WorldWideScience

Sample records for acute acetaminophen hepatotoxicity

  1. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity

    DEFF Research Database (Denmark)

    Schmidt, L.E.; Dalhoff, K.P.; Poulsen, Henrik E.

    2002-01-01

    . With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1...... was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due......The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were...

  2. Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.

    Science.gov (United States)

    Ajith, T A; Hema, U; Aswathy, M S

    2007-11-01

    A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (pHepatic lipid peroxidation was enhanced significantly (pofficinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.

  3. Mitochondrial–Lysosomal Axis in Acetaminophen Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Anna Moles

    2018-05-01

    Full Text Available Acetaminophen (APAP toxicity is the most common cause of acute liver failure and a major indication for liver transplantion in the United States and Europe. Although significant progress has been made in understanding the molecular mechanisms underlying APAP hepatotoxicity, there is still an urgent need to find novel and effective therapies against APAP-induced acute liver failure. Hepatic APAP metabolism results in the production of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI, which under physiological conditions is cleared by its conjugation with glutathione (GSH to prevent its targeting to mitochondria. APAP overdose or GSH limitation leads to mitochondrial NAPQI-protein adducts formation, resulting in oxidative stress, mitochondrial dysfunction, and necrotic cell death. As mitochondria are a major target of APAP hepatotoxicity, mitochondrial quality control and clearance of dysfunctional mitochondria through mitophagy, emerges as an important strategy to limit oxidative stress and the engagement of molecular events leading to cell death. Recent evidence has indicated a lysosomal–mitochondrial cross-talk that regulates APAP hepatotoxicity. Moreover, as lysosomal function is essential for mitophagy, impairment in the fusion of lysosomes with autophagosomes-containing mitochondria may compromise the clearance of dysfunctional mitochondria, resulting in exacerbated APAP hepatotoxicity. This review centers on the role of mitochondria in APAP hepatotoxicity and how the mitochondrial/lysosomal axis can influence APAP-induced liver failure.

  4. Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats

    Directory of Open Access Journals (Sweden)

    Shim Eugene

    2011-10-01

    Full Text Available Abstract Background Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO, olive oil (OO, and beef tallow (BT on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. Methods Male Sprague-Dawley rats were fed 15% (wt/wt CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg, samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. Results Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. Conclusions Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity.

  5. Necrostatin-1 protects against reactive oxygen species (ROS-induced hepatotoxicity in acetaminophen-induced acute liver failure

    Directory of Open Access Journals (Sweden)

    Kenji Takemoto

    2014-01-01

    Full Text Available Excessive acetaminophen (APAP use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK-dependent necrosis (or necroptosis, which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.

  6. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-01-01

    Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

  7. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

    Science.gov (United States)

    Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

    2018-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  8. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-12-01

    Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

  9. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

    Science.gov (United States)

    Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

    2012-02-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

  10. Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Nesreen E.M. Mohammed

    2016-11-01

    Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

  11. Lack of Direct Cytotoxicity of Extracellular ATP against Hepatocytes: Role in the Mechanism of Acetaminophen Hepatotoxicity

    NARCIS (Netherlands)

    Xie, Yuchao; Woolbright, Benjamin L.; Kos, Milan; McGill, Mitchell R.; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Jaeschke, Hartmut

    2015-01-01

    Acetaminophen (APAP) hepatotoxicity is a major cause of acute liver failure in many countries. Mechanistic studies in mice and humans have implicated formation of a reactive metabolite, mitochondrial dysfunction and oxidant stress as critical events in the pathophysiology of APAP-induced liver cell

  12. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration.

    Science.gov (United States)

    Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Priya; Gupta, Sanjeev

    2018-03-05

    Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. © 2018 John Wiley & Sons Ltd.

  13. Enhancement of acetaminophen overdosage-induced hepatotoxicity ...

    African Journals Online (AJOL)

    paracetamol) overdosage-induced hepatotoxicity in three groups of albino Wistar rats. Administration of the minimum toxic dose of paracetamol (150mg/kg body weight) to animals (group II) produced significantly (P≤0.05) higher levels of alanine ...

  14. Unexpected paracetamol (acetaminophen) hepatotoxicity at standard dosage in two older patients: time to rethink 1 g four times daily?

    Science.gov (United States)

    Ging, Patricia; Mikulich, Olga; O'Reilly, Katherine M A

    2016-07-01

    We present two cases of acute hepatotoxicity associated with elevated paracetamol (acetaminophen) levels in older patients. Both patients were receiving a standard European dose of oral paracetamol (2 × 500 mg QDS) with no risk factors for slowed metabolism (weight paracetamol can be hepatotoxic. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Acetaminophen-induced acute liver injury in HCV transgenic mice

    International Nuclear Information System (INIS)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

    2013-01-01

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  16. Acetaminophen-induced acute liver injury in HCV transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  17. The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model

    Directory of Open Access Journals (Sweden)

    Ben-Shachar Rotem

    2012-12-01

    Full Text Available Abstract Background Acetaminophen (N-acetyl-para-aminophenol is the most widely used over-the-counter or prescription painkiller in the world. Acetaminophen is metabolized in the liver where a toxic byproduct is produced that can be removed by conjugation with glutathione. Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC, which is given to stimulate the production of glutathione. Methods We have created a mathematical model for acetaminophen transport and metabolism including the following compartments: gut, plasma, liver, tissue, urine. In the liver compartment the metabolism of acetaminophen includes sulfation, glucoronidation, conjugation with glutathione, production of the toxic metabolite, and liver damage, taking biochemical parameters from the literature whenever possible. This model is then connected to a previously constructed model of glutathione metabolism. Results We show that our model accurately reproduces published clinical and experimental data on the dose-dependent time course of acetaminophen in the plasma, the accumulation of acetaminophen and its metabolites in the urine, and the depletion of glutathione caused by conjugation with the toxic product. We use the model to study the extent of liver damage caused by overdoses or by chronic use of therapeutic doses, and the effects of polymorphisms in glucoronidation enzymes. We use the model to study the depletion of glutathione and the effect of the size and timing of N-acetyl-cysteine doses given as an antidote. Our model accurately predicts patient death or recovery depending on size of APAP overdose and time of treatment. Conclusions The mathematical model provides a new tool for studying the effects of various doses of acetaminophen on the liver metabolism of acetaminophen and

  18. Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hongming Lv

    2018-03-01

    Full Text Available Acetaminophen (APAP overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2 is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These

  19. Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Cho, Sungjoon; Tripathi, Ashutosh; Chlipala, George; Green, Stefan; Lee, Hyunwoo; Chang, Eugene B; Jeong, Hyunyoung

    2017-01-01

    Acetaminophen (APAP) is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp) 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet) on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes) was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

  20. Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Sungjoon Cho

    Full Text Available Acetaminophen (APAP is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v fructose in water (or regular water for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold higher basal glutathione levels and (~2 fold lower basal (mRNA and activity levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

  1. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    Directory of Open Access Journals (Sweden)

    Miriam S. N. Hohmann

    2013-01-01

    Full Text Available 5-Lipoxygenase (5-LO converts arachidonic acid into leukotrienes (LTs and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/- mice and background wild type mice were challenged with APAP (0.3–6 g/kg or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10, superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

  2. Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

    OpenAIRE

    Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-01-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administra...

  3. Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.

    Science.gov (United States)

    Brillant, Nathalie; Elmasry, Mohamed; Burton, Neal C; Rodriguez, Josep Monne; Sharkey, Jack W; Fenwick, Stephen; Poptani, Harish; Kitteringham, Neil R; Goldring, Christopher E; Kipar, Anja; Park, B Kevin; Antoine, Daniel J

    2017-10-01

    The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration. Copyright © 2017

  4. Acetaminophen Induced Hepatotoxicity in Wistar Rats—A Proteomic Approach

    Directory of Open Access Journals (Sweden)

    Soundharrajan Ilavenil

    2016-01-01

    Full Text Available Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups—control, nontoxic (150 mg/kg and toxic dose (1500 mg/kg of APAP—were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD’s PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%, immunity (14%, neurological related (12% and transporter proteins (2%, whereas in non-toxic dose-induced rats they were  oxidative stress (9%, immunity (6%, neurological (14% and transporter proteins (9%. It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  5. Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

    Science.gov (United States)

    Antoine, Daniel James; Williams, Dominic P; Kipar, Anja; Laverty, Hugh; Park, B Kevin

    2010-01-01

    Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology. PMID:20811657

  6. Early predictors of severe acetaminophen-induced hepatotoxicity in a paediatric population referred to a tertiary paediatric department

    DEFF Research Database (Denmark)

    Hedeland, Rikke Lindgaard; Andersen, Jesper; Askbo, Natasha Louise Friis

    2014-01-01

    -acetylcysteine treatment on hepatotoxicity and the incidence of nephrotoxicity. METHODS: We carried out a retrospective case study on 25 children aged 11-16 years with severe acetaminophen poisoning. RESULTS: Initial biochemical parameters predicted hepatotoxicity, defined as the maximum levels of the international...

