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2.
Biol Pharm Bull ; 45(5): 596-604, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35491165

RESUMO

Drug-induced liver injury (DILI) occurs frequently worldwide. Acetaminophen (APAP) is a common drug causing DILI. Current treatment methods are difficult to achieve satisfactory results. Therefore, there is an urgent need to provide safe and effective treatment for patients. Schizandrin B (Sch B), the main component of Schisandra, has a protective effect on liver. However, the potential mechanism of Sch B in the treatment of APAP induced liver injury has not been elucidated to date. In our research, we studied the effect of Sch B on protecting damaged liver cells and explored the potential mechanism underlying its ability to reduce APAP liver injury. We found that Sch B could reduce hepatocyte apoptosis, oxidative stress injury and inflammatory response. These effects were positively correlated with the dose of Sch B. Sch B regulated glucose 6-phosphate dehydrogenase expression by upregulating the expression of p21-activated kinase 4 and polo-like kinase 1. Sch B could inhibit the mitogen-activated protein kinase (MAPK)-c-Jun N-terminal kinase (JNK)-extracellular signal-regulated kinase (ERK) signaling pathway and regulate the expression of apoptosis-related proteins to reduce the incidence of cell apoptosis. In addition, Sch B reduced the expression levels of reactive oxygen species and inflammatory cytokines in hepatocyte. Consequently, we described for the first time that Sch B could not only activate the pentose phosphate pathway but also inhibit the MAPK-JNK-ERK signaling pathway, thereby achieving antioxidative and anti-inflammatory effects and inhibiting hepatocyte apoptosis. These findings indicated the potential use of Sch B in curing liver damage induced by APAP.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/efeitos adversos , Proteínas Reguladoras de Apoptose , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ciclo-Octanos , Hepatócitos , Humanos , Lignanas , Quinases de Proteína Quinase Ativadas por Mitógeno , Compostos Policíclicos
3.
BMJ Open Gastroenterol ; 9(1)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35473828

RESUMO

OBJECTIVE: Persistent cholestasis may follow acute liver failure (ALF), but its course remains unknown. We aimed to describe the prevalence, onset, severity, duration and resolution of post-ALF cholestasis. DESIGN: Cohort of 127 adult patients with ALF at a liver transplantation centre identified using electronic databases. We obtained laboratory data every 6 hours for the first week, daily until day 30 and weekly, when documented, until day 180. RESULTS: Median age was 40.7 (IQR 31.0-52.4) years, median peak alanine aminotransferase level was 5494 (2521-8819) U/L and 87 (68.5%) cases had paracetamol toxicity. Overall, 12.6% underwent transplantation (3.4% for paracetamol vs 32.5% for non-paracetamol; p<0.001). Ninety-day mortality was 20.7% for paracetamol versus 30.0% for non-paracetamol patients. All non-transplanted survivors reached a bilirubin level>50 µmol/L, which peaked 3.5 (1.0-10.1) days after admission at 169.0 (80.0-302.0) µmol/L. At hospital discharge, 18.8% of patients had normal bilirubin levels and, at a median follow-up time from admission to last measurement of 16 (10-30) days, 46.9% had normal levels. Similarly, there was an increase in alkaline phosphatase (ALP) (207.0 (148.0-292.5) U/L) and gamma-glutamyl transferase (GGT) (336.0 (209.5-554.5) U/L) peaking at 4.5 days, with normalised values in 40.3% and 8.3% at hospital discharge. CONCLUSION: Post-ALF cholestasis is ubiquitous. Bilirubin, ALP and GGT peak at 3 to 5 days and, return to baseline in the minority of patients at median follow-up of 16 days. These data inform clinical expectations of the natural course of this condition.


