Effect of acetaminophen combined with ketorolac tromethamine on analgesia after laparoscopic chol-ecystectomy / 临床麻醉学杂志

Objective To investigate the effectiveness and safety of acetaminophen combined with ketorolac tromethamine in pain management early after laparoscopic cholecystectomy(LC).Methods Ninety patients with LC under general anesthesia,42 males and 48 females,aged 18-78 years,BMI 18-28 kg/m2,ASA physical statusⅠorⅡ,were selected and randomly divided into two groups by random num-ber table method:the acetaminophen combined with ketorolac tromethamine group(group AK)and the nal-buphine group(group NA),45 patients in each group.Group AK received 500 mg(diluted to 50 ml)of acetaminophen injection and 30 mg of ketorolac tromethamine(diluted to 10 ml)injection pumped 15 mi-nutes before induction of anesthesia,and group NA received 50 ml of NS injection and 0.2 mg/kg of nalbu-phine(diluted to 10 ml)injection pumped at the same time.Postoperative pain was recorded 0.5,3,6,12,and 24 hours after surgery using VAS pain scores(the non-inferiority boundary Δ = 1.0 score).The sleep quality score on the night of surgery,the number of remedial analgesia cases within 24 hours after sur-gery,the Ramsay sedation score 0.5,3,and 6 hours after surgery,the occurrence of adverse reactions such as nausea and vomiting within 24 hours after surgery,and the overall satisfaction of patients were recorded.Results Compared with group NA,the VAS pain scores 0.5 hour after surgery was reduced in group AK(P＜0.05).The sleep quality score and overall satisfaction in group AK were significantly higher than those in group NA(P＜0.05).There were no significant differences in the rate of remedial analgesia,the score of Ramsay sedation at different time points and the incidence of nausea and vomiting within 24 hours after surgery between the two groups.Conclusion Acetaminophen combined with ketorolac tromethamine is not less effective than nalbuphine in relieving early postoperative pain after laparoscopic cholecystectomy without increasing the incidence of nausea and vomiting.Patients receiving acetaminophen combined with ketorolac tromethamine have higher sleep quality scores on the night of surgery and overall satisfaction.

Protective effect of SRT1720 on acute liver injury induced by acetaminophen in mice and its mechanism / 中国生物制品学杂志

@#Objective To evaluate the protective effect of the activator of silent information regulator 2-related enzymes 1(SIRT1),SRT1720,on liver injury induced by acetaminophen(APAP)in mice and explore its mechanism. Methods Forty male C57BL/6J mice were randomly divided into normal control group,SRT1720 treatment group,APAP treatment group,and APAP + SRT1720 treatment group,with 10 mice in each group. Mice in SRT1720 and APAP + SRT1720 groups were given SRT1720(30 mg/kg body mass)by intragastric administration,while normal saline of equal volume was given by intragastric administration in control and APAP groups,once a day for 5 days;On the 6th day,mice in APAP and APAP + SRT1720 groups were injected i. p. with APAP(325 mg/kg body mass),while those in control and SRT1720 groups with equal volume of normal saline. After 24 hours,the peripheral blood was taken and the serum was separated,which were detected for the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)by the corresponding kits;The liver tissue of mice was taken aseptically,observed for the pathological changes by HE staining,detected for the mRNA transcription levels of GRP78,PERK,eIF2 α,ATF4 and CHOP genes related to PERK-eIF2α-CHOP signaling pathway by RT-qPCR and detected for the relative expression levels of these corresponding proteins and Caspase12 protein by Western blot. Results Compared with normal control group,the serum ALT and AST levels of mice in APAP group significantly increased(t = 55. 21 and34. 29 respectively,each P < 0. 01);significant necrosis of hepatocytes was observed in liver tissue,the structure of hepatic lobules changed significantly,and the swelling and deformation of hepatocytes in some areas were serious;the mRNA transcription and relative protein expression levels of GRP78,PERK,eIFα,ATF4 and CHOP genes increased significantly(t = 9. 85～33. 89,each P < 0. 05)and the relative expression level of Caspase12 protein increased significantly(t = 11. 78,P < 0. 01). Compared with APAP group,the serum ALT and AST levels of mice in APAP + SRT1720 group decreased significantly(t = 42. 92 and 18. 02 respectively,each P < 0. 01);the degree of hepatocyte injury was obviously reduced and the number of swollen and deformed cells also significantly decreased;the mRNA transcription and relative protein expression levels of GRP78,PERK,eIF2α,ATF4 and CHOP decreased significantly(t = 6. 19～22. 43,each P < 0. 05)and the expression level of Caspase12 protein showed no significant decrease(t = 0. 34,P > 0. 05). Conclusion SRT1720improved APAP-induced liver injury in mice,possibly by inhibiting PERK-eIF2α-CHOP signaling pathway in endoplasmic reticulum stress(ERS).

