Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field

Acetaminophen(APAP),the most frequently used mild analgesic and antipyretic drug worldwide,is implicated in causing 46%of all acute liver failures in the USA and between 40%and 70%in Europe.The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine(NAC);however,its efficacy is limited in cases of advanced liver injury or when administered at a late stage.In the current study,we discovered that treatment with a moderate intensity static magnetic field(SMF)notably reduced the mortality rate in mice subjected to high-dose APAP from 40%to 0%,proving effective at both the initial liver injury stage and the subsequent recovery stage.During the early phase of liver injury,SMF markedly reduced APAPinduced oxidative stress,free radicals,and liver damage,resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione(GSH).During the later stage of liver recovery,application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation.Moreover,the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery,even 24 h post overdose,when the effectiveness of NAC alone substantially declines.Overall,this study provides a noninvasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose.Of note,this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP,and potentially other toxic overdoses.

Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites

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 APAPinduced 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 p4503a11(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.

Effects of a bioartificial liver support system on acetaminophen induced acute liver failure canines

AIM To evaluate the safety and efficacy of the bioartificial liver support system in canines with acute liver failure (ALF). METHODS Nine canines with acute liver failure by acetaminophen induced received TECA Ⅰ bioartificial liver support system (BALSS) from Hong Kong TECA LTD Co. Blood was perfused through a hollow fiber tube containing (1 2)×10 10 the porcine hepatocytes. In contrast, another 10 canines with acute liver failure by Acetaminophen received drugs. Each treatment lasted 6 hours. RESULTS BALSS treatment resulted in beneficial effects for acetaminophen induced ALF canines with survival and with the recovery of the liver functions and tissues, and plasma ammonia decreased from 135 9μmol/L ± 17 5μmol/L to 65 7μmol/L ± 22 0μmol/L , 32 5μmol/L ± 8 8μmol/L , GPT from 97 8U/L ± 8 7U/L to 64 8U/L ± 11 9U/L , 19 0U/L ± 6 3U/L , GOT from 103 0U/L ± 16 7U/L to 75 7U/L ± 19 6U/L , 26 5U/L ± 5 0U/L , and AKP from 158 3U/L ± 12 1U/L to 114 5U/L ± 19 8U/L , 43 8U/L ± 5 6U/L during and after the treatment. In contrast, 10 ALF canines in both the drug and control groups died 1 or 2 days after treatment. CONCLUSION TECA 1 artificial liver support system is safe and efficacious for canines with acute liver failure.

Liuweiwuling tablets attenuate acetaminophen-induced acute liver injury and promote liver regeneration in mice

AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver injury in male C57BL/6 mice.A total of 24 healthy mice were randomly assigned to two groups: an acute liver injury group(control group) and a Liuweiwuling tablet group.Mice were given Liuweiwuling tablets or a vehicle(PBS) orally prior to the administration of acetaminophen.Serum alanine aminotransferase(ALT) and aspartate aminotransaminase(AST) levels were measured at different time points within one week,and pathological examinations of liver tissues were performed 36 h after induction of acute liver injury.Serum inflammatory cytokines,such as high mobility group box protein B1(HMGB1),tumor necrosis factor(TNF)-α and interleukin IL-1b,were detected using an ELISA method according to the manufacturer's instructions.Hepatic morphological changes at 36 h were assessed by hematoxylin and eosin staining.Expression of proliferating cell nuclear antigen(PCNA) in liver tissue was determined by Western blot analysis.The m RNA levels of hepatocyte proliferation markers(PCNA,Cyclin D1 and p21) were detected by real-time quantitative reverse transcription-polymerase chain reaction.RESULTS: The levels of ALT/AST in the Liuweiwuling tablet group were decreased significantly at 6,12 and 24 h compared to that of the control group(654.38 ± 120.87 vs 1566.17 ± 421.64,1154.18 ± 477.72 vs 4654.84 ± 913.71 and 935.13 ± 252.34 vs 4553.75 ± 727.37,P < 0.01).Serum HMGB1 levels at 6 and 12 h for the Liuweiwuling tablet group were significantly lower than those of the control group(23.49 ± 3.89 vs58.6 ± 3.65,61.62 ± 13.07 vs 27.32 ± 5.97,P < 0.01).Furthermore,serum TNF-α and IL-1b levels at 12 h in the Liuweiwuling tablet group were also significantly lower than those of the control group(299.35 ± 50.61 vs 439.03 ± 63.59,57.42 ± 12.98 vs 160.07 ± 49.87,P < 0.01).Centrilobular necrosis was evident in liver tissue of mice with acetaminophen-induced acute liver injury,but was almost abolished in the Liuweiwuling tablet group.The expression levels of PCNA and Cyclin D1 were up-regulated in liver tissue in the Liuweiwuling tablet group(321.08 ± 32.87 vs 157.91 ± 21.52,196.37 ± 25.39 vs 68.72 ± 11.27,P < 0.01); however,expression of p21 in liver tissue was downregulated compared to that of the control group(40.26 ± 9.97 vs 138.24 ± 13.66,P < 0.01).CONCLUSION: Liuweiwuling tablets can attenuate acute liver injury by decreasing inflammatory cytokine(HMGB1,TNF-α and IL-1b) levels and promoting liver regeneration.