Assuntos
Colestase , Falência Hepática Aguda , Acetaminofen/efeitos adversos , Adulto , Fosfatase Alcalina , Bilirrubina , Colestase/epidemiologia , Humanos , Falência Hepática Aguda/epidemiologia , Prevalência , gama-Glutamiltransferase
4.
Sci Rep ; 12(1): 6413, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440611

RESUMO

Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been presented as a broad-spectrum antiviral agent. This randomised clinical trial in a hospital setting evaluated the efficacy and safety of this drug in RT-PCR-positive coronavirus disease 2019 (COVID-19) patients. A total of 210 RT-PCR-positive COVID-19 patients who provided consent were allotted to the control or case arm, based on block randomisation. The control arm received standard of care comprising paracetamol, ivermectin, and other adjuvant therapies. The patients in the case arm received indomethacin instead of paracetamol, with other medications retained. The primary endpoint was the development of hypoxia/desaturation with SpO2 ≤ 93, while time to become afebrile and time for cough and myalgia resolution were the secondary endpoints. The results of 210 patients were available, with 103 and 107 patients in the indomethacin and paracetamol arms, respectively. We monitored patient profiles along with everyday clinical parameters. In addition, blood chemistry at the time of admission and discharge was assessed. As no one in either of the arms required high-flow oxygen, desaturation with a SpO2 level of 93 and below was the vital goal. In the indomethacin group, none of the 103 patients developed desaturation. On the other hand, 20 of the 107 patients in the paracetamol arm developed desaturation. Patients who received indomethacin also experienced more rapid symptomatic relief than those in the paracetamol arm, with most symptoms disappearing in half the time. In addition, 56 out of 107 in the paracetamol arm had fever on the seventh day, while no patient in the indomethacin group had fever. Neither arm reported any adverse event. The fourteenth-day follow-up revealed that the paracetamol arm patients had faced several discomforts; indomethacin arm patients mostly complained only of tiredness. Indomethacin is a safe and effective drug for treating patients with mild and moderate covid-19.


Assuntos
COVID-19 , Acetaminofen/efeitos adversos , COVID-19/tratamento farmacológico , Humanos , Indometacina/efeitos adversos , SARS-CoV-2 , Resultado do Tratamento
5.
PLoS One ; 17(4): e0267270, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35436308

RESUMO

BACKGROUND: Paracetamol is widely used to manage fever and pain during pregnancy worldwide. However, paracetamol may affect the pregnant woman and fetus, once this drug crosses the placental barrier after therapeutic doses and may impair fetal liver function, affecting fetus growth and development. Thus, this study aimed to investigate the association between paracetamol use during pregnancy and perinatal outcomes as preterm birth, low birth weight, and small for gestational age. METHODS AND FINDINGS: Data from 760 pregnant women within the NISAMI Cohort between June 2012 and February 2014 were analyzed. Logistic regression was used to estimate the association among paracetamol use during pregnancy and preterm birth, low birth weight, and small for gestational age. Multivariate analyses were adjusted for socioeconomic, maternal, pregnancy, and newborn covariates. Around 14% of women were exposed to paracetamol during pregnancy. A decrease in paracetamol use throughout pregnancy was observed. Lower risk of low birth weight in infants born to women exposed to the drug (OR 0.21; IC 95% 0.01-0.99) was found. Paracetamol use during pregnancy was not statistically associated with preterm birth or small for gestational age. CONCLUSIONS: The findings of this study do not suggest an increased risk of perinatal outcomes. However, it should not be assumed that paracetamol is a risk-free medication and its use must be rational.


Assuntos
Acetaminofen , Nascimento Prematuro , Acetaminofen/efeitos adversos , Feminino , Retardo do Crescimento Fetal , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Placenta , Gravidez , Resultado da Gravidez , Nascimento Prematuro/induzido quimicamente , Estudos Prospectivos
6.
Respir Res ; 23(1): 80, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35382818

RESUMO

BACKGROUND: In elderly populations, paracetamol may be used regularly for conditions such as osteoarthritis. Paracetamol has been associated with respiratory disease through a proposed mechanism of glutathione depletion and oxidative stress. Given that chronic obstructive pulmonary disease (COPD) is frequently co-morbid with osteoarthritis, this study investigated whether the dose and timing of paracetamol exposure may induce COPD exacerbations. METHODS: The study population was 3523 Australian Government Department of Veterans' Affairs full entitlement holders who had existing COPD on 1 January 2011, who were dispensed at least one prescription of paracetamol between 1 January 2011 and 30 September 2015, and had no paracetamol dispensed in the 6 months prior to 1 January 2011. The outcome was time to first hospitalisation for COPD exacerbation after initiation of paracetamol. A weighted cumulative exposure approach was used. RESULTS: The association between paracetamol exposure and COPD exacerbation was protective or harmful depending on the dose, duration, and recency of exposure. Compared to non-use, current use at the maximum dose of 4 g daily for 7 days was associated with a lower risk (HR = 0.78, 95% CI = 0.67-0.92) and a higher risk after 30 days (HR = 1.27, 95% CI = 1.06-1.52). Risk declined to baseline after 2 months. For past use, there was a short-term increase in risk on discontinuation depending of dose, duration and time since stopping. CONCLUSIONS: Patients and doctors should be aware of the possible risk of COPD exacerbation with higher dose paracetamol 1 to 6 weeks after initiation or discontinuation, but no increased risk after 2 months.