Prediction of potential mechanism of curcumin combined with berberine in improving drug-induced liver injury based on network pharmacology / 中国现代医生

@#Objective The potential mechanism of curcumin(CUR)combined with berberine(BBR)in improving drug-induced liver injury(DILI)was preliminarily predicted by a method of in vivo experiment in combination with network pharmacology.Methods The animal model was established by acetaminophen(APAP)-induced DILI and the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were detected in serum of mice.The network pharmacological approach was used to collect related targets of CUR,BBR,and DILI;Wayne mapping was carried out to screen intersection targets,followed by establishment of a protein-protein interaction(PPI)network of CUR-BBR-DILI.Functional enrichment analysis of gene ontology(GO)and pathway enrichment analysis of Kyoto Encyclopedia of Genes and Genomes(KEGG)were conducted finally.Results The in vivo experimental results showed that the combination of CUR and BBR can significantly reduce the serum ALT and AST levels in mice,which is better than administration alone;Network pharmacology experiment results exhibited that 291 related targets of CUR and 208 related targets of BBR were collected by PharmMapper database,and 904 related targets of DILI were collected by Genecards database;77 intersection targets were screened by Venny 2.1.0 database;52 gene functions and 20 signal pathways possibly in connection with the improvement of DILI via drug combination were obtained by GO and KEGG analysis,respectively;nine of the top ten core targets according to degree in PPI network were enriched to PI3K/AKT signaling pathway,which were in order as follows:SRC,EGFR,HSP90AA1,IGF1,HRAS,MAPK14,ESR1,CASP3,and PTK2.Conclusion DILI might be synergistically improved by CUR combined BBR through multi-target and multi-pathway manner,providing a theoretical basis for the elucidation of the mechanism of drug combination against DILI.

Prospective Protective Effects of Arthrospira platensis Against Acetaminophen Induced Hepato-Renal Toxicity in Rats / Efectos Protectores Prospectivos de Arthrospira platnesis Contra la Toxicidad Hepatorrenal Inducida por Paracetamol en Ratas

SUMMARY: The toxic effects of acetaminophen appear primarily in the liver and kidney. The protective effect of blue green alga Arthrospira platensis on hepato-renal toxicity caused by acetaminophen was evaluated in male rats. The obtained results showed that subcutaneous injection of acetaminophen at a dose 120 &240 սl acetaminophen/kg by weight resulted in an observed elevation in the enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline phosphatase (ALP), serum total lipids, total cholesterol, creatinine, total bilirubin, urea, nitric oxide (NO), L- malondialdehyde (MDA) and interleukins (IL-2 &IL-6). However, there is a decrease in the serum total protein, albumin and loss in antioxidant enzyme activities in liver including; superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH). This effect was found to be dose and time dependent. In spite of, pre- oral administration of Arthrospira platensis 1000 mg/kg .b. wt. prior acetaminophen injection succeeded to modulate the effect of the observed abnormalities caused by acetaminophen. Moreover, there were no remarkable changes in serum biomarkers of rats received Arthrospira platensis only at a dose of 1000 mg/kg by weight (group 2). The histopathological findings confirm the biochemical results that indicates the safety use of Arthrospira platensis at the selected dose in this study. Therefore, the present results clarified the protective effect of blue green alga Arthrospira platensis on oxidative stress, hepatic and nephrotoxicity induced by acetaminophen in male Wister rats.

Los efectos tóxicos del paracetamol aparecen principalmente en el hígado y el riñón. Se evaluó en ratas macho Wistar el efecto protector del alga verde azulada Arthrospira platensis sobre la toxicidad hepatorrenal causada por paracetamol. Los resultados obtenidos mostraron que la inyección subcutánea de paracetamol a dosis de 120 y 240 µl de paracetamol/kg, resultó en una elevación en las actividades enzimáticas de la aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina (ALP), lípidos séricos totales, colesterol total, creatinina, bilirrubina total, urea, óxido nítrico (NO), L- malondialdehído (MDA) e interleucinas (IL-2 e IL-6). Sin embargo, hay una disminución en la proteína sérica total, albúmina y pérdida en las actividades de las enzimas antioxidantes en el hígado, incluyendo; superóxido dismutasa (SOD), catalasa (CAT) y glutatión reductasa (GSH). Se encontró que este efecto era dependiente de la dosis y el tiempo. A pesar de la administración preoral de Arthrospira platensis 1000 mg/kg, la inyección previa de acetaminofeno logró modular el efecto de las anormalidades observadas causadas por el acetaminofeno. Además, no hubo cambios notables en los biomarcadores séricos de ratas que recibieron Arthrospira platensis solo a una dosis de 1000 mg/kg (Grupo 2). Los hallazgos histopatológicos confirman los resultados bioquímicos que indican la seguridad del uso de Arthrospira platensis a la dosis seleccionada en este estudio. Por lo tanto, los presentes resultados aclararon el efecto protector del alga verde azulada Arthrospira platensis sobre el estrés oxidativo, la toxicidad hepática y la nefrotoxicidad inducida por paracetamol en ratas Wistar macho.

