The NSWPIC database included 22 997 reports of intentional overdose with paracetamol (2004-2017); the annual number increased by 77.0% during the study period (3.3% per year; 95% CI, 2.5-4.2%). The median number of tablets taken increased from 15 (IQR, 10-24) in 2004 to 20 (IQR, 10-35) in 2017. Modified release paracetamol ingestion report numbers increased 38% between 2004 and 2017 (95% CI, 30-47%). 126 in-hospital deaths were recorded in the NHMD, and 205 deaths (in-hospital and out of hospital) in the NCIS, with no temporal trends. CONCLUSIONS: The frequency of paracetamol overdose-related hospital admissions has increased in Australia since 2004, and the rise is associated with greater numbers of liver injury diagnoses. Overdose size and the proportion of overdoses involving modified release paracetamol have each also increased.


Assuntos
Acetaminofen/envenenamento , Analgésicos não Entorpecentes/envenenamento , Centros de Controle de Intoxicações/estatística & dados numéricos , Envenenamento/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Medicamentos sem Prescrição , Estudos Retrospectivos , Adulto Jovem
13.
Lakartidningen ; 1162019 Jul 29.
Artigo em Sueco | MEDLINE | ID: mdl-31361324

RESUMO

Toxicological analysis is an important part of the acute treatment of various intoxications. Rapid laboratory responses are important for the patient to be assessed and treated correctly, and also to exclude poisoning and thus avoid unjustified and costly overtreatment. In Sweden, paracetamol (acetaminophen) is one of the most common pharmaceuticals in drug poisoning. Paracetamol overdose can cause severe liver damage unless treated early with the antidote acetylcysteine. A nation-wide initiative for improved laboratory measurement of paracetamol in plasma/serum samples has resulted in a marked reduction in the inter-laboratory coefficient of variation to generally below 10%. The introduction of a harmonized national reporting range for plasma/serum paracetamol covering at least 50-5 000 µmol/l was also recommended. This initiative will hopefully contribute to better healthcare from both a patient and health resource perspective in cases of paracetamol poisoning.


Assuntos
Acetaminofen , Analgésicos não Entorpecentes , Serviços de Laboratório Clínico/normas , Acetaminofen/sangue , Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Analgésicos não Entorpecentes/sangue , Analgésicos não Entorpecentes/envenenamento , Antídotos/administração & dosagem , Antídotos/uso terapêutico , Overdose de Drogas/diagnóstico , Overdose de Drogas/tratamento farmacológico , Humanos , Envenenamento/diagnóstico , Envenenamento/tratamento farmacológico , Guias de Prática Clínica como Assunto , Suécia , Fatores de Tempo
14.
Ann Glob Health ; 85(1)2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31298824

RESUMO

BACKGROUND: The dearth of information on the economic cost of childhood poisoning in sub-Saharan Africa necessitated this study. OBJECTIVE: This study has investigated the prevalence of childhood drug and non-drug poisoning, treatment modalities and economic costs in Nigeria. METHOD: A retrospective study of childhood drug and non-drug poisoning cases from January 2007 to June 2014 in the University of Port Harcourt Teaching Hospital (UPTH), Port Harcourt, Nigeria was carried out. Medical records were analysed for demographic and aetiological characteristics of poisoned children (0-14 years of age), as well as fiscal impact of poisoning cases. FINDINGS: Of the 100 poisoned patients, 46% were male and 54% female, with female/male ratio of 1.17:1. Most of the children were under five years of age. Paracetamol, amitriptyline, chlorpromazine, ferrous sulphate, kerosene, organophosphates, carbon monoxide, snake bite, alcohol and rodenticides were involved in the poisoning. The average cost of poison management per patient was about $168, which is high given the economic status of Nigeria. CONCLUSION: Childhood poisoning is still a significant cause of morbidity among children in Nigeria and accounts for an appreciable amount of health spending, therefore preventive strategies should be considered.