Assuntos
Acetaminofen , Doença Pulmonar Obstrutiva Crônica , Acetaminofen/efeitos adversos , Idoso , Austrália/epidemiologia , Estudos de Coortes , Progressão da Doença , Humanos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
7.
BMC Palliat Care ; 21(1): 42, 2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35346136

RESUMO

INTRODUCTION: Subcutaneous infusion (SC) or hypodermoclysis is an old perfusion technique that is often used off-label although it has been shown to be effective. Acetaminophen (paracetamol) subcutaneous injection is performed in some centers despite the lack of conclusive evidence on its effectiveness. This study aims to evaluate the efficacy of subcutaneous infusion of Acetaminophen in the treatment of pain and fever in geriatrics and in palliative care and to determine its safety profile and possible side effects. MATERIAL AND METHODS: This experimental study was conducted between 2018 and 2019 on adult patients in palliative care or in geriatrics in several hospitals and nursing homes in Lebanon. Primary outcomes were change in temperature; change in pain score on the numerical rating scale (NS) or on the Algoplus scale after 60 min from the start of the infusion; and the appearance of local side effects at the infusion site. Changes in the various parameters at 30 min and 180 min were also evaluated as secondary outcomes. RESULTS: Thirty-one patients were included in the study, with a total of 120 doses of acetaminophen. At 60 min, the mean decrease in pain on the NS was 5.35 points, while the mean decrease in temperature was 0.79 degrees Celsius. At 60 min, 75%, CI = [47.62-92.73] of the patients who received acetaminophen for pain and 66.67%, CI = [38.38-88.17] of those who received it for fever had clinically significant improvement. The overall effect of subcutaneous acetaminophen, defined as any clinically significant effect on pain or fever, was 70.97%, CI = [51.96-85.78]. The overall effect at 30 min and at 180 min was 23.33%, CI = [9.93-42.28] and 87.10%, CI = [70.17-96.37], respectively. The side effects reported 30 min after the injection and observed after at least one of the doses were: local edema in 16 patients (51.61%), induration in one patient (3.23%), local pain in one patient (3.23%) and local heat in one patient (3.23%). At 180 min, only 2 patients (6.45%) still had edema at the infusion site. CONCLUSION: Subcutaneous administration of acetaminophen is effective and well tolerated in geriatric and palliative care patients. It is appropriate when no other route is available, especially for home-based care. Comparative studies are needed to allow the expansion of this practice.


Assuntos
Analgésicos não Narcóticos , Geriatria , Acetaminofen/efeitos adversos , Adulto , Idoso , Analgésicos não Narcóticos/efeitos adversos , Analgésicos não Narcóticos/uso terapêutico , Humanos , Medição da Dor , Cuidados Paliativos
8.
Int J Mol Med ; 49(5)2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35302173