Comparación: acetaminofén vs ibuprofeno para el tratamiento de los síntomas en pacientes con infección por SARS-CoV-2 / Comparação: paracetamol vs ibuprofeno para o tratamento de sintomas em pacientes com infecção por SARS-CoV-2 / Comparison: acetaminophen vs ibuprofen for the treatment of symptoms in patients with SARS-CoV-2 infection

La propagación del COVID-19 fue expedita y tras varios informes la eficacia de algunos medicamentos antiinflamatorios no esteroideos, como el ibuprofeno, estuvo bajo sospecha. Mientas que el paracetamol (acetaminofén) se sugirió como una alternativa segura y recomendable para el manejo temprano y domiciliario del dolor y fiebre en pacientes. Objetivo. Comparar el uso del acetaminofén vs ibuprofeno para tratamiento de los síntomas en pacientes con infección por SARS-COV-2". Metodología. La investigación es una revisión sistemática, donde, se analizaron artículos científicos publicados en revistas vinculadas a áreas de salud, disponibles en buscadores y plataformas digitales tales, como Scienedirect, Pubmed, Elsevier y Springer Link. Las búsquedas se realizaron utilizando las palabras claves previamente definidas. Conclusión. El uso del ibuprofeno ha estado en duda desde sus inicios, en pacientes con COVID-19. Sin embargo, ningún estudio afirma asociar el uso del mismo con aumentos importantes en estadía hospitalaria, ingresos en UCI, necesidad de ventilación mecánica, ni mortalidad. Sin embargo, el acetaminofén ha sido utilizado desde un principio, su uso no estuvo en duda, pero los hallazgos recientes parecen indicar que no es tan eficaz como se pensaba en un principio. Siendo bastante inferior en la comparación directa con el ibuprofeno.

The spread of COVID-19 was expeditious and after several reports the efficacy of some non-steroidal anti-inflammatory drugs, such as ibuprofen, was under suspicion. While paracetamol (acetaminophen) was suggested as a safe and recommended alternative for early and home management of pain and fever in patients. Objective. To compare the use of acetaminophen vs ibuprofen for symptom management in patients with SARS-COV-2 infection". Methodology. The research is a systematic review, where scientific articles published in journals related to health areas, available in search engines and digital platforms such as Scienedirect, Pubmed, Elsevier and Springer Link, were analyzed. Searches were performed using previously defined keywords. Conclusion. The use of ibuprofen has been in question since its inception in patients with COVID-19. However, no study claims to associate its use with significant increases in hospital stay, ICU admissions, need for mechanical ventilation, or mortality. However, acetaminophen has been used from the beginning, its use was not in doubt, but recent findings seem to indicate that it is not as effective as originally thought. It is quite inferior in direct comparison with ibuprofen.

A disseminação da COVID-19 foi rápida e, após vários relatos, a eficácia de alguns anti-inflamatórios não esteroides, como o ibuprofeno, ficou sob suspeita. Já o paracetamol (acetaminofeno) foi sugerido como uma alternativa segura e recomendada para o tratamento precoce e domiciliar da dor e da febre nos pacientes. Objetivo. Comparar o uso de acetaminofeno versus ibuprofeno para o controle dos sintomas em pacientes com infecção por SARS-COV-2". Metodologia. A pesquisa é uma revisão sistemática, onde foram analisados artigos científicos publicados em periódicos relacionados às áreas de saúde, disponíveis em sites de busca e plataformas digitais como Scienedirect, Pubmed, Elsevier, e Springer Link. As buscas foram realizadas por meio de palavras-chave previamente definidas. Conclusões. O uso do ibuprofeno tem sido questionado desde sua criação em pacientes com COVID-19. No entanto, nenhum estudo afirma associar seu uso a aumentos significativos na permanência hospitalar, internações em UTI, necessidade de ventilação mecânica ou mortalidade. No entanto, o acetaminofeno tem sido usado desde o início, seu uso não foi questionado, mas descobertas recentes parecem indicar que ele não é tão eficaz quanto se pensava originalmente. Ele é muito inferior em comparação direta com o ibuprofeno.

Sobredosis de acetaminofén y comportamientos relacionados con suicidio / Acetaminophen overdose and suicide-related behaviors / Overdose de paracetamol e comportamentos suicidas

Objetivo: este trabajo busca caracterizar el comportamiento relacionado con el suicidio en la población admitida al Hospital San Vicente Fundación, Rionegro, con sobredosis de acetaminofén entre enero 2019 y diciembre 2020 y detectar factores asociados con la dosis tóxica. Metodología: análisis descriptivo con información obtenida de historias clínicas. Resultados: 63 individuos presentaron ingestión aguda de dosis tóxica de acetaminofén como comportamiento relacionado con suicidio. Cuarenta y tres eran mujeres, 60% tenía antecedente de enfermedad psiquiátrica, 35% reportó al menos un intento suicida previo y 22% consumieron 25g o más. La lesión hepática aguda se asoció con una dosis tóxica. Conclusiones: evidenciamos una alta prevalencia de antecedente de enfermedad psi­quiátrica y comportamiento relacionado con suicidio y casi un tercio de los pacientes ingirió dosis mayores al umbral de riesgo para falla hepática. Además, la impulsividad e ingesta en casa sugiere que políticas públicas restrictivas pueden no impactar en la reducción de estos eventos en la población.