  7. Cuscuta arvensis Beyr "Dodder": In Vivo Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    Koca-Caliskan, Ufuk; Yilmaz, Ismet; Taslidere, Asli; Yalcin, Funda N; Aka, Ceylan; Sekeroglu, Nazim

    2018-05-02

    Cuscuta arvensis Beyr. is a parasitic plant, and commonly known as "dodder" in Europe, in the United States, and "tu si zi shu" in China. It is one of the preferred spices used in sweet and savory dishes. Also, it is used as a folk medicine for the treatment particularly of liver problems, knee pains, and physiological hepatitis, which occur notably in newborns and their mothers in the southeastern part of Turkey. The purpose of this study was to investigate the hepatoprotective effects and antioxidant activities of aqueous and methanolic extracts of C. arvensis Beyr. on acetaminophen (APAP)-induced acute hepatotoxicity in rats. The results were supported by subsequent histopathological studies. The hepatoprotective activity of both the aqueous and methanolic extracts at an oral dose of 125 and 250 mg/kg was investigated by observing the reduction levels or the activity of alkaline phosphatase, alkaline transaminase, aspartate aminotransferase, blood urine nitrogen, and total bilirubin content. In vivo antioxidant activity was determined by analyzing the serum superoxide dismutase, malondialdehyde, glutathione, and catalase levels. Chromatographic methods were used to isolate biologically active compounds from the extract, and spectroscopic methods were used for structure elucidation. Both the methanolic and aqueous extracts exerted noticable hepatoprotective and antioxidant effects supporting the folkloric usage of dodder. One of the bioactive compounds was kaempferol-3-O-rhamnoside, isolated and identified from the methanolic extract.

  8. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning. Prospect......Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning...... Hospital (KCH) criteria. Phosphate concentrations were significantly higher in nonsurvivors than in survivors at 48 to 72 hours after overdose (mean 2.65 +/- 1.18 mmol/L vs. 0.68 +/- 0.22 mmol/L, P L vs. 0.59 +/- 0.23 mmol/L, P ...). A threshold phosphate concentration of 1.2 mmol/L at 48 to 96 hours after overdose had sensitivity 89%, specificity 100%, accuracy 98%, positive predictive value 100%, and negative predictive value 98%. The phosphate criteria had higher sensitivity, accuracy, and positive and negative predictive values than...

  9. Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Lin, Chun-Ching

    2007-04-20

    Tu-Si-Zi, the seeds of Cuscuta chinensis Lam. (Convolvulaceae), is a traditional Chinese medicine that is commonly used to nourish and improve the liver and kidney conditions in China and other Asian countries. As oxidative stress promotes the development of acetaminophen (APAP)-induced hepatotoxicity, the aim of the present study was to evaluate and compare the hepatoprotective effect and antioxidant activities of the aqueous and ethanolic extracts of C chinensis on APAP-induced hepatotoxicity in rats. The C chinensis ethanolic extract at an oral dose of both 125 and 250mg/kg showed a significant hepatoprotective effect relatively to the same extent (PCuscuta chinensis can prevent hepatic injuries from APAP-induced hepatotoxicity in rats and this is likely mediated through its antioxidant activities.

  10. Silymarin prevents acetaminophen-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Zuzana Papackova

    Full Text Available Acetaminophen or paracetamol (APAP overdose is a common cause of liver injury. Silymarin (SLM is a hepatoprotective agent widely used for treating liver injury of different origin. In order to evaluate the possible beneficial effects of SLM, Balb/c mice were pretreated with SLM (100 mg/kg b.wt. per os once daily for three days. Two hours after the last SLM dose, the mice were administered APAP (300 mg/kg b.wt. i.p. and killed 6 (T6, 12 (T12 and 24 (T24 hours later. SLM-treated mice exhibited a significant reduction in APAP-induced liver injury, assessed according to AST and ALT release and histological examination. SLM treatment significantly reduced superoxide production, as indicated by lower GSSG content, lower HO-1 induction, alleviated nitrosative stress, decreased p-JNK activation and direct measurement of mitochondrial superoxide production in vitro. SLM did not affect the APAP-induced decrease in CYP2E1 activity and expression during the first 12 hrs. Neutrophil infiltration and enhanced expression of inflammatory markers were first detected at T12 in both groups. Inflammation progressed in the APAP group at T24 but became attenuated in SLM-treated animals. Histological examination suggests that necrosis the dominant cell death pathway in APAP intoxication, which is partially preventable by SLM pretreatment. We demonstrate that SLM significantly protects against APAP-induced liver damage through the scavenger activity of SLM and the reduction of superoxide and peroxynitrite content. Neutrophil-induced damage is probably secondary to necrosis development.

  11. Reversal of acetaminophen-generated oxidative stress and concomitant hepatotoxicity by a phytopharmaceutical product

    Directory of Open Access Journals (Sweden)

    Afolabi C. Akinmoladun

    2017-03-01

    Full Text Available The increasing popularity of herbal medicine and the well-established health benefits of phytochemicals have spurred the multiplicity of nutraceutical and phytopharmaceutical products. In this study, Trévo™, a nutraceutical and phytopharmaceutical product, was evaluated for beneficial effects in acetaminophen-induced hepatic toxicity in Wistar rats. Animals received Trévo™ (1.5 mL/kg, 3.0 mL/kg or 4.5 mL/kg orally for 14 days. Hepatotoxicity was induced by the oral administration of acetaminophen (2 g/kg, 24 h prior to sacrifice. Biochemical liver function tests, oxidative stress indicators and histoarchitectural changes were evaluated. Acetaminophen administration occasioned significant increase (P < 0.05 in serum bilirubin level and activities of the aminotransferases, alkaline phosphatase, γ-glutamyltransferase and lactate dehydrogenase accompanied by a significant decrease (P < 0.05 in albumin level as well as histopathological alterations in liver sections. Promotion of hepatic oxidative stress by acetaminophen was revealed by significant (P < 0.05 increase in lipid peroxidation, depletion of reduced glutathione, and decrease in superoxide dismutase and catalase activities. Administration of Trévo™ remarkably ameliorated acetaminophen-induced histopathological alterations and changes in serum and tissue biochemical markers. The protective effect of Trévo™ (4.5 mL/kg was at par with that of Silymarin (25 mg/kg. The present study indicates that Trévo™ has notable salubrious effects.

  12. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  13. Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.

    Directory of Open Access Journals (Sweden)

    Andrew K Smith

    2016-12-01

    Full Text Available Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite formation within hepatic lobules (NAPQI zonation are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1 influential variables cannot be controlled, and 2 it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1 a glutathione depletion threshold diminishes in the CV direction; and 2 ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour

  14. Effects of α-Melanocortin Enantiomers on Acetaminophen-Induced Hepatotoxicity in CBA Mice

    Directory of Open Access Journals (Sweden)

    Dražen Vikić-Topić

    2009-12-01

    Full Text Available Proteins and peptides in mammals are based exclusively on L-amino acids. Recent investigations show that D-amino acids exhibit physiological effects in vivo, despite of their very small quantities. We have investigated the hepatoprotective effects of the Land D-enantiomers of α-melanocortin peptide (α-MSH. The results showed that peptideenantiomerism is related to the protective effects of melanocortin peptides in vivo. L-α-MSH exhibited potent hepatoprotective effect in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice, while its D-mirror image was inefficient. Furthermore, the antibody to the L-peptide did not recognize the D-structure. The results indicate that the opposite peptide configuration may be used to modulate its function and metabolism in vivo and in vitro.

  15. Acetaminophen hepatotoxicity and HIF-1α induction in acetaminophen toxicity in mice occurs without hypoxia

    International Nuclear Information System (INIS)

    Chaudhuri, Shubhra; McCullough, Sandra S.; Hennings, Leah; Letzig, Lynda; Simpson, Pippa M.; Hinson, Jack A.; James, Laura P.