Protective effects of Phyllanthus acidus(L.) Skeels leaf extracts on acetaminophen and thioacetamide induced hepatic injuries in Wistar rats

Objective:To investigate and compare the hepatoprotective effects of crude ethanolic and aqueous extracts of Phyllanthus acidus（L.） Skeels（P.acidus） leaves on acetaminophen（APAP） and thioacetamide（TAA） induced liver toxicity in wistar rats.Silymarin was the reference hepatoprotective agent.Methods:In two different sets of experiments,the P.acidus extracts （200 and 400 mg/kg,body weight） and silymarin（100 mg/kg,body weight） were given orally for 7 days and a single dose of APAP（2 g/kg,per oral） or TAA（100 mg/kg,subcutaneous） were given to rats.The level of serum aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,total bilirubin and total protein were monitored to assess hepatotoxicity and hepatoprotection.Results:APAP or TAA administration caused severe hepatic damage in rats as evident from significant rise in serum AST,ALT,ALP,total bilirubin and concurrent depletion in total serum protein.The P.acidus extracts and silymarin prevented the toxic effects of APAP or TAA on the above serum parameters indicating the hepatoprotective action.The aqueous extract was found to be more potent than the corresponding ethanolic extract against both toxicants.The phenolic and flavonoid content（175.02±4.35 and 74.68±1.28,respectively） and 2,2-diphenyl-1- picrylhydrazil（DPPH）[IC50=（33.2±0.31）μg/mL]scavenging potential was found maximum with aqueous extract as compared to ethanolic extract.Conclusions:The results of present study suggests that the aqueous extract of P.acidus leaves has significant hepatoprotective activity on APAP and TAA induced hepatotoxicity,which might be associate with its high phenolic and flavonoid content and antioxidant properties.

Curcumin protects against acetaminophen-induced apoptosis in hepatic injury

AIM:To explore the effects of curcumin(CMN)on hepatic injury induced by acetaminophen(APAP)in vivo.METHODS:Male mice were randomly divided into three groups:groupⅠ(control)mice received the equivalent volumes of phosphate-buffered saline(PBS)intraperitoneally(ip);GroupⅡ[APAP+carboxymethylcellulose(CMC)]mice received 1%CMC(vehicle)2h before APAP injection;GroupⅢ(APAP+CMN)mice received curcumin(10 or 20 mg/kg,ip)2 h before before or after APAP challenge.In GroupsⅡandⅢ,APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg.CMN was dissolved in 1%CMC.Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase(ALT)levels in serum and malondialdehyde(MDA)accumulation,superoxide dismutase(SOD)activity and hepatocyte apoptosis in liver tissues.RESULTS:Both pre-and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group(10 mg/kg:801.46±661.34 U/L;20 mg/kg:99.68±86.48 U/L vs 5406.80±1785.75 U/L,P<0.001,respectively).The incidence of liver necrosis was significantly lowered in CMN treated animals.MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group,but increased in APAP treated group(10.96±0.87 nmol/mg protein vs 16.03±2.58 nmol/mg protein,P<0.05).The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected(24.54±4.95 U/mg protein vs 50.21±1.93 U/mg protein,P<0.05).Furthermore,CMN treatment efficiently protected against APAPinduced apoptosis via increasing Bcl-2/Bax ratio.CONCLUSION:CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases.