Objective: this work seeks to characterize the behavior related to suicide in the po­pulation admitted to the Hospital San Vicente Fundación, Rionegro, with an overdose of acetaminophen between January 2019 and December 2020, and to identify factors associated with the toxic dose. Methodology: descriptive analysis with information obtained from medical records. Results: 63 individuals presented acute ingestion of a toxic dose of acetaminophen as behavior related to suicide. Forty-three were women, 60% had a history of psychiatric illness, 35% reported at least one previous suicide attempt, and 22% consumed 25g or more. Acute liver injury was associated with a toxic dose. Conclusions: we evidenced a high prevalence of a history of psychiatric illness and beha­vior related to suicide; almost a third of the patients ingested doses greater than the risk threshold for liver failure. In addition, impulsiveness and eating at home suggests that res­trictive public policies may not have an impact on reducing these events in the population.

Objetivo: Este trabalho busca caracterizar o comportamento relacionado ao suicídio na população internada no Hospital San Vicente Fundación, Rionegro, com overdose de acetaminofeno entre janeiro de 2019 e dezembro de 2020 e detectar fatores associados à dose tóxica. Metodologia: análise descritiva com informações obtidas dos prontuários. Resultados: 63 indivíduos apresentaram ingestão aguda de dose tóxica de paracetamol como comportamento relacionado ao suicídio. Quarenta e três eram mulheres, 60% tinham histórico de doença psiquiátrica, 35% relataram pelo menos uma tentativa de suicídio anterior e 22% consumiram 25g ou mais. A lesão hepática aguda foi associada a uma dose tóxica. Conclusões: evidenciamos alta prevalência de história de doença psiquiátrica e com-portamento relacionado ao suicídio e quase um terço dos pacientes ingeriu doses superiores ao limiar de risco para insuficiência hepática. Além disso, a impulsividade e a alimentação em casa sugerem que políticas públicas restritivas podem não ter impacto na redução desses eventos na população.

Uso del esquema Scottish and Newcastle Anti-Emetic Pretreatment (SNAP) en la recuperación de una intoxicación por sobredosis masiva de acetaminofén (paracetamol) con injuria hepática aguda - Reporte de caso

Acetaminophen is a drug widely used in the world and easily accessible due to its antipyretic, analgesics characteristics, among others (1); however, exposure to toxic doses causes organic damage and even death. We present the case of an 18-year-old female patient who ingested 40 grams of acetaminophen and developed severe liver dysfunction, being treated with N-acetylcysteine (NAC) antidotal therapy according to the simplified scheme: Scottish and Newcastle Anti-emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presenting improvement in the clinical course and decrease in liver profiles, coagulation disorder, INR and resolution of the condition.

El acetaminofén es un fármaco ampliamente usado en el mundo y de fácil acceso por sus características antipiréticas, analgésicas, entre otras (1); sin embargo la exposición a dosis tóxicas produce daños a nivel orgánico e incluso la muerte. Presentamos el caso de una paciente mujer de 18 años que ingirió 40 gramos de acetaminofén y desarrolló injuria hepática severa, siendo tratada con terapia antidotal de N-acetilcisteína (NAC) según el esquema simplificado: Scottish and Newcastle Anti-Emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presentando mejoría del curso clínico y disminución de los perfiles hepáticos, trastorno de coagulación, INR y resolución del cuadro.

Fluorine-thiol displacement probes for acetaminophen's hepatotoxicity

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

Rapid determination of acetaminophen in plasma by LC-MS/MS / 中华劳动卫生职业病杂志

Objective: To establish a method for the rapid determination of acetaminophen (APAP) in human plasma by LC-MS/MS. Methods: The plasma samples were extracted by methanol and acetonitrile (1: 1) and purified directly. C(18) column was used for sample separation. The mobile phase were methanol (5 mmol/L ammonium acetate) and water (5 mmol/L ammonium acetate). Samples were analyzed by LC MS/MS with the electrospray ionization multi reaction monitoring (MRM) mode. Results: The calibration curves of APAP was linear in the concentration range of 0~10 mg/L, the correlation coefficient (r) was greater than 0.999 0. The relative standard deviation within and between batches was less than 10%. The recovery rate were 96.81%~101.7%. The detection limit of the method was 0.1 μg/L and the lower limit of quantification was 0.3 μg/L. Conclusion: This method has strong specificity, high sensitivity and reliable determination results. It is suitable for the rapid analysis of clinical plasma samples.

Ferroptosis and drug-induced liver injury / 中华肝脏病杂志

Ferroptosis is a type of regulated cell death driven by iron-dependent lipid peroxidation that has received extensive attention in recent years. A growing body of evidence suggests that ferroptosis contributes to the progression of drug-induced liver injury. Therefore, the role and mechanism of ferroptosis in the process of drug-induced liver injury deserve further extensive and in-depth exploration, which will aid in the discovery of novel biomarkers as well as the identification of potential approches of targeting ferroptosis to intervene in drug-induced liver injury.