    2011-01-01

    HIF-1α is a nuclear factor important in the transcription of genes controlling angiogenesis including vascular endothelial growth factor (VEGF). Both hypoxia and oxidative stress are known mechanisms for the induction of HIF-1α. Oxidative stress and mitochondrial permeability transition (MPT) are mechanistically important in acetaminophen (APAP) toxicity in the mouse. MPT may occur as a result of oxidative stress and leads to a large increase in oxidative stress. We previously reported the induction of HIF-1α in mice with APAP toxicity and have shown that VEGF is important in hepatocyte regeneration following APAP toxicity. The following study was performed to examine the relative contribution of hypoxia versus oxidative stress to the induction of HIF-1α in APAP toxicity in the mouse. Time course studies using the hypoxia marker pimonidazole showed no staining for pimonidazole at 1 or 2 h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48 h and no staining was observed in centrilobular hepatocytes, the sites of the toxicity. Subsequent studies with the MPT inhibitor cyclosporine A showed that cyclosporine A (CYC; 10 mg/kg) reduced HIF-1α induction in APAP treated mice at 1 and 4 h and did not inhibit the metabolism of APAP (depletion of hepatic non-protein sulfhydryls and hepatic protein adduct levels). The data suggest that HIF-1α induction in the early stages of APAP toxicity is secondary to oxidative stress via a mechanism involving MPT. In addition, APAP toxicity is not mediated by a hypoxia mechanism.

  16. Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2

    International Nuclear Information System (INIS)

    Aleksunes, Lauren M.; Slitt, Angela L.; Maher, Jonathan M.; Augustine, Lisa M.; Goedken, Michael J.; Chan, Jefferson Y.; Cherrington, Nathan J.; Klaassen, Curtis D.; Manautou, Jose E.

    2008-01-01

    The transcription factor NFE2-related factor 2 (Nrf2) mediates detoxification and antioxidant gene transcription following electrophile exposure and oxidative stress. Mice deficient in Nrf2 (Nrf2-null) are highly susceptible to acetaminophen (APAP) hepatotoxicity and exhibit lower basal and inducible expression of cytoprotective genes, including NADPH quinone oxidoreductase 1 (Nqo1) and glutamate cysteine ligase (catalytic subunit, or Gclc). Administration of toxic APAP doses to C57BL/6J mice generates electrophilic stress and subsequently increases levels of hepatic Nqo1, Gclc and the efflux multidrug resistance-associated protein transporters 1-4 (Mrp1-4). It was hypothesized that induction of hepatic Mrp1-4 expression following APAP is Nrf2 dependent. Plasma and livers from wild-type (WT) and Nrf2-null mice were collected 4, 24 and 48 h after APAP. As expected, hepatotoxicity was greater in Nrf2-null compared to WT mice. Gene and protein expression of Mrp1-4 and the Nrf2 targets, Nqo1 and Gclc, was measured. Induction of Nqo1 and Gclc mRNA and protein after APAP was dependent on Nrf2 expression. Similarly, APAP treatment increased hepatic Mrp3 and Mrp4 mRNA and protein in WT, but not Nrf2-null mice. Mrp1 was induced in both genotypes after APAP, suggesting that elevated expression of this transporter was independent of Nrf2. Mrp2 was not induced in either genotype at the mRNA or protein levels. These results show that Nrf2 mediates induction of Mrp3 and Mrp4 after APAP but does not affect Mrp1 or Mrp2. Thus coordinated regulation of detoxification enzymes and transporters by Nrf2 during APAP hepatotoxicity is a mechanism by which hepatocytes may limit intracellular accumulation of potentially toxic chemicals

  17. Potential Role of Activated Nonparenchymal Cells in Acetaminophen-Induced Potentiation of Hepatotoxicity

    Science.gov (United States)

    1991-06-14

    ALT is either being degraded or the activity is inhibited by something in the 133 media. AST activity in cocultures of NPCs and hepatocytes was... Paracetamol Hepatotoxicity: IN VITRO Studies in Isolated Mouse Hepatocytes. Toxicology Letters. 2229: 37-48. Casini, A. M., P. A. Ferrali and M...Acute Liver Necrosis Following Overdose of Paracetamol . British Medical Journal. 2: 497-499. Decker, T., M. L. Lohmann-Matthes, U. Karck, T. Peters

  18. Nanoparticles formulation of Cuscuta chinensis prevents acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Cham, Thau-Ming; Lin, Chun-Ching

    2008-05-01

    Cuscuta chinensis is a commonly used traditional Chinese medicine to nourish the liver and kidney. Due to the poor water solubility of its major constituents such as flavonoids and lignans, its absorption upon oral administration could be limited. The purpose of the present study was to use the nanosuspension method to prepare C. chinensis nanoparticles (CN), and to compare the hepatoprotective and antioxidant effects of C. chinensis ethanolic extract (CE) and CN on acetaminophen-induced hepatotoxicity in rats. An oral dose of CE at 125 and 250 mg/kg and CN at 25 and 50mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. These biochemical assessments were supported by rat hepatic biopsy examinations. In addition, the antioxidant activities of CE and CN both significantly increased superoxide dismutase, catalase, glutathione peroxidase, and reduced malondialdehyde (P<0.05). Moreover, the results also indicated that the hepatoprotective and antioxidant effects of 50 mg/kg CN was effectively better than 125 mg/kg CE (P<0.05), and an oral dose of CN that is five times as less as CE could exhibit similar levels of outcomes. In conclusion, we suggest that the nanoparticles system can be applied to overcome other water poorly soluble herbal medicines and furthermore to decrease the treatment dosage.

  19. Trifluoperazine inhibits acetaminophen-induced hepatotoxicity and hepatic reactive nitrogen formation in mice and in freshly isolated hepatocytes

    Directory of Open Access Journals (Sweden)

    Sudip Banerjee

    Full Text Available The hepatotoxicity of acetaminophen (APAP occurs by initial metabolism to N-acetyl-p-benzoquinone imine which depletes GSH and forms APAP-protein adducts. Subsequently, the reactive nitrogen species peroxynitrite is formed from nitric oxide (NO and superoxide leading to 3-nitrotyrosine in proteins. Toxicity occurs with inhibited mitochondrial function. We previously reported that in hepatocytes the nNOS (NOS1 inhibitor NANT inhibited APAP toxicity, reactive nitrogen and oxygen species formation, and mitochondrial dysfunction. In this work we examined the effect of trifluoperazine (TFP, a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in murine hepatocytes and in vivo. In freshly isolated hepatocytes TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein, reactive oxygen formation (superoxide, loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation. TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibited. Since we previously reported that TFP inhibits the hepatotoxicity of APAP in mice without altering hepatic APAP-protein adduct formation, we examined the APAP treated mouse livers for evidence of reactive nitrogen formation. 3-Nitrotyrosine in hepatic proteins and GSNO were significantly increased in APAP treated mouse livers and decreased in the livers of mice treated with APAP plus TFP. These data are consistent with a hypothesis that APAP hepatotoxicity occurs with altered calcium metabolism, activation of nNOS leading to increased reactive nitrogen formation, and mitochondrial dysfunction. Keywords: Acetaminophen, Neuronal nitric oxide, Oxidative stress, Mitochondria

  20. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    Science.gov (United States)

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  1. Acetaminophen

    Science.gov (United States)

    Apra® ... Acetaminophen is used to relieve mild to moderate pain from headaches, muscle aches, menstrual periods, colds and ... reactions to vaccinations (shots), and to reduce fever. Acetaminophen may also be used to relieve the pain ...

  2. Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Ebbesen, Maria S.; Nygaard, Ulrikka; Rosthøj, Susanne

    2017-01-01

    Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine...

  3. Acetaminophen (Paracetamol) Induces Hypothermia During Acute Cold Stress.

    Science.gov (United States)

    Foster, Josh; Mauger, Alexis R; Govus, Andrew; Hewson, David; Taylor, Lee

    2017-11-01

    Acetaminophen is an over-the-counter drug used to treat pain and fever, but it has also been shown to reduce core temperature (T c ) in the absence of fever. However, this side effect is not well examined in humans, and it is unknown if the hypothermic response to acetaminophen is exacerbated with cold exposure. To address this question, we mapped the thermoregulatory responses to acetaminophen and placebo administration during exposure to acute cold (10 °C) and thermal neutrality (25 °C). Nine healthy Caucasian males (aged 20-24 years) participated in the experiment. In a double-blind, randomised, repeated measures design, participants were passively exposed to a thermo-neutral or cold environment for 120 min, with administration of 20 mg/kg lean body mass acetaminophen or a placebo 5 min prior to exposure. T c , skin temperature (T sk ), heart rate, and thermal sensation were measured every 10 min, and mean arterial pressure was recorded every 30 min. Data were analysed using linear mixed effects models. Differences in thermal sensation were analysed using a cumulative link mixed model. Acetaminophen had no effect on T c in a thermo-neutral environment, but significantly reduced T c during cold exposure, compared with a placebo. T c was lower in the acetaminophen compared with the placebo condition at each 10-min interval from 80 to 120 min into the trial (all p  0.05). This preliminary trial suggests that acetaminophen-induced hypothermia is exacerbated during cold stress. Larger scale trials seem warranted to determine if acetaminophen administration is associated with an increased risk of accidental hypothermia, particularly in vulnerable populations such as frail elderly individuals.