RESUMO

As the current clinical treatment of acetaminophen (APAP)­induced liver injury (AILI) has its limitations, new and effective treatment methods are required. Fingolimod (FTY720) is an immunosuppressive drug developed in recent years that has been shown to have a protective effect against ischemia/reperfusion liver injury. However, the role of FTY720 in AILI remains unclear. The aim of the present study was to determine whether FTY720 has a protective effect on AILI. AILI was induced using intraperitoneal injection of 300 mg/kg APAP in male C57BL/6J mice. Following APAP challenge, the mice were administered 5 mg/kg FTY720 for 30 min. Protein expression levels were measured using western blot analysis. Cell viability was examined using Cell Counting Kit­8 assays. mRNA levels were measured using reverse transcription­quantitative PCR. Inflammation levels were evaluated using immunohistochemistry. Cell death and reactive oxygen species levels were examined using immunofluorescence. Furthermore, laser scanning intravital microscopy was used to directly observe immune cell recruitment. APAP treatment increased the serum levels of alanine transaminase and aspartate transaminase at the 6­ and 12­h time­points, suggesting liver tissue damage. However, FTY720 attenuated the liver injury induced by APAP by reducing the recruitment of immune cells and the release of pro­inflammatory cytokines and chemokines. FTY720 activated JAK2/STAT3 signaling and regulated the expression of BAX, BCL­2 and p65 to inhibit apoptosis and inflammation. In addition, compared with APAP treatment, the viability of primary hepatocytes treated with APAP and FTY720 was increased. Inhibition of JAK2/STAT3 signaling attenuated the protective, antioxidant effects of FTY720. In conclusion, FTY720 reduced liver injury by regulating the JAK2/STAT3 signaling pathway. This compound was capable of inhibiting oxidative stress to reduce hepatocyte death and the infiltration of neutrophils in the liver.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/efeitos adversos , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
9.
Curr Med Res Opin ; 38(5): 811-825, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35253560

RESUMO

Acute pain is among the most common reasons that people consult primary care physicians, who must weigh benefits versus risks of analgesics use for each patient. Paracetamol (acetaminophen) is a first-choice analgesic for many adults with mild to moderate acute pain, is generally well tolerated at recommended doses (≤4 g/day) in healthy adults and may be preferable to non-steroidal anti-inflammatory drugs that are associated with undesirable gastrointestinal, renal, and cardiovascular effects. Although paracetamol is widely used, many patients and physicians still have questions about its suitability and dosing, especially for older people or adults with underlying comorbidities, for whom there are limited clinical data or evidence-based guidelines. Inappropriate use may increase the risks of both overdosing and inadequate analgesia. To address knowledge deficits and augment existing guidance in salient areas of uncertainty, we have researched, reviewed, and collated published evidence and expert opinion relevant to the acute use of paracetamol by adults with liver, kidney, or cardiovascular diseases, gastrointestinal disorders, asthma, or/and who are older. A concern is hepatotoxicity, but this is rare among adults who use paracetamol as directed, including people with cirrhotic liver disease. Putative epidemiologic associations of paracetamol use with kidney or cardiovascular disease, hypertension, gastrointestinal disorders, and asthma largely reflect confounding biases and are of doubtful relevance to short-term use (<14 days). Paracetamol is a suitable first-line analgesic for mild to moderate acute pain in many adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, and/or who are older. No evidence supports routine dose reduction for older people. Rather, dosing for adults who are older and/or have decompensated cirrhosis, advanced kidney failure, or analgesic-induced asthma that is known to be cross-sensitive to paracetamol, should be individualized in consultation with their physician, who may recommend a lower effective dose appropriate to the circumstances.


Assuntos
Dor Aguda , Analgésicos não Narcóticos , Asma , Doenças Cardiovasculares , Gastroenteropatias , Acetaminofen/efeitos adversos , Dor Aguda/tratamento farmacológico , Adulto , Idoso , Analgésicos , Analgésicos não Narcóticos/efeitos adversos , Asma/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/tratamento farmacológico , Humanos , Rim , Fígado
10.
Biochem Biophys Res Commun ; 602: 105-112, 2022 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-35259588

RESUMO

Amygdalin is a natural compound from Bitter Apricot Seed which is reported to have anti-inflammatory activity. Acetaminophen (APAP) resulted in drug-induced liver injury is the main cause of acute liver failure (ALI) worldwide and only N-acetylcysteine is the accepted detoxification drug. However, there is no effective medicine to perfect the hepatocyte death and secondary inflammation injury. In this study, we aim to investigate the protective effect of Amygdalin in the APAP-induced acute liver failure mice model. We establish the ALI model via intraperitoneal APAP injection and mice were treated with Amygdalin with intraperitoneal injection. We detected liver enzyme and histological change to evaluate the liver injury. We measured oxidative damage markers and inflammatory cell infiltration of liver tissues. At last, we investigated the mechanism of Amygdalin on protecting hepatocytes. Results showed that Amygdalin reduced ALT/AST level and decreased necrotic area of liver tissue. In addition, Amygdalin reduced the count of MPO+(neutrophils) and F4/80+(macrophages) of the liver and inhibited IL-6, TNF-a, and IL-1b expression. Amygdalin reduced liver SOD and MDA levels and increased Nrf2/NQO1/HO1 protein expression. Moreover, Amygdalin reduced TUNEL+ and P-MLKL + staining cells in liver tissue. Mechanically, Amygdalin promoted phosphorylation of AKT and suppressed JNK/RIP3/MLKL signaling.