Oral acetaminophen or high-dose ibuprofen as rescue treatment for very preterm infants with patent ductus arteriosus / 中国新生儿科杂志

Objective:To study the efficacy and safety of oral acetaminophen or high-dose ibuprofen as rescue treatment after failure of conservative management in very preterm infants (VPIs) with haemodynamically significant patent ductus arteriosus (hsPDA).Methods:From May 2020 to November 2022, VPIs with hsPDA (gestational age<32 weeks and age 4~6 d) admitted to NICU of our hospital were prospectively enrolled. The rescue treatment was initiated if hsPDA still exist after 3~4 d of conservative management. The infants were randomly assigned into acetaminophen group (oral acetaminophen 15 mg/kg, once every 6 h for 3 d) and high-dose ibuprofen group (oral ibuprofen 20 mg/kg for the first dose, 10 mg/kg each dose after 24 h and 48 h). Before and after rescue treatment, the following were recorded: echocardiography, complete blood count, biochemistry, B-type natriuretic peptide (BNP), fecal occult blood test (FOBT) and transcranial Doppler ultrasound. Urine output and complications were also examined. SPSS 20.0 was used for statistical analysis.Results:A total of 36 cases were in the acetaminophen group and 37 in the high-dose ibuprofen group. The two groups showed similar efficacy as rescue treatment [80.6% (29/36) vs. 78.4% (29/37), P>0.05]. No significant differences existed in the incidences of upper gastrointestinal bleeding, positive FOBT, oliguria, stage Ⅱ-Ⅲ necrotizing enterocolitis and stage Ⅲ-Ⅳ intraventricular hemorrhage between the two groups ( P>0.05). After rescue treatment, the serum cystatin C in high-dose ibuprofen group was higher [(1.72±0.29) mg/L vs. (1.58±0.26) mg/L] and 24-hours urine output was lower [(3.1±1.0) ml/(kg·h) vs. (3.7±0.7) ml/(kg·h)] than the acetaminophen group (all P<0.05). No significant differences existed in serum creatinine, platelet count, BNP, alanine aminotransferase and total serum bilirubin between the two groups ( P>0.05). Conclusions:After failure of early conservative management in VPIs with hsPDA, when initiated within 7-10 d after birth, rescue treatment with oral acetaminophen or high-dose ibuprofen has a similar efficacy of 80%, and both drugs are safe. Oral high-dose ibuprofen may have a greater effect on renal function than acetaminophen.

Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites / 药物分析学报

Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1-/-)and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAP-induced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1-/- mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p450 3a 11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.

Effect and Mechanism of Puerarin Protects APAP-Induced Acute Liver Injury in Mice Through Inhibition of Ferroptosis / 中药新药与临床药理

Objective To explore the role and mechanism of puerarin in ameliorating acetaminophen(APAP)-induced acute liver injury in mice based on ferroptosis signaling pathway.Methods Twenty-four C57BL/6J mice were randomly divided into normal group,model group,and puerarin low-and high-dose groups(50 and 200 mg·kg-1),6 mice in each group;all the administration groups were given continuous gavage(10 mL·kg-1)once a day pre-dosed for 3 days.One hour after the last dose,APAP(300 mg·kg-1)was intraperitoneally injected into the mice of the model group and the puerarin low-and high-dose groups to replicate the drug-induced liver injury(DILI)mouse model.After 24 hours,the serum levels of alanine transaminase(ALT),aspartate aminotransferase(AST),and lactate dehydrogenase(LDH)were measured by the microplate assay;HE staining was used to observe the histopathological changes in liver tissue;the apoptosis of hepatocytes was observed by the TUNEL staining assay;the levels of malondialdehyde(MDA)were measured by the TBA assay;the mRNA expression levels of reactive oxygen species(ROS),4-hydroxynonenal(4-HNE),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11)were detected by immunofluorescence;qRT-PCR was performed to measure the mRNA levels of ferroptosis-related genes GPX4,transferrin receptor(TFRC),and solute carrier family 11 member 2(SLC11A2)in liver tissue.Results Compared with the normal group,the serum ALT,AST,and LDH levels of mice in the model group were significantly elevated(P＜0.01);the liver lobules showed obvious damage,with swelling and rupture of hepatocytes,cytoplasmic vacuolisation,fragmentation of nuclei,congestion of the hepatic blood sinusoids and infiltration of inflammatory cells,and an increase in apoptotic cells;the level of MDA in the hepatic tissues was significantly elevated(P＜0.05);the red fluorescence(positive expression)of ROS and 4-HNE was significantly enhanced(P＜0.05,P＜0.01),and the red fluorescence(positive expression)of GPX4 and SLC7A11 was significantly weakened in liver tissue(P＜0.01);the mRNA expressions of GPX4 and SLC11A2 in liver tissue were significantly down-regulated(P＜0.05),and there was a tendency for the down-regulation of TFRC expression but the difference was not statistically significant(P＞0.05).Compared with the model group,the serum AST and LDH levels of mice in the low-and high-dose groups of puerarin were significantly reduced(P＜0.05,P＜0.01),and there was a decrease in serum ALT,but the difference was not statistically significant(P＞0.05);the structure of the liver lobules was clearer,with radial arrangement of hepatic cords,and the area of necrotic liver tissue and apoptotic cells were significantly reduced;the level of MDA in the liver tissue was significantly reduced(P＜0.05);the red fluorescence(positive expression)of ROS and 4-HNE in liver tissue were significantly attenuated(P＜0.05,P＜0.01).The red fluorescence(positive expression)of GPX4 and SLC7A11 in liver tissue of the mice in the puerarin low-dose group were significantly enhanced(P＜0.05,P＜0.01),and there was a tendency to enhance the red fluorescence(positive expression)of GPX4 and SLC7A11 in the liver tissue of the mice in the puerarin high-dose group,but the difference was not statistically significant(P＞0.05).The mRNA expressions of GPX4 and TFRC in liver tissue of mice in low-dose puerarin group was significantly up-regulated(P＜0.05),while the mRNA expressions of GPX4 and SLC11A2 in high-dose puerarin group were significantly up-regulated(P＜0.05).Conclusion Puerarin had a significant protective effect on APAP-DILI,which may be related to its inhibition of cellular ferroptosis through the SLC7A11/GPX4 pathway.