  4. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPARα with clofibrate

    International Nuclear Information System (INIS)

    Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.; Latendresse, John R.; Mehendale, Harihara M.

    2008-01-01

    The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPARα via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. 14 C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAP hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by 3 H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPARα was tested. PPARα was downregulated in NASH. To investigate whether downregulation of PPARα in NASH is the critical mechanism of compromised liver tissue repair, PPARα was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPARα expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity

  5. Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

    International Nuclear Information System (INIS)

    O'Connor, Meeghan A.; Koza-Taylor, Petra; Campion, Sarah N.; Aleksunes, Lauren M.; Gu, Xinsheng; Enayetallah, Ahmed E.; Lawton, Michael P.; Manautou, José E.

    2014-01-01

    Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430 2 GeneChip. Statistically significant genes were determined and gene expression changes were also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct gene expression

  6. Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

    Energy Technology Data Exchange (ETDEWEB)

    O' Connor, Meeghan A., E-mail: meeghan.oconnor@boehringer-ingelheim.com [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368 (United States); Koza-Taylor, Petra, E-mail: petra.h.koza-taylor@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Campion, Sarah N., E-mail: sarah.campion@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Aleksunes, Lauren M., E-mail: aleksunes@eohsi.rutgers.edu [Rutgers University, Department of Pharmacology and Toxicology, Environmental and Occupational Health Sciences Institute, Piscataway, NJ 08854 (United States); Gu, Xinsheng, E-mail: xinsheng.gu@uconn.edu [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Enayetallah, Ahmed E., E-mail: ahmed.enayetallah@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Lawton, Michael P., E-mail: michael.lawton@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Manautou, José E., E-mail: jose.manautou@uconn.edu [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States)

    2014-01-01

    Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430{sub 2} GeneChip. Statistically significant genes were determined and gene expression changes were also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct gene

  7. Experimental models of hepatotoxicity related to acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Maes, Michaël [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Vinken, Mathieu, E-mail: mvinken@vub.ac.be [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City (United States)

    2016-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.

  8. Efficacy of free glutathione and niosomal glutathione in the treatment of acetaminophen-induced hepatotoxicity in cats

    Directory of Open Access Journals (Sweden)

    L.A. Denzoin Vulcano

    2013-06-01

    Full Text Available Acetaminophen (APAP administration results in hepatotoxicity and hematotoxicity in cats. The response to three different treatments against APAP poisoning was evaluated. Free glutathione (GSH (200mg/kg, niosomal GSH (14 mg/kg and free amino acids (180 mg/kg of N-acetylcysteine and 280 mg/kg of methionine were administered to cats that were intoxicated with APAP (a single dose of 150 mg/kg, p.o.. Serum concentration of alanine aminotransferase (ALT along with serum, liver and erythrocyte concentration of GSH and methemoglobin percentage were measured before and 4, 24 and 72 hours after APAP administration. Free GSH (200 mg/kg and niosomal GSH (14 mg/kg were effective in reducing hepatotoxicity and hematotoxicity in cats intoxicated with a dose of 150 mg/kg APAP. We conclude that both types of treatments can protect the liver and haemoglobin against oxidative stress in APAP intoxicated cats. Furthermore, our results showed that treatment with niosomal GSH represents an effective therapeutic approach for APAP poisoning.

  9. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Abeer Hanafy

    2016-01-01

    Full Text Available The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

  10. Caspase-Mediated Anti-Apoptotic Effect of Ginsenoside Rg5, a Main Rare Ginsenoside, on Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Wang, Zi; Hu, Jun-Nan; Yan, Meng-Han; Xing, Jing-Jing; Liu, Wen-Cong; Li, Wei

    2017-10-25

    Frequent overdose of acetaminophen (APAP) is one of the most common and important incentives of acute hepatotoxicity. Prior to this work, our research group confirmed that black ginseng (Panax ginseng, BG) showed powerful protective effects on APAP-induced ALI. However, it is not clear which kind of individual ginsenoside from BG plays such a liver protection effect. The objective of the current investigation was to evaluate whether ginsenoside Rg5 (G-Rg5) protected against APAP-induced hepatotoxicity and the involved action mechanisms. Mice were administrated with G-Rg5 at two dosages of 10 or 20 mg/kg for 7 consecutive days. After the last treatment, all of the animals that received a single intraperitoneal injection of APAP (250 mg/kg) showed severe liver toxicity after 24 h, and the liver protection effects of G-Rg5 were examined. The results clearly indicated that pretreatment with G-Rg5 remarkably inhibited the production of serum tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) compared with the APAP group. Meanwhile, G-Rg5 decreased the hepatic malondialdehyde (MDA) content, the protein expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 2E1 (CYP2E1) in the liver tissues. G-Rg5 decreased APAP caused the hepatic overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Furthermore, analysis of immunohistochemistry and Western blotting also indicated that G-Rg5 pretreatment inhibited activation of apoptotic pathways mainly via increasing the expression of Bcl-2 protein, decreasing the expression of Bax protein, proliferating cell nuclear antigen (PCNA), cytochrome c, caspase-3, caspase-8, and caspase-9. Liver histopathological observation provided further evidence that pretreatment with G-Rg5 could significantly inhibit hepatocyte necrosis, inflammatory cell infiltration, and apoptosis caused by APAP. In conclusion, the present study clearly demonstrates that G-Rg5 exerts a liver protection effect against

  11. Lycopene pretreatment improves hepatotoxicity induced by acetaminophen in C57BL/6 mice.

    Science.gov (United States)

    Bandeira, Ana Carla Balthar; da Silva, Rafaella Cecília; Rossoni, Joamyr Victor; Figueiredo, Vivian Paulino; Talvani, André; Cangussú, Silvia Dantas; Bezerra, Frank Silva; Costa, Daniela Caldeira

    2017-02-01

    Acetaminophen (APAP) is an antipyretic and analgesic drug that, in high doses, leads to severe liver injury and potentially death. Oxidative stress is an important event in APAP overdose. Researchers are looking for natural antioxidants with the potential to mitigate the harmful effects of reactive oxygen species in different models. Lycopene has been widely studied for its antioxidant properties. The aim of this study was to evaluate the antioxidant potential of lycopene pretreatment in APAP-induced liver injury in C57BL/6 mice. C57BL/6 male mice were divided into the following groups: control (C); sunflower oil (CO); acetaminophen 500mg/kg (APAP); acetaminophen 500mg/kg+lycopene 10mg/kg (APAP+L10), and acetaminophen 500mg/kg+lycopene 100mg/kg (APAP+L100). Mice were pretreated with lycopene for 14 consecutive days prior to APAP overdose. Analyses of blood serum and livers were performed. Lycopene was able to improve redox imbalance, decrease thiobarbituric acid reactive species level, and increase CAT and GSH levels. In addition, it decreased the IL-1β expression and the activity of MMP-2. This study revealed that preventive lycopene consumption in C57BL/6 mice can attenuate the effects of APAP-induced liver injury. Furthermore, by improving the redox state, and thus indicating its potential antioxidant effect, lycopene was also shown to have an influence on inflammatory events. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2011-01-01

    AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses. PMID:21219409

  13. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

    Directory of Open Access Journals (Sweden)

    Hyunseong Kim

    Full Text Available The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2 from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg in mice. Acetaminophen (APAP is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/- mice were injected with PLA2 once a day for five days and sacrificed 24 h (h after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST and alanine aminotransferase (ALT. PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

  14. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

    Science.gov (United States)

    Kim, Hyunseong; Keum, Dong June; Kwak, Jung won; Chung, Hwan-Suck; Bae, Hyunsu

    2014-01-01

    The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/-) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

  15. Acute interstitial nephritis with acetaminophen and alcohol intoxication

    Directory of Open Access Journals (Sweden)

    Alexopoulou Iakovina

    2011-04-01

    Full Text Available Abstract Drug-induced acute interstitial nephritis (AIN represents a growing cause of renal failure in current medical practice. While antimicrobials and non-steroidal anti-inflammatory drugs are typically associated with drug-induced AIN, few reports have been made on the involvement of other analgesics. We report our experience in managing a 17-year-old female with AIN and subsequent renal injury following an acetaminophen overdose in conjunction with acute alcohol intoxication. It is well established that acetaminophen metabolism, particularly at high doses, produces reactive metabolites that may induce renal and hepatic toxicity. It is also plausible however, that such reactive species could instead alter renal peptide immunogenicity, thereby inducing AIN. In the following report, we review a possible mechanism for the acetaminophen-induced AIN observed in our patient and also discuss the potential involvement of acute alcohol ingestion in disease onset. The objective of our report is to increase awareness of healthcare professionals to the potential involvement of these commonly used agents in AIN pathogenesis.