Assuntos
Amigdalina , Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Acetaminofen/efeitos adversos , Amigdalina/metabolismo , Amigdalina/farmacologia , Amigdalina/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/prevenção & controle , Camundongos , Estresse Oxidativo
11.
PLoS One ; 17(3): e0264440, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35271621

RESUMO

INTRODUCTION: Dipyrone (metamizol) is regularly used in critical care for pain and fever treatment, especially in Germany and Spain. However, indication for antipyretic therapy in critically ill patients is currently unclear and data for both the risk and benefit of dipyrone treatment in the intensive care environment are scarce. We hypothesized that antipyretic efficiency of dipyrone would not exceed antipyretic efficiency of acetaminophen. We therefore aimed to compare temperature courses in critically ill patients receiving either intravenous dipyrone, acetaminophen or no antipyretic medication. MATERIAL AND METHODS: We included 937 intensive care unit (ICU) patients with body temperature recordings of at least 37.5°C. We investigated temperature decrease associated with dipyrone or acetaminophen and additionally compared it to an untreated control group. RESULTS: Within the eight-hour study interval, maximum body temperature decrease in patients without antipyretic medication was -0.6°C (IQR: -1.0 to -0.4°C; n = 315). Maximal decrease in body temperature was higher both with dipyrone (-0.8°C (IQR: -1.2 to -0.4°C); p = 0.016; n = 341) and acetaminophen (-0.9°C (IQR: -1.6 to -0.6°C); p<0.001; n = 71), but did not differ between dipyrone and acetaminophen (p = 0.066). As compared to untreated patients, dipyrone only led to a marginal additional decrease in body temperature of only -0.1°C. Maximum of antipyretic effectiveness was reached four hours after administration. CONCLUSION: Antipyretic effectiveness of dipyrone in ICU patients may be overestimated. Given the lack of prospective data, clinical evidence for antipyretic dipyrone therapy in the ICU is insufficient and warrants further critical evaluation.


Assuntos
Antipiréticos , Dipirona , Acetaminofen/efeitos adversos , Antipiréticos/uso terapêutico , Estado Terminal/terapia , Dipirona/farmacologia , Dipirona/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Estudos Retrospectivos
12.
Neurosci Biobehav Rev ; 136: 104607, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35276298

RESUMO

Emerging evidence from reviews suggests that analgesic drug exposure during pregnancy may contribute to child neurodevelopment outcomes. A comprehensive overview of existing evidence is needed for firm conclusions to inform clinical guidelines. This umbrella review aims to synthesise high-quality evidence on prenatal analgesic drug exposure and risk of ASD and ADHD in children. Seven databases were searched from inception to May 2021 to identify relevant reviews of any design. The AMSTAR 2 and the GRADE quality assessments were used to evaluate risk of bias and heterogeneity. A narrative synthesis approach was used to summarise findings. Five systematic reviews and meta-analyses met the inclusion criteria. All reviews reported significant associations between maternal prenatal acetaminophen use and ADHD outcomes (risk ratio range: 1.08-1.34; no pooled incidence rate), with a potential dose-dependent relationship. Potential sources of heterogeneity included usage timing and dosage. Findings suggest minimisation of prenatal acetaminophen exposure due to risk for ADHD outcomes. Future studies should include assessing potentially interacting mechanisms associating acetaminophen use with future neurodevelopmental outcomes.


Assuntos
Acetaminofen , Analgésicos , Acetaminofen/efeitos adversos , Criança , Feminino , Humanos , Gravidez
13.
Zhongguo Zhong Yao Za Zhi ; 47(4): 1017-1023, 2022 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-35285202