Artificial liver support in pigs with acetaminophen-induced acute liver failure

AIM To establish a reversible porcine model of acute liver failure(ALF) and treat it with an artificial liver system. METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen(APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group(n = 11), in which a treatment procedure was performed, or a control group(n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. RESULTS Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased(P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h(at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group(P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution.Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment(P < 0.05). CONCLUSION This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system(ZHj-3) is safe and effective for the APAP-induced porcine ALF model.

Chrysanthemum extract alleviates acetaminophen-induced liver injury by inhibiting oxidative stress via AMPK pathway in rats

OBJECTIVE Acetaminophen(APAP),also known as paracetamol,is a commonly used antipyretic,anal⁃gesic and anti-inflammatory drug.However,during the use of APAP for more than half a century,people have not only used APAP to fight diseases but have also suffered the adverse effects brought about by APAP for more than half a cen⁃tury.The most serious adverse reaction to APAP is hepatotoxicity caused by overdose or long-term use.In Chinese tra⁃ditional medicine,chrysanthemums have the functions of dispelling wind,dissipating heat,clearing the liver and improv⁃ing eyesight.Although the chrysanthemum variety named Bianliang ziyu from Kaifeng is not a medicinal variety,it has good value for medicine and food.The aim of this study was to investigate the protective effect of Bianliang Ziyu extract(BZE)on APAP-damaged rats and the potential molecular mechanism.METHODS Male Sprague-Dawley rats(200-220 g)were intragastrically administered BZE(110,220 and 440 mg·kg^-1)for 8 d.On the ninth day,APAP(800 mg·kg^-1)was administered intragastrically to the rats 0.5 h after BZE administration to induced drug-induced liver injury.The serum and liver samples were collected after 24 h.The levels of alanine aminotransferase(ALT),aspartic aminotransferase(AST),reactive oxygen species(ROS),malondialdehyde(MDA),superoxide dismutase(SOD)and glutathione(GSH)in serum and liver tissue of rats were detected by kit method.HE staining was used to observe the histopathological changes in the liver of rat.The effects of BZE on the expression of the oxidative stress related proteins and the mitochondrial biosyn⁃thesis related proteins were detected by Western blot.RESULTS The results showed that BZE significantly reduced the levels of ALT,AST,MDA and ROS and increased the levels of GSH and SOD caused by APAP.Moreover,BZE increased phosphorylation of AMP-activated protein kinase(AMPK)and glycogen synthase kinase 3β(GSK3β),promoted the nuclear translocation of nuclear factor-erythroid 2-related factor 2(Nrf2).BZE also upregulated the expression of mitochondrial biosynthesis related proteins such as peroxisome proliferator-activated receptorγ(PPAR-γ),peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α),mitochondrial transcription factor(TFAM)and nuclear respira⁃tory factor 1(NRF1).CONCLUSION BZE alleviates APAP-induced liver injury in rats by inhibiting oxidative stress via GSK3β-Nrf2 signaling and the mitochondrial biosynthesis pathway mediated by AMPK.

Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity

Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminopheninduced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature.

Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice

AIM:To examine the effects of 2,4-dihydroxybenzophenone(BP-1),a benzophenone derivative used as an ultraviolet light absorbent,on acetaminophen(APAP)induced hepatotoxicity in C57BL/6J mice.METHODS:Mice were administered orally with BP-1 at doses of 200,400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP(350 mg/kg body weight) was given subcutaneously.Twenty four hours after APAP intoxication,the serum enzyme including serum alaine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH) were measured and liver histopathologic changes were examined.RESULTS:BP-1 administration dramatically reduced serum ALT,AST and LDH levels.Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner.Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment,and glutathione depletion was ameliorated obviously.CONCLUSION:BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity,and reduction of oxidative stress might be part of the protection mechanism.