  16. Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David; Bajt, Mary Lynn [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Sharpe, Matthew R. [Department of Internal Medicine, University of Kansas Hospital, Kansas City, KS (United States); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2014-03-01

    Following acetaminophen (APAP) overdose there is an inflammatory response triggered by the release of cellular contents from necrotic hepatocytes into the systemic circulation which initiates the recruitment of neutrophils into the liver. It has been demonstrated that neutrophils do not contribute to APAP-induced liver injury, but their role and the role of NADPH oxidase in injury resolution are controversial. C57BL/6 mice were subjected to APAP overdose and neutrophil activation status was determined during liver injury and liver regeneration. Additionally, human APAP overdose patients (ALT: > 800 U/L) had serial blood draws during the injury and recovery phases for the determination of neutrophil activation. Neutrophils in the peripheral blood of mice showed an increasing activation status (CD11b expression and ROS priming) during and after the peak of injury but returned to baseline levels prior to complete injury resolution. Hepatic sequestered neutrophils showed an increased and sustained CD11b expression, but no ROS priming was observed. Confirming that NADPH oxidase is not critical to injury resolution, gp91{sup phox}−/− mice following APAP overdose displayed no alteration in injury resolution. Peripheral blood from APAP overdose patients also showed increased neutrophil activation status after the peak of liver injury and remained elevated until discharge from the hospital. In mice and humans, markers of activation, like ROS priming, were increased and sustained well after active liver injury had subsided. The similar findings between surviving patients and mice indicate that neutrophil activation may be a critical event for host defense or injury resolution following APAP overdose, but not a contributing factor to APAP-induced injury. - Highlights: • Neutrophil (PMN) function increases during liver repair after acetaminophen overdose. • Liver repair after acetaminophen (APAP)-overdose is not dependent on NADPH oxidase. • Human PMNs do not appear

  17. Acute liver failure after recommended doses of acetaminophen in patients with myopathies

    NARCIS (Netherlands)

    I. Ceelie (Ilse); L.P. James (Laura); V.M.G.J. Gijsen (Violette); R.A.A. Mathôt (Ron); S. Ito (Shinya); C.D. Tesselaar (Coranne); D. Tibboel (Dick); G. Koren (Gideon); S.N. de Wildt (Saskia)

    2011-01-01

    textabstractObjective: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Design: Retrospective analysis. Setting: Level III pediatric intensive care unit. Patients: Two pediatric patients with myopathies and acute

  18. Acute liver failure after recommended doses of acetaminophen in patients with myopathies

    NARCIS (Netherlands)

    Ceelie, Ilse; James, Laura P.; Gijsen, Violette; Mathot, Ron A. A.; Ito, Shinya; Tesselaar, Coranne D.; Tibboel, Dick; Koren, Gideon; de Wildt, Saskia N.

    2011-01-01

    To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Retrospective analysis. Level III pediatric intensive care unit. Two pediatric patients with myopathies and acute liver failure. CLINICAL INVESTIGATIONS: We

  19. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity

    International Nuclear Information System (INIS)

    Ramachandran, Anup; Lebofsky, Margitta; Weinman, Steven A.; Jaeschke, Hartmut

    2011-01-01

    Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after APAP overdose. Treatment of C57Bl/6J wild type animals with 200 mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870 ± 180 U/L) and centrilobular necrosis at 6 h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to-GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK. SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation. Conclusions: the impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and more necrosis.

  20. Early Risk Factors of Moderate/Severe Hepatotoxicity After Suicide Attempts With Acetaminophen in 11- to 15-Year-Old Children

    DEFF Research Database (Denmark)

    Hedeland, Rikke Lindgaard; Christensen, Vibeke Brix; Jørgensen, Marianne Hørby

    2014-01-01

    Objective. To characterize early risk factors of moderate/severe hepatotoxicity in a pediatric population with acetaminophen overdose, due to suicide attempt, admitted to a general secondary-level pediatric department. Methods. A retrospective case study of 107 patients, 11 to 15 years old. Results...... was significantly related to the elevation of several hepatologically relevant biochemical parameters (eg, maximum γ-glutamyl transferase; P = .0001). Patients suffering from illness prior to their suicide attempt had significantly greater elevations of their hepatologically relevant biochemical parameters...

  1. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.

    Science.gov (United States)

    Elinav, Eran; Pinsker, Galia; Safadi, Rifaat; Pappo, Orit; Bromberg, Michal; Anis, Emilia; Keinan-Boker, Lital; Broide, Efrat; Ackerman, Zvi; Kaluski, Dorit Nitzan; Lev, Boaz; Shouval, Daniel

    2007-10-01

    Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease.

  2. Therapeutic potential of alpha-ketoglutarate against acetaminophen-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Lalita Mehra

    2016-01-01

    Full Text Available Objective: Alpha-ketoglutarate (α-KG is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP induced toxicity in rats. Materials and Methods: Animals were divided into three groups of six animals each. Group I (Vehicle control: Normal Saline, Group II (APAP: A single intraperitoneal injection of 0.6 g/kg, Group III (APAP + α-KG: APAP as in Group II with α-KG treatment at a dose of 2 g/kg, orally for 5 days. Then the levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and alkaline phosphatase (ALP with oxidative stress markers including malondialdehyde (MDA, reduced glutathione (GSH, superoxide dismutase (SOD, catalase (CAT, and histopathology were analyzed. Results: The results indicate that APAP caused significant elevations in ALT, AST, ALP, and MDA levels, while GSH, SOD, and CAT were significantly depleted while co-administration of α-KG showed a significant (P < 0.05 reduction in the severity of these damages. Histologically, the liver showed inflammation and necrosis after APAP treatment, which were significantly restored with co-administration of α-KG. Conclusion: These results indicate the possible therapeutic potential of α-KG in protecting liver damage by APAP in rats.

  3. False positive acetaminophen concentrations in icteric serum

    Directory of Open Access Journals (Sweden)

    L. de Jong

    2016-04-01

    Full Text Available Introduction: Serum concentrations of acetaminophen are measured to predict the risk of hepatotoxicity in cases of acetaminophen overdose and to identify acetaminophen use in patients with acute liver injury without a known cause. The acetaminophen concentration determines if treatment with N-acetyl cysteine, the antidote for acetaminophen poisoning, is warranted. Description: A 49-year-old woman was admitted to our hospital with a hepatic encephalopathy and a total serum bilirubin concentration of 442 µmol/l. The acetaminophen concentration of 11.5 mg/l was measured with an enzymatic-colorimetric assay, thus treatment with N-acetyl cysteine was started. Interestingly, the acetaminophen concentration remained unchanged (11.5–12.3 mg/l during a period of 4 consecutive days. In contrast, the acetaminophen concentration measured by HPLC, a chromatographic technique, remained undetectable Discussion: In the presented case, elevated bilirubin was the most likely candidate to interfere with acetaminophen assay causing false positive results. Bilirubin has intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum and for that reason it causes interference in an enzymatic-colorimetric assay. Conclusion: False positive acetaminophen laboratory test results may be found in icteric serum, when enzymatic-colorimetric assays are used for determination of an acetaminophen concentration. Questionable acetaminophen results in icteric serum should be confirmed by a non-enzymatic method, by means of ultrafiltration of the serum, or by dilution studies. Keywords: Acetaminophen, Enzymatic-colorimetric assays, HPLC, Bilirubin, Interference, Paracetamol, Liver failure, Jaundice

  4. Hepatoprotective Effect of Metadoxine on Acetaminophen-induced Liver Toxicity in Mice

    Directory of Open Access Journals (Sweden)

    Parvin Mazraati

    2018-01-01

    Full Text Available Background: Metadoxine (pyridoxine pyrrolidone carboxylate is considered to be a beneficial agent for the treatment of experimental hepatotoxicity due to alcohol, CCl4, and bile duct ligation. Hence, the therapeutic effect of metadoxine and N-acetylcysteine (NAC as reference drug was investigated in mice exposed to acute hepatotoxicity induced by a single oral toxic dose of acetaminophen (650 mg/kg. Materials and Methods: Metadoxine (200 and 400 mg/kg and NAC (300 mg/kg were given orally (p. o., 2 h after acetaminophen administration. Serum aminotransferases, aspartate transaminase (AST, alanine transaminase (ALT, alkaline phosphatase (ALP, total bilirubin, hepatic glutathione (GSH, and malondialdehyde (MDA levels were determined for evaluating the extent of hepatotoxicity due to acetaminophen and its protection by metadoxine. Results: Findings indicated that metadoxine significantly reduced the level of serum ALT, AST, and ALP but not total bilirubin which increased by acetaminophen intoxication. Administration of metadoxine also attenuated oxidative stress by suppressing lipid peroxidation (MDA and prevented the depletion of reduced GSH level which caused by acetaminophen toxicity. Besides, metadoxine ameliorated histopathological hepatic tissue injury induced by acetaminophen. Conclusion: In most parameters examined, the effect of metadoxine was comparable to NAC. Hence, metadoxine could be considered as a beneficial therapeutic candidate to protect against acute acetaminophen hepatotoxicity.