RESUMO

This study explored the protective effect of atractylenolide Ⅰ(AO-Ⅰ) against acetaminophen(APAP)-induced acute liver injury(ALI) in mice and its underlying mechanism. C57 BL/6 J mice were randomly divided into a control group, an APAP group(500 mg·kg~(-1)), a low-dose combination group(500 mg·kg~(-1) APAP + 60 mg·kg~(-1) AO-Ⅰ), and a high-dose combination group(500 mg·kg~(-1) APAP + 120 mg·kg~(-1) AO-Ⅰ). ALI was induced by intraperitoneal injection of APAP(500 mg·kg~(-1)). AO-Ⅰ by intragastric administration was performed 2 hours before APAP treatment, and the control group received the same dose of solvent by intragastric administration or intraperitoneal injection. The protective effect of AO-Ⅰ against APAP-induced ALI was evaluated by detecting alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels in the plasma and H&E staining in liver tissues of mice. The malondialdehyde(MDA) and glutathione(GSH) content and catalase(CAT) activity in mouse liver tissues were detected to evaluate the effect of AO-Ⅰ on APAP-induced oxidative stress in the liver. The proteins in the liver p38 mitogen-activated protein kinase(p38 MAPK), c-jun N-terminal kinase(JNK), and nuclear factor kappa-B p65(NF-κB p65) signaling pathways were measured by Western blot, and the liver inflammatory cytokines interleukin-1ß(IL-1ß) and interleukin-6(IL-6) were detected by real-time PCR. Compared with the APAP group, the combination groups showed reduced APAP-induced ALT level and liver MDA content, potentiated liver CAT activity, and elevated GSH content. Mechanistically, AO-Ⅰ treatment significantly inhibited APAP-up-regulated MAPK phosphorylation and NF-κB p65, and significantly reduced the transcriptional activities of IL-1ß and IL-6, downstream targets of NF-κB p65. AO-Ⅰ can improve APAP-induced ALI and the underlying mechanism is related to the inhibition of the MAPK/NF-κB p65 signaling pathway in APAP-challenged mice.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/efeitos adversos , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Lactonas , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Sesquiterpenos , Transdução de Sinais
14.
Acute Med ; 21(1): 47-49, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35342910

RESUMO

High anion gap metabolic acidosis (HAGMA) is a common diagnosis in the emergency department, which requires a systematic work-up in order to identify and treat the underlying cause. We present an unusual case of HAGMA due to 5-oxoproline accumulation caused by prolonged treatment with both acetaminophen (paracetamol) and flucloxacillin. This paper describes the diagnostic work-up of HAGMA and emphasizes on the approach and initial treatment in case the underlying etiology is unclear.


Assuntos
Acetaminofen , Acidose , Acetaminofen/efeitos adversos , Acidose/induzido quimicamente , Acidose/diagnóstico , Floxacilina/efeitos adversos , Humanos , Ácido Pirrolidonocarboxílico
16.
Biomed Res Int ; 2022: 8121124, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35265717

RESUMO

Acetaminophen (APAP) can cause acute liver failure, but treatment options are still limited. Kahweol is the main diterpene compound of coffee and possesses antioxidant and anti-inflammatory properties. Emerging evidence suggests that this natural diterpene exerts favorable effects on several inflammatory diseases. However, the action of kahweol on APAP toxicity has not been addressed. The purpose of this study was to explore whether kahweol has a protective activity against APAP-induced hepatotoxicity and to investigate the mechanism. Administration of kahweol reduced serum levels of liver injury indicators and ameliorated histological abnormalities in APAP-treated mice. Kahweol inhibited lipid peroxidation and nucleic acid oxidation with restoration of glutathione content and stimulation of nuclear factor erythroid-2-related factor 2-dependent cellular defense system. Hepatocyte death was also decreased by kahweol, which was associated with inhibition of endoplasmic reticulum (ER) stress. Moreover, kahweol reduced hepatic levels of inflammatory mediators, inhibited nuclear factor-κB activation, and attenuated infiltration of neutrophils and macrophages. These findings suggest that kahweol has a protective activity against APAP-induced liver injury and this effect is related to the suppression of oxidative stress, hepatocyte death, ER stress, and inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Acetaminofen/efeitos adversos , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diterpenos/efeitos adversos , Hepatócitos/patologia , Inflamação/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo
17.
Arq. bras. cardiol ; 118(3): 548-555, mar. 2022. tab, graf
Artigo em Inglês, Português | LILACS | ID: biblio-1364352