Hepatoprotective effects of Nigella sativa seed extract against acetaminophen-induced oxidative stress

Objective:To investigate the protective effects of Nigella sativa seed extract(NSSE) against acetaminophen(APAP)-induced hepaloloxicity in TIB-73 cells and rats.Methods:Toxicity in TIB-73 cells was induced with 10 μmol/L APAP and the protective effects of NSSE were evaluated at 25.50.75,100 μg/mL.For in rim examination,a total of 30 rals were equally divided into five experimental groups:normal control(vehicle),APAP(800 mg/kg body weight single IP injection) as a hepatotoxic control,and three APAP and NS pretreated(2 weeks) groups(APAP+NSSE 100 mg:APAP+NSSE 300 mg and APAP+NSSK 900 mg/kg).Results:TIB-73 cell viability was drastically decreased by(49.0±l.9)%after the 10 μmol/L APAP treatment,which also increased reactive oxygen species production.Co-treatment with NSSE at 25.50.75,and 100 μg/mL significantly improved cell viability and suppressed reactive oxygen species generation.In viro the APAP induced alterations in blood lactate levels,pH,anionic gap,and ion levels(HCO_3^-,Mg^(2+) and K^+),which tended to normalize with the NSSE pretreatment.The NSSE also significantly decreased elevated serum levels of alanine aminotransferase,aspartate aminotransferase,lactate dehydrogenase,and alkaline phosphatase induced by APAP,which correlated with decreased levels of hepatic lipid peroxidation(nialondialdehyde),increased superoxide dismutase levels,and reduced glutathione concentrations.Improved hepatic histology was also found in the treatment groups other than APAP group.Conclusions:The in vitro and in vim findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepalotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation.

Acetaminophen-induced acute pancreatitis: A case report and literature review

Acute pancreatitis is rarely associated with drugs. Acetaminophen overdose is a well-known cause of hepatic toxicity, but drug-induced pancreatitis is rarely reported, especially after mild overdose. A 32-yearold woman presented with nausea and vomiting for 12 h, but no abdominal pain following an overdose of eight Tylenol tablets containing acetaminophen(325 mg acetaminophen per tablet). Laboratory results on admission showed abnormal amylase and lipase levels but completely normal liver function. Magnetic resonance cholangiopancreatography revealed mild swelling of the pancreas without fluid collection around the pancreas. The patient complained of severe abdominal pain five days after admission when attempting to drink water and liquids. Eight days after admission, fluid around the pancreas was observed by computed tomography. The patient was subsequently diagnosed with acetaminophen-induced acute pancreatitis after exclusion of common causes. Routine treatment for pancreatitis and N-acetylcysteine were administered to prevent disease progression. The patient was discharged in good condition.

N-acetylcysteine and glycyrrhizin combination:Benefit outcome in a murine model of acetaminophen-induced liver failure

BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries.Substantial progress has been made in understanding the mechanism of hepatocellular injury,but N-acetylcysteine remains the only effective treatment despite its short therapeutic window.Thus,other hepatoprotective drugs are needed for the delayed treatment of acetaminopheninduced hepatotoxicity.Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1(HMGB1)protein,a member of the family of damage-associated molecular pattern,known to play an important pathological role in various diseases.AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments.Mice fasted for 15 h were treated with acetaminophen(500 mg/kg)or vehicle(phosphate-buffered saline)by intraperitoneal injection and separated into the following groups:Glycyrrhizin(200 mg/kg);N-acetylcysteine(150 mg/kg);and N-acetylcysteine/glycyrrhizin.In all groups,mice were sacrificed 12 h following acetaminophen administration.The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase.Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections.Survival rates were compared between various groups using Kaplan-Meier curves.RESULTS Consistent with data published in the literature,we confirmed that intraperitoneal administration of acetaminophen(500 mg/kg)in mice induced severe liver injury as evidenced by increases in alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score.Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury.Thus,the co-administration of glycyrrhizin and N-acetylcysteine was investigated.Administered concomitantly with acetaminophen,the combination significantly reduced the severity of liver injury.Delayed administration of the combination of drugs,2 h or 6 h after acetaminophen,also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone.In addition,administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.CONCLUSION We demonstrate that,compared to N-acetylcysteine alone,co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury.Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.

Protective effects of 5-methoxypsoralen against acetaminophen-induced hepatotoxicity in mice