  5. Effect of paracetamol (acetaminophen) on body temperature in acute stroke: A meta-analysis.

    Science.gov (United States)

    Fang, Junjie; Chen, Chensong; Cheng, Hongsen; Wang, Ren; Ma, Linhao

    2017-10-01

    The objective of this study was to assess the efficacy of paracetamol (acetaminophen) on body temperature in acute stroke. Medline, Cochrane Central Register of Controlled Trials, EMBASE, Chinese BioMedical Literature Database, China National Knowledge Infrastructure, and the World Health Organization (WHO) International Clinical Trials Registry Platform were searched electronically. Relevant journals and references of studies included were hand-searched for randomized controlled trials (RCT) and controlled clinical trials (CCT) regarding the efficacy of paracetamol (acetaminophen) on body temperature in acute stroke. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.3 software by the Cochrane Collaboration. Five studies were included. To compare the efficacy of paracetamol (acetaminophen) in acute stroke, the pooled RR (Risk Ratio) and its 95% CI of body temperature reduction at 24h from the start of treatment were -0.3 (95% CI: -0.52 to -0.08), with statistical significance (P=0.007). Consistently, the pooled RR (Risk Ratio) and its 95% CI of body temperature at 24h from the start of treatment were -0.22 (-0.29, -0.15), with statistical significance (PParacetamol (acetaminophen) is one of the most commonly used antipyretic drugs and has some capability to reduce body temperature through acting on central nervous system. Acetaminophen showed some capability to decrease body temperature for acute stroke. Acetaminophen could not improve functional outcome and reduce adverse events of patients with acute stroke. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans

    Science.gov (United States)

    McGill, Mitchell R.; Cao, Mengde; Svetlov, Archie; Sharpe, Matthew R.; Williams, C. David; Curry, Steven C.; Farhood, Anwar; Jaeschke, Hartmut; Svetlov, Stanislav I.

    2014-01-01

    Context New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate. Objective Characterize ASS in APAP hepatotoxicity. Methods ASS was measured in plasma from rodents and humans with APAP hepatotoxicity. Results In mice, ASS increased before injury, peaked before ALT, and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all. Conclusions : ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity. PMID:24597531

  7. Acute acetaminophen (paracetamol) ingestion improves time to exhaustion during exercise in the heat.

    Science.gov (United States)

    Mauger, Alexis R; Taylor, Lee; Harding, Christopher; Wright, Benjamin; Foster, Josh; Castle, Paul C

    2014-01-01

    Acetaminophen (paracetamol) is a commonly used over-the-counter analgesic and antipyretic and has previously been shown to improve exercise performance through a reduction in perceived pain. This study sought to establish whether its antipyretic action may also improve exercise capacity in the heat by moderating the increase in core temperature. On separate days, 11 recreationally active participants completed two experimental time-to-exhaustion trials on a cycle ergometer in hot conditions (30°C, 50% relative humidity) after ingesting a placebo control or an oral dose of acetaminophen in a randomized, double-blind design. Following acetaminophen ingestion, participants cycled for a significantly longer period of time (acetaminophen, 23 ± 15 min versus placebo, 19 ± 13 min; P = 0.005; 95% confidence interval = 90-379 s), and this was accompanied by significantly lower core (-0.15°C), skin (-0.47°C) and body temperatures (0.19°C; P 0.05). This is the first study to demonstrate that an acute dose of acetaminophen can improve cycling capacity in hot conditions, and that this may be due to the observed reduction in core, skin and body temperature and the subjective perception of thermal comfort. These findings suggest that acetaminophen may reduce the thermoregulatory strain elicited from exercise, thus improving time to exhaustion.

  8. Protective Effects of Tormentic Acid, a Major Component of Suspension Cultures of Eriobotrya japonica Cells, on Acetaminophen-Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Wen-Ping Jiang

    2017-05-01

    Full Text Available An acetaminophen (APAP overdose can cause hepatotoxicity and lead to fatal liver damage. The hepatoprotective effects of tormentic acid (TA on acetaminophen (APAP-induced liver damage were investigated in mice. TA was intraperitoneally (i.p. administered for six days prior to APAP administration. Pretreatment with TA prevented the elevation of serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, total bilirubin (T-Bil, total cholesterol (TC, triacylglycerol (TG, and liver lipid peroxide levels in APAP-treated mice and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, TA attenuated the APAP-induced production of nitric oxide (NO, reactive oxygen species (ROS, tumor necrosis factor-alpha (TNF-α, interleukin-1beta (IL-1β, and IL-6. Furthermore, the Western blot analysis showed that TA blocked the protein expression of inducible NO synthase (iNOS and cyclooxygenase-2 (COX-2, as well as the inhibition of nuclear factor-kappa B (NF-κB and mitogen-activated protein kinases (MAPKs activation in APAP-injured liver tissues. TA also retained the superoxidase dismutase (SOD, glutathione peroxidase (GPx, and catalase (CAT in the liver. These results suggest that the hepatoprotective effects of TA may be related to its anti-inflammatory effect by decreasing thiobarbituric acid reactive substances (TBARS, iNOS, COX-2, TNF-α, IL-1β, and IL-6, and inhibiting NF-κB and MAPK activation. Antioxidative properties were also observed, as shown by heme oxygenase-1 (HO-1 induction in the liver, and decreases in lipid peroxides and ROS. Therefore, TA may be a potential therapeutic candidate for the prevention of APAP-induced liver injury by inhibiting oxidative stress and inflammation.

  9. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Gonzalez Ponce, Herson Antonio; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  10. Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Koerner, Michael R., E-mail: mkoern2@illinois.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Lampe, Jed N. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Farhood, Anwar [Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2011-12-15

    The mechanisms of acetaminophen (APAP)-mediated hepatic oncotic necrosis have been extensively characterized. However, it was recently demonstrated that fed CD-1 mice have a transient caspase activation which initiates apoptosis. To evaluate these findings in more detail, outbred (Swiss Webster, SW) and inbred (C57BL/6) mice were treated with APAP with or without pan-caspase inhibitor and compared to the apoptosis model of galactosamine (GalN)/endotoxin (ET). Fasted or fed APAP-treated C57BL/6 mice showed no evidence of caspase-3 processing or activity. Interestingly, a minor, temporary increase in caspase-3 processing and activity (150% above baseline) was observed after APAP treatment only in fed SW mice. The degree of caspase-3 activation in SW mice after APAP was minor compared to that observed in GalN/ET-treated mice (1600% above baseline). The pancaspase inhibitor attenuated caspase activation and resulted in increased APAP-induced injury (plasma ALT, necrosis scoring). The caspase inhibitor did not affect apoptosis because regardless of treatment only < 0.5% of hepatocytes showed consistent apoptotic morphology after APAP. In contrast, > 20% apoptotic cells were observed in GalN/ET-treated mice. Presence of the caspase inhibitor altered hepatic glutathione levels in SW mice, which could explain the exacerbation of injury. Additionally, the infiltration of hepatic neutrophils was not altered by the fed state of either mouse strain. Conclusion: Minor caspase-3 activation without apoptotic cell death can be observed only in fed mice of some outbred strains. These findings suggest that although the severity of APAP-induced liver injury varies between fed and fasted animals, the mechanism of cell death does not fundamentally change. -- Highlights: Black-Right-Pointing-Pointer During acetaminophen overdose caspase-3 can be activated in fed mice of certain outbred strains. Black-Right-Pointing-Pointer Hepatic ATP levels are not the determining factor for caspase

  11. Phytoextract of Indian mustard seeds acts by suppressing the generation of ROS against acetaminophen-induced hepatotoxicity in HepG2 cells.

    Science.gov (United States)

    Parikh, Harita; Pandita, Nancy; Khanna, Aparna

    2015-07-01

    Indian mustard [Brassica juncea (L.) Czern. & Coss. (Brassicaceae)] is reported to possess diverse pharmacological properties. However, limited information is available concerning its hepatoprotective activity and mechanism of action. To study the protective mechanism of mustard seed extract against acetaminophen (APAP) toxicity in a hepatocellular carcinoma (HepG2) cell line. Hepatotoxicity models were established using APAP (2.5-22.5 mM) based on the cytotoxicity profile. An antioxidant-rich fraction from mustard seeds was extracted and evaluated for its hepatoprotective potential. The mechanism of action was elucidated using various in vitro antioxidant assays, the detection of intracellular generation of reactive oxygen species (ROS), and cell cycle analysis. The phytoconstituents isolated via HPLC-DAD were also evaluated for hepatoprotective activity. Hydromethanolic seed extract exhibited hepatoprotective activity in post- and pre-treatment models of 20 mM APAP toxicity and restored the elevated levels of liver indices to normal values (p DAD analysis revealed the presence quercetin, vitamin E, and catechin, which exhibited hepatoprotective activity. A phytoextract of mustard seeds acts by suppressing the generation of ROS in response to APAP toxicity.