Assuntos
Etanol/envenenamento , Custos de Cuidados de Saúde , Envenenamento/economia , Envenenamento/epidemiologia , Mordeduras de Serpentes/epidemiologia , Acetaminofen/envenenamento , Adolescente , Distribuição por Idade , Amitriptilina/envenenamento , Analgésicos não Entorpecentes/envenenamento , Antipsicóticos/envenenamento , Intoxicação por Monóxido de Carbono/economia , Intoxicação por Monóxido de Carbono/epidemiologia , Criança , Pré-Escolar , Clorpromazina/envenenamento , Feminino , Compostos Ferrosos/envenenamento , Humanos , Lactente , Recém-Nascido , Querosene/envenenamento , Tempo de Internação , Masculino , Nigéria/epidemiologia , Intoxicação por Organofosfatos/economia , Intoxicação por Organofosfatos/epidemiologia , Envenenamento/etiologia , Prevalência , Estudos Retrospectivos , Rodenticidas/envenenamento , Distribuição por Sexo , Mordeduras de Serpentes/economia
15.
Medicina (Kaunas) ; 55(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117289

RESUMO

Background and objectives: Ascorbic acid, alpha lipoic acid (ALA) and silymarin are well-known antioxidants that have hepatoprotective effects. This study aims to investigate the effects of these three compounds combined with attenuating drug-induced oxidative stress and cellular damage, taking acetaminophen (APAP)-induced toxicity in rats as a model both in vivo and in vitro. Materials and Methods: Freshly cultured primary rat hepatocytes were treated with ascorbic acid, ALA, silymarin and their combination, both with and without the addition of APAP to evaluate their in vitro impact on cell proliferation and mitochondrial activity. In vivo study was performed on rats supplemented with the test compounds or their combination for one week followed by two toxic doses of APAP. Results: Selected liver function tests and oxidative stress markers including superoxide dismutase (SOD), malondialdehyde (MDA) and oxidized glutathione (GSSG) were detected. The in vivo results showed that all three pretreatment compounds and their combination prevented elevation of SOD and GSSG serum levels indicating a diminished burden of oxidative stress. Moreover, ascorbic acid, ALA and silymarin in combination reduced serum levels of liver enzymes; however, silymarin markedly maintained levels of all parameters to normal ranges. Silymarin either alone or combined with ascorbic acid and ALA protected cultured rat hepatocytes and increased cellular metabolic activity. The subjected agents were capable of significantly inhibiting the presence of oxidative stress induced by APAP toxicity and the best result for protection was seen with the use of silymarin. Conclusions: The measured liver function tests may suggest an augmented hepatoprotection of the combination preparation than when compared individually.


Assuntos
Acetaminofen/efeitos adversos , Ácido Ascórbico/farmacocinética , Fatores de Proteção , Silimarina/farmacocinética , Ácido Tióctico/farmacocinética , Acetaminofen/envenenamento , Animais , Ácido Ascórbico/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/complicações , Modelos Animais de Doenças , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Silimarina/uso terapêutico , Ácido Tióctico/uso terapêutico
16.
Ugeskr Laeger ; 181(21)2019 May 20.
Artigo em Dinamarquês | MEDLINE | ID: mdl-31124443

RESUMO

In this case report, a 19-year-old woman was admitted with delayed acute renal failure due to a paracetamol intake of 7 g. No liver damage was present, and the renal function recovered spontaneously after a few weeks. Paracetamol is the most common cause of medical induced overdose or death. It is well known, that poisoning from paracetamol may cause liver damage, but the risk of renal toxicity is known to a lesser extent. Acute renal failure due to paracetamol overdose may easily be missed due to the delayed manifestation.


Assuntos
Acetaminofen , Lesão Renal Aguda , Analgésicos não Entorpecentes , Overdose de Drogas , Hepatopatias , Acetaminofen/envenenamento , Lesão Renal Aguda/induzido quimicamente , Analgésicos não Entorpecentes/envenenamento , Feminino , Hospitalização , Humanos , Adulto Jovem
17.
BMJ Case Rep ; 12(4)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30954964

RESUMO

An 84-year-old woman presented to hospital with severe clinical and metabolic sequelaesequelae of a massive paracetamol overdose (concentration=822 mg/L). In spite of N-acetylcysteine therapy, she deteriorated with evidence of mitochondrial dysfunction. Although the EXtracorporeal TReatments In Poisoning group recommend adjunct haemodialysis (HD) in such a context, this was difficult to start due to haemodynamic instability. Instead, a trial of continuous venovenous haemodiafiltration (CVVHDF) was initiated in an attempt to restore normal mitochondrial function, normal pH and to actively remove the offending drug. Fortunately, plasma paracetamol levels fell exponentially over the subsequent 24-48 hours without the need to commence HD. The patient made a full recovery and was later discharged from the hospital. This case highlights that CVVHDF can be a reasonable alternative to HD for managing massive paracetamol overdoses in the context of mitochondrial dysfunction.