AIM:To investigate the hepatic protective effects of 5-methoxypsoralen(5-MOP) and to learn if 5-MOP causes hepatotoxicity at protective doses.METHODS:C57BL/6J mice were administrated orally with 5-MOP at doses of 12.5,25 and 50 mg/kg body weight respectively every morning for 4 d before given acetaminophen(APAP) subcutaneously at a dose of 500 mg/kg.The 5-MOP alone group was treated with 5-MOP orally at a dose of 50 mg/kg body weight for 4 d without APAP.Twenty-four hours after APAP administration,blood samples of mice were analyzed for serum enzyme alanine transaminase(ALT),aspartate transaminase(AST),lactate dehydrogenase(LDH) levels,and malondialdehyde(MDA),reduced glutathione(GSH) and oxidized glutathione(GSSG) of liver tissues were measured and histopathologic changes of the liver were observed.RESULTS:Compared with the vehicle control group,the serum levels(IU/L) of ALT,AST and LDH were all increased significantly in APAP group(8355 ± 3940 vs 30 ± 21,P < 0.05;6482 ± 4018 vs 146 ± 58,P <0.05;24627 ± 10975 vs 1504 ± 410,P < 0.05).Compared with APAP group,the serum ALT levels(IU/L)(1674 ± 1810 vs 8355 ± 3940,P < 0.05;54 ± 39 vs 8355 ± 3940,P < 0.05;19 ± 9 vs 8355 ± 3940,P < 0.05),AST levels(IU/L)(729 ± 685 vs 6482 ± 4108,P < 0.05;187 ± 149 vs 6482 ± 4108,P < 0.05;141 ± 12 vs 6482 ± 4108,P < 0.05) and LDH levels(IU/L)(7220 ± 6317 vs 24 627 ± 10 975,P < 0.05;1618 ± 719 vs 24 627 ± 10 975,P < 0.05;1394 ± 469 vs 24 627 ± 10 975,P < 0.05) were all decreased drastically in the three-dosage 5-MOP pretreatment groups.Pretreatment of 5-MOP could attenuate histopathologic changes induced by APAP,including hepatocellular necrosis and infiltration of inflammatory cells,and the effect was dose-dependent.MDA levels(nmol/mg) were decreased by 5-MOP in a dose-dependent manner(0.98 ± 0.45 vs 2.15 ± 1.07,P > 0.05;0.59 ± 0.07 vs 2.15 ± 1.07,P < 0.05;0.47 ± 0.06 vs 2.15 ± 1.07,P < 0.05).The pretreatment of 5-MOP could also increase the GSH/GSSG ratio(3.834 ± 0.340 vs 3.306 ± 0.282,P > 0.05;5.330 ± 0.421 vs 3.306 ± 0.282,P < 0.05;6.180 ± 0.212 vs 3.306 ± 0.282,P < 0.05).In the group treated with 5-MOP but without APAP,the serum enzyme levels,the liver histopathologic manifestation,and the values of MDA and GSH/GSSG ratio were all normal.CONCLUSION:5-MOP can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity and possesses an antioxidative activity,and does not cause liver injury at the protective doses.

Simultaneous determination of acetaminophen and oxycodone in human plasma by LC–MS/MS and its application to a pharmacokinetic study

A simple and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was de- veloped and validated for simultaneous determination of acetaminophen and oxycodone in human plasma. Acetaminophen-d4 and oxycodone-d3 were used as internal standards. The challenge en- countered in the method development that the high plasma concentration level of acetaminophen made the MS response saturated while the desired lower limit of quantification （LLOQ,） for oxycodone was hard to reach was well solved. The analytes were extracted by protein precipitation using acetonitrile. The matrix effect of the analytes was avoided by chromatographic separation using a hydrophilic C18 column coupled with gradient elution. Multiple reaction monitoring in positive ion mode was performed on tandem mass spectrometer employing electrospray ion source. The calibration curves were linear over the concentration ranges of 40.0-8000 ng/mL and 0.200-40.0 ng/mL for acetaminophen and oxycodone, respectively. This method, which could contribute to high throughput analysis and better clinical drug monitoring, was successfully applied to a pharmacokinetic study in healthy Chinese volunteers.

Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose.METHODSEight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy.RESULTSAcute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 mL/min at study end. Thrombocyte values (baseline 307 × 103/µL ± 34 × 103/µL) of intoxicated animals declined slowly to values of 145 × 103/µL ± 46 × 103/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 103/µL ± 3 × 103/µL preceding fatality within few hours which was significant (P > 0.01).CONCLUSIONDeclining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model.

The Simultaneous Determination of Five Components Including Acetaminophen by Ridge Regression Spectrophotometry

Ridge regression spectrophotometry(LHG)is used for thesimultaneous determination of five components(acetaminophen,p-aminophenol, caffeine, chlorphenamine maleate and guaifenesin)incough syr- up. The computer program of LHG is based on VB language.The difficulties in overlapping of absorption spectrums of fivecompounds are overcome by this procedure. The experimental resultsshow that the recovery of each component is in the range from97.9/100 to 103.3/100 and each component obtains satisfactory resultswithout any pre-separation.