  12. Risk prediction of hepatotoxicity in paracetamol poisoning.

    Science.gov (United States)

    Wong, Anselm; Graudins, Andis

    2017-09-01

    Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. A systematic literature review was conducted using the search terms: "paracetamol" OR "acetaminophen" AND "overdose" OR "toxicity" OR "risk prediction rules" OR "hepatotoxicity" OR "psi parameter" OR "multiplication product" OR "half-life" OR "prothrombin time" OR "AST/ALT (aspartate transaminase/alanine transaminase)" OR "dose" OR "biomarkers" OR "nomogram". The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half

  13. Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase

    International Nuclear Information System (INIS)

    Du, Kuo; Williams, C. David; McGill, Mitchell R.; Jaeschke, Hartmut

    2014-01-01

    Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300 mg/kg) caused severe liver injury in male mice but 69–77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in the mitochondria at 4 h, and 2.5 and 3.3 fold higher in the total liver at 4 h and 6 h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6 h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4 h post-APAP, it was 3.1 fold lower at 6 h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery. Conclusion: The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery. - Highlights: • Female mice are less susceptible to acetaminophen overdose than males. • GSH depletion and protein adduct formation are similar in both genders. • Recovery of hepatic GSH levels is faster in females and correlates with Gclc. • Reduced oxidant stress in females leads to reduced JNK activation. • JNK activation and mitochondrial translocation are critical

  14. Induction of Mkp-1 and Nuclear Translocation of Nrf2 by Limonoids from Khaya grandifoliola C.DC Protect L-02 Hepatocytes against Acetaminophen-Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Arnaud F. Kouam

    2017-09-01

    Full Text Available Drug-induced liver injury (DILI is a major clinical problem where natural compounds hold promise for its abrogation. Khaya grandifoliola (Meliaceae is used in Cameroonian traditional medicine for the treatment of liver related diseases and has been studied for its hepatoprotective properties. Till date, reports showing the hepatoprotective molecular mechanism of the plant are lacking. The aim of this study was therefore to identify compounds from the plant bearing hepatoprotective activity and the related molecular mechanism by assessing their effects against acetaminophen (APAP-induced hepatotoxicity in normal human liver L-02 cells line. The cells were exposed to APAP (10 mM or co-treated with phytochemical compounds (40 μM over a period of 36 h and, biochemical and molecular parameters assessed. Three known limonoids namely 17-epi-methyl-6-hydroxylangolensate, 7-deacetoxy-7-oxogedunin and deacetoxy-7R-hydroxygedunin were identified. The results of cells viability and membrane integrity, reactive oxygen species generation and lipid membrane peroxidation assays, cellular glutathione content determination as well as expression of cytochrome P450 2E1 demonstrated the protective action of the limonoids. Immunoblotting analysis revealed that limonoids inhibited APAP-induced c-Jun N-terminal Kinase phosphorylation (p-JNK, mitochondrial translocation of p-JNK and Bcl2-associated X Protein, and the release of Apoptosis-inducing Factor into the cytosol. Interestingly, limonoids increased the expression of Mitogen-activated Protein Kinase Phosphatase (Mkp-1, an endogenous inhibitor of JNK phosphorylation and, induced the nuclear translocation of Nuclear Factor Erythroid 2-related Factor-2 (Nrf2 and decreased the expression of Kelch-like ECH-associated Protein-1. The limonoids also reversed the APAP-induced decreased mRNA levels of Catalase, Superoxide Dismutase-1, Glutathione-S-Transferase and Methionine Adenosyltransferase-1A. The obtained results

  15. Simultaneous Voltammetric Determination of Acetaminophen and Isoniazid (Hepatotoxicity-Related Drugs) Utilizing Bismuth Oxide Nanorod Modified Screen-Printed Electrochemical Sensing Platforms.

    Science.gov (United States)

    Mahmoud, Bahaa G; Khairy, Mohamed; Rashwan, Farouk A; Banks, Craig E

    2017-02-07

    To overcome the recent outbreaks of hepatotoxicity-related drugs, a new analytical tool for the continuously determination of these drugs in human fluids is required. Electrochemical-based analytical methods offer an effective, rapid, and simple tool for on-site determination of various organic and inorganic species. However, the design of a sensitive, selective, stable, and reproducible sensor is still a major challenge. In the present manuscript, a facile, one-pot hydrothermal synthesis of bismuth oxide (Bi 2 O 2.33 ) nanostructures (nanorods) was developed. These BiO nanorods were cast onto mass disposable graphite screen-printed electrodes (BiO-SPEs), allowing the ultrasensitive determination of acetaminophen (APAP) in the presence of its common interference isoniazid (INH), which are both found in drug samples. The simultaneous electroanalytical sensing using BiO-SPEs exhibited strong electrocatalytic activity toward the sensing of APAP and INH with an enhanced analytical signal (voltammetric peak) over that achievable at unmodified (bare) SPEs. The electroanalytical sensing of APAP and INH are possible with accessible linear ranges from 0.5 to 1250 μM and 5 to 1760 μM with limits of detection (3σ) of 30 nM and 1.85 μM, respectively. The stability, reproducibility, and repeatability of BiO-SPE were also investigated. The BiO-SPEs were evaluated toward the sensing of APAP and INH in human serum, urine, saliva, and tablet samples. The results presented in this paper demonstrate that BiO-SPEs sensing platforms provide a potential candidate for the accurate determination of APAP and INH within human fluids and pharmaceutical formulations.

  16. Interventions for paracetamol (acetaminophen) overdoses

    DEFF Research Database (Denmark)

    Brok, J; Buckley, N; Gluud, C

    2002-01-01

    Self-poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Interventions for paracetamol poisoning encompass inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation.......Self-poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Interventions for paracetamol poisoning encompass inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation....

  17. Profile of extended-release oxycodone/acetaminophen for acute pain

    Directory of Open Access Journals (Sweden)

    Bekhit MH

    2015-10-01

    Full Text Available Mary Hanna Bekhit1–51David Geffen School of Medicine, 2Ronald Reagan UCLA Medical Center, 3UCLA Ambulatory Surgery Center, 4UCLA Wasserman Eye Institute, 5UCLA Martin Luther King Community Hospital, University of California Los Angeles, Los Angeles, CA, USA Abstract: This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen, are available solely in immediate-release (IR formulations. Keywords: opioid, analgesic, xartemis, acute postsurgical pain, substance abuse, acetaminophen, extended release 

  18. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Chun-Hung Chiu

    2016-07-01

    Full Text Available Lipopolysaccharide (LPS-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST, a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10 for seven days and then were LPS-challenged (i.p., 5 mg/kg. The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT, glutamic oxaloacetic transaminase (GOT, blood urea nitrogen (BUN, creatinine (CRE, hepatic malondialdehyde (MDA and glutathione peroxidase (GSH-Px, IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS, suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day. Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  19. A case of moderate liver enzyme elevation after acute acetaminophen overdose despite undetectable acetaminophen level and normal initial liver enzymes.

    Science.gov (United States)

    Bebarta, Vikhyat S; Shiner, Drew C; Varney, Shawn M

    2014-01-01

    Liver function test (LFT) increase is an early sign of acetaminophen (APAP) toxicity. Typically, when an acute overdose patient is evaluated and has an initial undetectable APAP level and normal liver enzymes, the patient is not treated with N-acetylcysteine, and liver enzymes are not expected to increase later. We report a case of moderate LFT increase despite normal LFTs and an undetectable APAP level after delayed presentation of an APAP ingestion. A 22-year-old male with no medical history ingested 15-25 hydrocodone/APAP tablets (5 mg/500 mg). His suicide note and his bunkmate corroborated the overdose time. He arrived at the emergency department 16 hours after ingestion. At that time, his APAP level was enzymes were normal [aspartate transaminase (AST) 31 U/L and alanine transaminase (ALT) 34 U/L]. Twenty-nine hours after ingestion, the psychiatry team obtained LFTs (AST 45, ALT 61). He had persistent nausea and diffuse abdominal pain. On repeat analysis, the APAP level at 36 hours was found to be <10 μg/mL, AST 150, and ALT 204. After 2 more days of increasing LFTs and persistent abdominal pain and nausea, the toxicology department was consulted, the patient was transferred to the medicine department, and intravenous N-acetylcysteine was started 66 hours after ingestion. He was treated for 16 hours and had a significant decline in LFTs and symptom resolution. His prothrombin time, bilirubin, lactate, creatinine, and mental status were normal throughout the admission. Other cases of LFT increase were excluded. Our case report illustrates that a moderate increase in liver transaminase may occur despite an initial undetectable APAP level and normal transaminases after a delayed presentation. In our case, no serious clinical effects were reported.