RESUMO

Resumo Fundamento É importante saber qual medicamento usar como tratamento de primeira linha para fechar o duto. Objetivos O objetivo deste estudo é comparar a eficácia e os efeitos colaterais das formas intravenosas (IV) de ibuprofeno e paracetamol e contribuir para a literatura investigando o primeiro medicamento selecionado no tratamento clínico da persistência do canal arterial (PCA). Métodos Nosso estudo foi realizado entre janeiro de 2017 e dezembro de 2019. Foram incluídos no estudo bebês prematuros com peso ao nascer (PN) ≤1500 g e idade gestacional (IG) ≤32 semanas. No período do estudo, todos os bebês com persistência do canal arterial hemodinamicamente significativa (hsPCA) receberam ibuprofeno intravenoso (IV) como resgate como tratamento clínico primário ou tratamento com paracetamol IV se houvesse contraindicações para o ibuprofeno. Os pacientes foram divididos em dois grupos: pacientes que receberam ibuprofeno IV e pacientes que receberam paracetamol IV. Resultados Desses pacientes, 101 receberam paracetamol IV e 169 receberam ibuprofeno IV. A taxa de sucesso do fechamento da PCA com o primeiro curso do tratamento foi de 74,3% no grupo de paracetamol IV e 72,8% no grupo de ibuprofeno IV (p=0,212). Conclusões Nossos resultados mostram que o paracetamol IV é tão eficaz quanto o ibuprofeno IV no tratamento de primeira linha de hsPCA, podendo se tornar o tratamento preferencial para o controle de hsPCA.


Abstract Background It is important which medicine to use as a first-line treatment to close the duct. Objectives The aim of this study is to compare the effectiveness and side effects of intravenous (IV) forms of ibuprofen and paracetamol and to contribute to the literature investigating the first drug selected in the medical treatment of patent ductus arteriosus (PDA). Methods Our study was conducted between January 2017 and December 2019. Premature infants with birth weight (BW) ≤1500 g and gestational age (GA) ≤32 weeks were included in the study. In the study period, all infants with hemodynamically significant patent ductus arteriosus (hsPDA) were given rescue intravenous (IV) ibuprofen as a primary medical treatment or IV paracetamol treatment if there were contraindications for ibuprofen. The patients were divided into two groups: patients receiving IV ibuprofen and patients receiving IV paracetamol. Results Of these patients, 101 were given IV paracetamol and 169 were given IV ibuprofen. The success rate of PDA closure with first-course treatment was 74.3% in the IV paracetamol group and 72.8% in the IV ibuprofen group (p=0.212). Conclusions Our results show that IV paracetamol is as effective as IV ibuprofen in the first-line treatment of hsPDA, and can become the preferred treatment for the management of hsPDA.


Assuntos
Humanos , Recém-Nascido , Lactente , Permeabilidade do Canal Arterial/tratamento farmacológico , Recém-Nascido de Baixo Peso , Recém-Nascido Prematuro , Ibuprofeno/efeitos adversos , Ibuprofeno/uso terapêutico , Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico
18.
Hypertension ; 79(5): e89-e99, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35232225

RESUMO

BACKGROUND: Postural tachycardia syndrome (POTS) is characterized by excessive upright tachycardia and disabling presyncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal; it is unknown, however, what is the precise underlying mechanism. We seek to investigate the effect of glucose intake on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. METHODS: Prospective, case-control study, 12 women with POTS who reported a postprandial worsening of their POTS symptoms and 13 age-matched female controls received 75-g oral glucose and 20 mg/kg acetaminophen to assess nutrient absorption. Hemodynamic, gastrointestinal hormone and acetaminophen levels were measured for up to 120 minutes postingestion while supine and standing. RESULTS: Patients with POTS had significant orthostatic tachycardia, 48.7±11.2 versus 23.3±8.1 bpm, P=0.012 and elevated upright norepinephrine levels, 835.2±368.4 versus 356.9±156.7 pg/mL, P=0.004. After oral glucose, upright heart rate significantly increased in POTS, 21.2±11.9% versus 6.0±19.9%, P=0.033 with a concomitant decline in upright stroke volume, -10.3±11.90% versus 3.3±13.7%, P=0.027; total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707), indicating comparable nutrient absorption rates. POTS had increased plasma levels of C-peptide (P=0.001), GIP (glucose-dependent insulinotropic polypeptide; P=0.001), peptide YY (P=0.016), and pancreatic polypeptide (P=0.04) following glucose consumption, but only GIP had a time-dependent association with the worsening upright tachycardia and stroke volume fall. CONCLUSIONS: The glucose-induced worsening orthostatic tachycardia in POTS was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, was maximally elevated.