Binder jet 3D printing composite bilayer tablet of extended-release printing technology in the study / 药学学报

Based on the dual needs of analgesia and anti-inflammation in trauma treatment, this study uses acetaminophen and moxifloxacin hydrochloride as active pharmaceutical ingredients and develops a composite bilayer tablet with a dual-phase drug release system by using binder jet 3D printing technology. Due to the complexity of the 3D printing process, there is an interaction between the various parameters. Through the optimization of the process, the relationship between the key process parameters can be determined more intuitively. In this study, the process of extended-release tablets was optimized to maintain the mechanical properties of the tablets while realizing the regulation of release. The full-factor experimental design of three central points 23 was used to analyze the factors that significantly affect the quality attributes of extended-release tablets and the interaction between factors. The optimal extended-release process parameters were obtained by the response optimizer: the inkjet quantity of the printing ink was 10 (about 13.8 pL), the powder thickness was 180 μm, and the running speed was 360 mm·s-1. The in vitro of release of 3D printed composite bilayer tablets showed that the in vitro of release of 3D printed tablets and commercially available tablets conformed to the Ritger-Peppas release model. The results of porosity showed that the immediate-release layer of the preparation has many pores and large pore size, and the dissolution of the immediate release layer within 15 min was greater than 85%. The internal pore size of the extended release layer is large, but it can still release slowly for up to 8 h, the mechanism may be related to the extended release of HPMC gelation. On the basis of verifying the rationality of the design goal of 3D printed composite bilayer tablets, this study also provides a theoretical basis for the preparation of 3D printing complex preparations.

Honokiol attenuates acetaminophen-induced acute liver injury by inhibiting hepatic CYP1A2 activity and improving liver mitochondrial dysfunction / 中草药·英文版

OBJECTIVE@#Acetaminophen (APAP) overdose is a common cause of liver injury. This study aimed to investigate the protective effect of honokiol (Hon) against APAP-induced hepatotoxicity and its potential mechanism.@*METHODS@#C57BL/6 mice were administrated with Hon (10 and 30 mg/kg) after APAP (300 mg/kg) treatment. On 1.5 h and 5 h after Hon treatment, mice were sacrificed. Serum and liver were collected. And then, liver injury-related indexes, APAP metabolism-related indexes, mitochondrial respiratory chain function-related indexes, and mitochondrial membrane function-related protein expression were evaluated.@*RESULTS@#It was found that Hon significantly decreased serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activity and glutathione (GSH) depletion, increased hepatic catalase (CAT) and GSH peroxidase (GSH-Px) activities, reduced hepatic MDA and 3-nitrotyrosine contents, inhibited hepatic CYP1A2 activity and APAP protein adducts (APAP-CYS) formation. Meanwhile, oxidative phosphorylation capacity of complex I and electron transfer capacity of complex IV in mitochondrial respiratory chain was increased, whereas the release of H2O2 in the mitochondria was decreased following Hon treatment. Furthermore, Hon markedly down-regulated p-JNK in both cytosol and mitochondria, and obviously inhibited the release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from mitochondria to cytosol.@*CONCLUSION@#Hon alleviated APAP-induced liver injury through the following pathways: Reducing the production of APAP-CYS by inhibiting CYP1A2 activity; Ameliorating hepatic oxidative stress by increasing the levels of hepatic CAT, GSH-Px and GSH; Improving mitochondrial respiratory chain function by promoting oxidative phosphorylation capacity of complex I and electron transfer capacity of complex IV; Improving the function of mitochondrial membrane by inhibiting p-JNK and its translocation to mitochondria, thereby reducing the release of AIF and EndoG.

The E3 ubiquitin ligase NEDD4-1 protects against acetaminophen-induced liver injury by targeting VDAC1 for degradation

Acetaminophen (APAP) overdose is a major cause of liver injury. Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases; however, its role in APAP-induced liver injury (AILI) is unclear. Thus, this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI. We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes. Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury, while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro. Additionally, hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1 (VDAC1) and increased VDAC1 oligomerization. Furthermore, VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency. Mechanistically, NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1. Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.