Assuntos
Acetaminofen/envenenamento , Analgésicos não Entorpecentes/envenenamento , Overdose de Drogas/terapia , Hemodiafiltração , Acetilcisteína/administração & dosagem , Idoso de 80 Anos ou mais , Antídotos/administração & dosagem , Overdose de Drogas/fisiopatologia , Feminino , Humanos , Tentativa de Suicídio , Resultado do Tratamento
18.
Hum Exp Toxicol ; 38(6): 646-654, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30838890

RESUMO

Paracetamol overdose is common and microRNA (miR)-122 expression is increased with liver injury. We aimed to measure miR-122 in the setting of an abbreviated paracetamol overdose treatment regimen. We compared miRNA expression in patients treated for paracetamol poisoning with an abbreviated 12-h intravenous acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) or a 20-h regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) (NACSTOP trial). miR-122 expression is increased (decreased cycle threshold (Ct) values) with paracetamol liver injury. We assessed miR-122 expression in patients receiving the two acetylcysteine regimens and in a separate group with acute liver injury (ALI). We examined 121 blood samples in 38 patients. After 20 h of acetylcysteine, median alanine transaminase (ALT) was 12 U/L (18, 14) versus 16 U/L (11, 21) ( p = 0.17) and median miR-122 Ct was 30.1 (interquartile range (IQR): 28.9, 33.3) versus 31.4 (28.9, 33.9) ( p = 0.7) in the NACSTOP abbreviated and control groups, respectively. Median normalized miR-122 Ct after 20 h of acetylcysteine was 2.2 (IQR 1.9, 6.4), 1.1 (0.7, 2.9), 63.9 (2.5, 168), 123.2 (40.9, 207.8) in the NACSTOP-abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was no significant difference in ALT or miRNA between NACSTOP treatment groups and no signal of increased liver injury from an abbreviated 12-h acetylcysteine regimen. These findings suggest that an abbreviated acetylcysteine regimen in low-risk patients who have overdosed on paracetamol is safe. Further study is required to validate this finding utilizing miRNA as a comparative biomarker.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Analgésicos não Entorpecentes/envenenamento , Overdose de Drogas/tratamento farmacológico , MicroRNAs , Adolescente , Adulto , Overdose de Drogas/genética , Feminino , Humanos , Infusões Intravenosas , Masculino , Adulto Jovem
19.
Semin Liver Dis ; 39(2): 221-234, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30849782

RESUMO

Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.


Assuntos
Acetaminofen , Analgésicos não Entorpecentes , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Acetaminofen/farmacocinética , Acetaminofen/envenenamento , Analgésicos não Entorpecentes/farmacocinética , Analgésicos não Entorpecentes/envenenamento , Animais , Apoptose/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos
20.
Biotech Histochem ; 94(5): 313-319, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30777790

RESUMO

Exposure to high doses of acetaminophen is the most common cause of drug induced liver injury. We investigated the protective effects of Hedera helix extract against acetaminophen induced oxidative stress and hepatotoxicity using a mouse model. We used two control groups: group A was given 0.9% NaCl, group B was an acetaminophen control that was given a single injection of 600 mg/kg acetaminophen. T1-T4 groups were pretreated orally with different doses of H. helix extract. The mice were sacrificed and blood samples were collected to estimate the levels of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) and total bilirubin. Liver samples also were used for histopathological studies. We found that acetaminophen significantly increased the levels of serum ALP, ALT, AST and MDA, and also significantly reduced the antioxidant factors, CAT, GPX and SOD. H. helix extract treatment produced a significant reduction in the levels of ALP, ALT, AST and MDA in serum and restored the levels of CAT, GPX and SOD to control levels. The histopathological findings were consistent with the biochemical findings. H. helix extract exhibited antioxidant and hepatoprotective effects against acetaminophen induced liver damage.


Assuntos
Acetaminofen/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hedera , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Acetaminofen/envenenamento , Alanina Transaminase/metabolismo , Animais , Antioxidantes/uso terapêutico , Aspartato Aminotransferases/metabolismo , Antagonismo de Drogas , Glutationa Peroxidase/metabolismo , Interações Ervas-Drogas , Fígado/enzimologia , Fígado/fisiopatologia , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Superóxido Dismutase/metabolismo
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