Assuntos
Hormônios Gastrointestinais , Síndrome da Taquicardia Postural Ortostática , Acetaminofen/efeitos adversos , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Feminino , Glucose , Frequência Cardíaca/fisiologia , Humanos , Masculino , Estudos Prospectivos , Taquicardia
19.
Cell Death Dis ; 13(2): 100, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110525

RESUMO

Acetaminophen (APAP)-induced liver injury (AILI) is the most frequent cause of acute liver failure; but the underlying mechanisms still remain obscure. Macrophages and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of AILI. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified 18-kDa soluble protein, whose expression and secretion are stimulated by ER stress. To investigate the role of myeloid cell MANF in the pathogenesis of AILI, we assayed serum and liver samples from AILI model mice and patients with drug-induced liver injury (DILI). We demonstrated that the levels of MANF were elevated in patients with DILI and in mice with AILI. Moreover, myeloid-specific MANF knockout mice were generated and used. It was observed that a delayed liver recovery from myeloid-specific MANF gene knockout mice following APAP overdose compared to that from wild-type mice. MANF deficiency in myeloid cells resulted in increased infiltrating monocyte-derived macrophages (MoMFs) but reduced restorative Ly6Clow macrophages after APAP treatment. MANF supplementation increased restorative Ly6Clow macrophages and subsequently alleviated liver injury. Moreover, MANF could enhance IL-10 expression and phagocytosis in macrophages via p38 MAPK pathway. Altogether, MANF seems to be a critical immune modulator in promoting liver repair via reducing and reprogramming MoMFs. MANF perhaps promoted the phenotype conversion of pro-inflammatory MoMFs to pro-restorative Ly6Clow MoMFs via p38 MAPK pathway, particularly through enhancing IL-10 and phagocytosis.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Macrófagos/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Interleucina-10/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Células Mieloides/metabolismo , Fatores de Crescimento Neural/uso terapêutico , Fagocitose , Transdução de Sinais
20.
Eur Heart J ; 43(18): 1743-1755, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35201347

RESUMO

AIMS: Previous studies have found high sodium intake to be associated with increased risks of cardiovascular disease (CVD) and all-cause mortality among individuals with hypertension; findings on the effect of intake among individuals without hypertension have been equivocal. We aimed to compare the risks of incident CVD and all-cause mortality among initiators of sodium-containing acetaminophen with the risk of initiators of non-sodium-containing formulations of the same drug according to the history of hypertension. METHODS AND RESULTS: Using The Health Improvement Network, we conducted two cohort studies among individuals with and without hypertension. We examined the relation of sodium-containing acetaminophen to the risk of each outcome during 1-year follow-up using marginal structural models with an inverse probability weighting to adjust for time-varying confounders. The outcomes were incident CVD (myocardial infarction, stroke, and heart failure) and all-cause mortality. Among individuals with hypertension (mean age: 73.4 years), 122 CVDs occurred among 4532 initiators of sodium-containing acetaminophen (1-year risk: 5.6%) and 3051 among 146 866 non-sodium-containing acetaminophen initiators (1-year risk: 4.6%). The average weighted hazard ratio (HR) was 1.59 [95% confidence interval (CI) 1.32-1.92]. Among individuals without hypertension (mean age: 71.0 years), 105 CVDs occurred among 5351 initiators of sodium-containing acetaminophen (1-year risk: 4.4%) and 2079 among 141 948 non-sodium-containing acetaminophen initiators (1-year risk: 3.7%), with an average weighted HR of 1.45 (95% CI 1.18-1.79). Results of specific CVD outcomes and all-cause mortality were similar. CONCLUSION: The initiation of sodium-containing acetaminophen was associated with increased risks of CVD and all-cause mortality among individuals with or without hypertension. Our findings suggest that individuals should avoid unnecessary excessive sodium intake through sodium-containing acetaminophen use.


Assuntos
Doenças Cardiovasculares , Hipertensão , Infarto do Miocárdio , Sódio na Dieta , Acetaminofen/efeitos adversos , Idoso , Doenças Cardiovasculares/epidemiologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Fatores de Risco , Sódio
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