Role of Toll⁃like receptor 4 in the early stage of acetaminophen⁃induced acute liver inj ury in mice / 安徽医科大学学报

Objective @#To used Toll⁃like receptor 4( TLR4) inhibitor ( TAK⁃242) investigate the role of TLR4 in the early stage of acetaminophen (APAP) Ⅳinduced acute liver injury in mice. @*Methods @# Fifty⁃eight male institute of cancer research( ICR) mice were randomly divided into control group ( normal control group , solvent control group , inhibitor control group) and experimental group (APAP 4 ⁃ hour group , APAP + TAK⁃242 4 ⁃ hour group , APAP 12 ⁃ hour group , APAP + TAK⁃242 12 ⁃ hour group) . Mice in the experimental group were given a single dose of APAP (300 mg/kg) and TAK⁃242 (3 mg/kg) were given intraperitoneal injection 3 ⁃ hour before APAP injection. The serum alanine aminotransferase (ALT) level and liver index of mice in each group were compared ; HE staining showed pathological changes of liver tissue;the level of high mobility group box⁃1 (HMGB1) was determined by immunohistochemistry;the levels of TLR4 , HMGB1 and nuclear factor kappa B(NF⁃κB) protein were detected by Western blot;the levels of monocyte chemoattractant protein⁃1( MCP⁃1) , interleukin( IL) Ⅳ1β , tumor necrosis factor⁃α ( TNF⁃α ) and IL⁃6 genes were determined by real⁃time fluorescence quantitative PCR ( RT⁃qPCR) . The content of IL⁃6 in liver tissue was determined by enzyme linked immunosorbent assay (ELISA) .@*Results @#HE staining showed liver tissue of mice obvious swelling and congestion of in APAP group at 4 ⁃hour and typical lobular central necrosis in APAP group at 12 ⁃ hour;the degree of liver necrosis in APAP + TAK⁃242 groups at 4 ⁃ hour and 12⁃ hour was less than that in APAP group at the same time point. Compared with the normal control group , serum ALT level , liver index , TLR4 , HMGB1 , NF⁃κB protein content , MCP⁃1 , IL⁃1β , TNF⁃α , IL⁃6 gene levels and IL⁃6 content in liver tissue of APAP 4 ⁃ hour group increased ; serum ALT level , liver index , HMGB1 protein content and IL⁃6 content in liver tissue increased in APAP 12 ⁃ hour group. Compared with APAP 4 ⁃ hour group , serum ALT level , liver index , TLR4 , HMGB1 , NF⁃κB protein content , MCP⁃1 , IL⁃1β , TNF⁃α , IL⁃6 gene level and IL⁃6 content in liver tissue decreased in APAP + TAK⁃242 4 ⁃ hour group. Compared with APAP 12 ⁃hour group , the levels of TLR4 , HMGB1 protein and MCP⁃1 , IL⁃1β , TNF⁃α genes in APAP + TAK⁃242 12 ⁃ hour group decreased.@*Conclusion @#nhibition of TLR4 may inhibit TLR4/HMGB1 pathway to reduce the inflammatory response in the early stage of acetaminophen⁃induced acute liver injury in mice.

Effect of Toll-like receptor 4 on liver regeneration during acetaminophen-induced liver injury in mice / 临床肝胆病杂志

Objective To investigate whether Toll-like receptor 4 (TLR4) inhibition affects liver regeneration during acetaminophen (APAP)-induced liver injury in mice, as well as the mechanism of TLR4 involved in liver regeneration. Methods A total of 78 male CD-1 mice were divided into nine groups using a random number table, i.e., three control groups (normal control group, solvent control group, inhibitor control group) with 6 mice in each group and six experimental groups (APAP 24-hour group, TAK-242+APAP 24-hour group, APAP 48-hour group, TAK-242+APAP 48-hour group, APAP 72-hour group, TAK-242+APAP 72-hour group) with 10 mice in each group. The mice in the experimental groups were given a single dose of intraperitoneally injected APAP (300 mg/kg), and TAK-242 was intraperitoneally injected at a dose of 3 mg/kg at 3 hours before APAP administration. Serum and liver tissue samples were collected at different time points. The biochemical method was used to measure the serum level of alanine aminotransferase (ALT); HE staining was used to observe liver pathological changes; RT-PCR, Western blot, and immunohistochemistry were used to measure the expression levels of Cyclin D1, PCNA, Ki-67, STAT3, and p-STAT3. The t -test was used for comparison of normally distributed continuous data between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t -test was used for further comparison between two groups. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups and further comparison between two groups. Results Compared with the normal control group, the APAP 24-hour and 48-hour groups had a significantly higher serum level of ALT (both P < 0.05), and the TAK-242+APAP 24-hour and 48-hour groups had a significantly higher serum level of ALT than the APAP group at the same time point (both P < 0.05). HE staining showed typical central lobular necrosis in the liver of APAP-treated mice, and the TAK-242+APAP 24-hour and 48-hour groups had a significantly larger necrotic area than the APAP group at the same time point (both P < 0.05). RT-PCR, Western blot, and immunohistochemistry showed that the TAK-242+APAP 24-hour, 48-hour, and 72-hour groups had significantly lower mRNA and protein expression levels of Cyclin D1 than the APAP group at the same time point (all P < 0.05); the TAK-242+APAP 24-hour, 48-hour, and 72-hour groups had a significantly lower mRNA expression level of PCNA than the APAP group at the same time point (all P < 0.05), and the TAK-242+APAP 24-hour and 48-hour groups had a significantly lower protein expression level of PCNA than the APAP group at the same time point (all P < 0.05); the TAK-242+APAP 24-hour and 72-hour groups had a significantly lower mRNA expression level of Ki-67 than the APAP group at the same time point (all P < 0.05), and the TAK-242+APAP 24-hour, 48-hour, and 72-hour groups had a significantly lower protein expression level of Ki-67 than the APAP group at the same time point (all P < 0.05). In addition, the TAK-242+APAP 24-hour and 48-hour groups had a significantly lower phosphorylation level of STAT3 than the APAP group at the same time point (both P < 0.05). Conclusion TLR4 may promote liver regeneration by increasing the phosphorylation level of STAT3 during APAP-induced liver injury in mice.