Defensive nature of Sargassum polycystum (Brown alga) against acetaminophen-induced toxic hepatitis in rats: Role of drug metabolizing microsomal enzyme system, tumor necrosis factor-a and fate of liver cell structural integrity

AIM： To assess the defensive nature of Sargassum polycystum （S. polycystum） （Brown alga） against acetaminophen （AAP）-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor （TNF-α） and fine structural features of the liver during toxic hepatitis in rats. METHODS： Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group Ⅰ consisted of normal control rats fed with standard diet. Group II rats were administered with acetaminophen （800 mg/kg body weight, intraperitoneally）. Group Ⅲ rats were pre-treated with S. polycystum extract alone. Group IV rats were orally pre-treated with S. polycystum extract （200 mg/kg body weight for 21 d） prior to acetaminophen induction （800 mg/kg body weight, intraperitoneally）. Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and bs. Serum TNF-α was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy. RESULTS： Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and bs when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-a when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably pretreated with S. polycystum. prevented in the rats The rats pretreated withS. polycystum showed considerable inhibition in the elevation of TNF-α compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats, whereas the rats treated with S. polycystum showed considerable protection against acetaminophen-induced alterations in structural integrity. CONCLUSION： These observations suggest that the animals treated with S. polycystum extract may have the ability to protect the drug metabolizing enzyme system and mitochondrial functional status from free radical attack, thereby showing its defense mechanism in protecting hepatic cells from acetaminophen toxic metabolite N-acetyl-para-benzoquinone-imine （NAPQI）.

Vancomycin pretreatment attenuates acetaminophen-induced liver injury through 2-hydroxybutyric acid

Liver injury caused by acetaminophen(AP)overdose is a leading public health problem.Although APinduced liver injury is well recognized as the formation of N-acetyl-p-benzoquinone(NAPQI),a toxic metabolite of AP,resulting in cell damage,emerging evidence indicates that AP-induced liver injury is also associated with gut microbiota.However,the gut microbiota-involved mechanism remains largely unknown.In our study,we found that vancomycin(Vac)pretreatment(100 mg/kg,twice a day for 4 days)attenuated AP-induced liver injury,altered the composition of gut microbiota,and changed serum metabolic profile.Moreover,we identified Vac pretreatment elevated cecum and serum 2-hydroxybutyric acid(2-HB),which ameliorated AP-induced cell damage and liver injury in mice by reducing AP bioavailability and elevating GSH levels.Our current results revealed the novel role of 2-HB in protecting AP-induced liver injury and add new evidence for gut microbiota in affecting AP toxicity.

Comparative efficacy of ketamine,lidocaine,acetaminophen,and dexmedetomidine combined with morphine patient-controlled analgesia in treating opium-addicted patients undergoing tibia fracture surgery:A randomized clinical trial

Objective:To compare the effect of ketamine,lidocaine,acetaminophen,and dexmedetomidine combined with morphine patient-controlled analgesia for opium addicts after tibial fracture surgery.Methods:This double-blind clinical trial included opium-addicted patients undergoing tibia fracture surgery.Patients were recruited and randomized to four different groups including the ketamine group,the lidocaine group,the acetaminophen group,and the dexmedetomidine group.The hemodynamic parameters such as heart rate(HR),mean arterial pressure,and arterial SaO2,alongside visual analog scale pain scores,sedation assessed by Ramsay score,nausea and vomiting,and opioid use were recorded and compared among the four groups.Results:This study included 140 patients,aged 37(32,41)years,with 92 males and 48 females,and each group had 35 patients.Dexmedetomidine-sedated subjects had the lowest blood pressure from 1 to 24 h after surgery,decreased HR at 12 and 24 h after surgery,and more satisfactory sedation(P<0.05).Notwithstanding no significant difference was noted in the pain scores,or nausea and vomiting among the groups(P>0.05).Conclusions:Dexmedetomidine has a better sedation effect compared to ketamine,lidocaine,and acetaminophen for pain control,but the final choice hinges on the patients’physical condition and the anesthesiologist's preference.Clinical registration:It is registered in Iranian Registry Clinical Trial by code IRCT20141209020258N146.