Fixed and on-demand regimens of acetaminophen in periodontal surgery: randomized clinical trial

Aim: to evaluate the clinical efficacy of an acetaminophen analgesic by comparing its prescription in fixed versus ondemand schedules after periodontal surgery. The hypothesis of the study was that the fixed regimen would be more effective than the on-demand regimen for postoperative analgesics following periodontal surgery. Methods: An open randomized clinical trial was conducted. The 68 patients who needed total flap surgery to restore supracrestal tissue attachment or surgical treatment of periodontitis were randomized". Visual Analogue Scale was used to assess pain. The fixed group (n = 34) received 500 mg of acetaminophen every 4 hours for 2 days. The on-demand group (n = 34) was instructed to use the acetaminophen "as needed," at intervals of no less than 4 hours between doses. Ibuprofen was the rescue medication for both groups. Pain scores and medication use were recorded 2, 6, 12, 24 and 48 hours after the surgical procedure. The study was registered at the Brazilian Registry of Clinical Trials under RBR-7wv259. Results: The two groups did not differ in relation to the frequency or the intensity of pain in a 48-hour period (n=20 in the fixed group, and n=22 in the on-demand group), or even in the intention-to-treat (n=34 in each group). Individuals who experienced moderate to severe pain used rescue medication more frequently in both groups. No adverse events were reported. Conclusion: Both regimens were effective in controlling postoperative pain after periodontal surgery

Investigation of antioxidant activity of ethanolic extract of the bark of Caesalpinia ferrea in Swiss mice exposed to paracetamol / Investigação da atividade antioxidante do extrato etanólico da casca de Caesalpinia ferrea em camundongos Swiss expostos ao paracetamol

Aims: it was evaluated the antioxidant effect of the ethanolic extract of Caesal-pinia ferrea bark in a model of oxidative stress induced by paracetamol (PCM). Methods: male Swiss mice were subdivided into four groups (control; PCM; PCM+extract; extract; n=8) in which a dose of paracetamol (250 mg.kg-1) was administered and after 3 hours the treatment with the extract (100 mg.kg-1/day) was administered for seven days, via gavage. Oxidative stress biomarkers were determined, such as catalase, glutathione-S-transferase, reduced gluta-thione, ascorbic acid, thiobarbituric acid reactive substances and carbonylated proteins of liver, kidneys and brain and plasma parameters through the dosage of glucose, cholesterol, triglycerides, aspartate aminotransferase and alanine aminotransferase. Results: the Caesalpinia ferrea extract was able to reverse the lipid and protein damage caused by the drug in the liver tissue and caused the same effect in the renal and brain tissues in the carbonylated proteins. The extract alone decreased liver glutathione-S-transferase and increased catalase and brain glutathione-S-transferase activity, in addition to lowering glucose and cholesterol, but without altering the triglycerides. Conclusions: it was possible to conclude that the ethanolic extract of the bark of Caesalpinia ferrea has a good antioxidant activity, probably due to dose of paracetamol in the samples investigated. However, more studies are needed for a better understanding of the effects of this extract compared to the effects found in this research

Objetivos: foi avaliado o efeito antioxidante do extrato etanólico da casca de Caesalpinia ferrea em modelo de estresse oxidativo induzido por paracetamol (acetaminofeno, PCM). Métodos: camundongos Swiss machos foram subdivididos em quatro grupos (controle; PCM; PCM+extrato; extrato; n=8) nos quais foi administrada uma dose de paracetamol (250 mg.kg-1) e após três horas foi administrado o tratamento com o extrato (100 mg.kg-1/ dia) por sete dias, via gavagem. Foram determinados biomarcadores de estresse oxidativo, como catalase, glutationa-S-transferase, glutationa reduzida, ácido ascórbico, substâncias reativas ao ácido tiobarbitúrico e proteínas carboniladas do fígado, rins e cérebro, além de parâmetros plasmáticos através da dosagem de glicose, colesterol, triglicerídeos, aspartato aminotransferase e alanina aminotransferase. Resultados: o extrato de Caesalpinia ferrea foi capaz de reverter os danos lipídicos e proteicos causados pela droga no tecido hepático, e também causou o mesmo efeito nos tecidos renal e cerebral nas proteínas carboniladas. O extrato sozinho diminuiu a atividade da glutationa-S-transferase hepática e aumentou a da catalase e glutationa-S-transferase cerebral, além de diminuir a glicose e o colesterol, mas sem alterar os triglicerídeos. Conclusões: foi possível concluir que o extrato etanólico da casca de Caesalpinia ferrea apresenta uma boa atividade antioxidante, provavelmente devido à presença de taninos, tendo em vista os danos causados pela alta dose de paracetamol nas amostras investigadas. Entretanto, mais estudos são necessários para um melhor entendimento dos efeitos deste extrato frente aos efeitos encontrados nesta pesquisa