  20. Protective Effect of Hydroalcoholic Extract of Salvia officinalis L. against Acute Liver Toxicity of Acetaminophen in Mice

    Directory of Open Access Journals (Sweden)

    H. Foruozandeh

    2016-09-01

    Full Text Available Aims: The medical herbs play important roles in the treatment of liver diseases. In the traditional medicine, Salvia officinalis is highly used to heal a wide range of diseases. The aim of this study was to investigate the treatment effects of Saliva officinalis on hepatotoxicity due to acetaminophen. Materials & Methods: In the experimental study, 60 albino mice were studied. The rats were divided into 6 groups. The first, second, and third groups were physiological serum, crude extract of Saliva officinalis, and 500mg acetaminophen per 1Kg consumed as single dose, respectively. The fourth, fifth, and sixth groups received 5-day 125, 250, and 500mg per 1Kg extract of Saliva officinalis, respectively. Then, they received 500mg acetaminophen one hour after the last administration of extract. Blood sampling was done from the carotids of the rats 24hour later, and the levels of bilirubin and liver enzymes were measured. In addition, their liver tissues were studied. Data was analyzed by SPSS 16 software using one-way ANOVA. Findings: There were significant increases in the direct and complete bilirubin concentration and liver enzymes due to acetaminophen compared to control group (p<0.05. There were significant reductions in the direct and complete bilirubin and liver enzymes due to 125, 250, and 500mg per 1Kg of the extract of Saliva officinalis compared to control group (p<0.05. The results were confirmed by the histology studies. Conclusion: 250 and 500mg per 1Kg of Saliva officinalis potentially protect the damages caused by acetaminophen. In addition, they considerably improve the tissue damage and the biochemical indices in the liver damages.

  1. Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells

    Directory of Open Access Journals (Sweden)

    Yu Ri Kim

    2013-01-01

    Full Text Available High doses of acetaminophen (APAP; N-acetyl-p-aminophenol cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg. Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity.

  2. Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    Shen, Zhenyu; Wang, Yu; Su, Zhenhui; Kou, Ruirui; Xie, Keqin; Song, Fuyong

    2018-02-25

    Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Interventions for paracetamol (acetaminophen) overdoses. Protocol for a Cochrane Review

    DEFF Research Database (Denmark)

    Brok, J; Buckley, N; Gluud, C

    2001-01-01

    Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning.......Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning....

  4. Acetaminophen (Paracetamol induced acute liver failure – A social problem in an era of increasing tendency to self-treatment

    Directory of Open Access Journals (Sweden)

    Tadeusz Wróblewski

    2015-12-01

    Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

  5. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

    Energy Technology Data Exchange (ETDEWEB)

    Jetten, Marlon J.A.; Gaj, Stan [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Ruiz-Aracama, Ainhoa [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Kok, Theo M. de [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Delft, Joost H.M. van, E-mail: j.vandelft@maastrichtuniversity.nl [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Lommen, Arjen [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Someren, Eugene P. van [Research Group Microbiology and Systems Biology, TNO, PO Box 360 3700 AJ Zeist (Netherlands); Jennen, Danyel G.J.; Claessen, Sandra M. [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Peijnenburg, Ad A.C.M. [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Stierum, Rob H. [Research Group Microbiology and Systems Biology, TNO, PO Box 360 3700 AJ Zeist (Netherlands); Kleinjans, Jos C.S. [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands)

    2012-03-15

    Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques

  6. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

    International Nuclear Information System (INIS)

    Jetten, Marlon J.A.; Gaj, Stan; Ruiz-Aracama, Ainhoa; Kok, Theo M. de; Delft, Joost H.M. van; Lommen, Arjen; Someren, Eugene P. van; Jennen, Danyel G.J.; Claessen, Sandra M.; Peijnenburg, Ad A.C.M.; Stierum, Rob H.; Kleinjans, Jos C.S.

    2012-01-01

    Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques outperformed

  7. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7 hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do

  8. Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice

    International Nuclear Information System (INIS)

    Wang, Tao; Yang, Ping; Zhan, Yibei; Xia, Lin; Hua, Zichun; Zhang, Jianfa

    2013-01-01

    The severity of ethanol-induced liver injury is associated with oxidative stress and lipid accumulation in the liver. Core circadian clock is known to mediate antioxidative enzyme activity and lipid metabolism. However, the link between circadian clock and ethanol-induced hepatotoxicity remains unclear. Here we showed that extents of acute ethanol-induced liver injury and steatosis in mice exhibit circadian variations consistent with hepatic expression of Period (Per) genes. Mice lacking clock gene Per1 displayed less susceptible to ethanol-induced liver injury, as evidenced by lower serum transaminase activity and less severe histopathological changes. Ethanol-induced lipid peroxidation was alleviated in Per1−/− mice. However, Per1 deletion had no effect on antioxidants depletion caused by ethanol administration. Ethanol-induced triglycerides (TG) accumulation in the serum and liver was significantly decreased in Per1−/− mice compared with that in wild-type (WT) mice. Analysis of gene expression in the liver revealed peroxisome proliferators activated receptor-gamma (PPARγ) and its target genes related to TG synthesis are remarkably down-regulated in Per1−/− mice. HepG2 cells were treated with ethanol at 150 mM for 3 days. Per1 overexpression augmented lipid accumulation after treatment with ethanol in HepG2 cells, but had no effect on ethanol-induced oxidative stress. Expression of genes related to lipogenesis, including PPARγ and its target genes, was up-regulated in cells overexpressing Per1. In conclusion, these results indicated that circadian rhythms of ethanol-induced hepatotoxicity are controlled by clock gene Per1, and deletion of Per1 protected mice from ethanol-induced liver injury by decreasing hepatic lipid accumulation

  9. Non-Steroid Anti-Inflammatory Drugs Are Better than Acetaminophen on Fever Control at Acute Stage of Fracture.

    Directory of Open Access Journals (Sweden)

    Kuang-Ting Yeh

    Full Text Available In addition to adequate surgical fixation and an aggressive rehabilitation program, pain relief is one of the most critical factors in the acute stage of fracture treatment. The most common analgesics are nonsteroid anti-inflammatory drugs and Acetaminophen, both of which relieve pain and reduce body temperature. In clinical experiences, they exhibit effective pain control; however, their influence on body temperature remains controversial. This study is aimed at determining the effects of analgesics at the acute stage of traumatic fracture by performing a clinical retrospective study of patients with fractures and a fracture animal model. The retrospective study revealed that, in the acetaminophen group, the mean value of postmedication body temperature (BT was significantly higher than that of the premedication BT. The change in BT was highly related with the medication rather than other risk factors. Forty eight 12-week-old male Wistar rats were divided into 6 groups: a control group, fracture group, fracture-Acetaminophen group, Acetaminophen group, fracture-Arcoxia group, and Arcoxia group. Fracture rats were prepared by breaking their unilateral tibia and fibula. Their inflammation conditions were evaluated by measuring their serum cytokine level and their physiological status was evaluated by estimating their central temperature, heart rate, and mean blood pressure. The hepatic adverse effects were assessed by measuring the serum levels of aspartate aminotransferase (sGOT and alanine aminotransferase (sGPT. The central temperature in the fracture-Acetaminophen group exceeded that in the groups fed normal saline water or Arcoxia. Accumulated hepatic injury was presented as steadily ascending curves of sGOT and sGPT. Inflammation-related cytokine levels were not higher in the Acetaminophen fracture group and were significantly lower in the fracture-Arcoxia group. Fever appeared to be aggravated by acetaminophen and more related to the

  10. Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

    Directory of Open Access Journals (Sweden)

    Howie Forbes

    2010-03-01

    Full Text Available Abstract Background The development of effective therapies for acute liver failure (ALF is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein. Control pigs (n = 4 survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg, increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3. Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3 observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02 and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14 coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis

  11. Prophylactic Acetaminophen or Ibuprofen Results in Equivalent Acute Mountain Sickness Incidence at High Altitude: A Prospective Randomized Trial.

    Science.gov (United States)

    Kanaan, Nicholas C; Peterson, Alicia L; Pun, Matiram; Holck, Peter S; Starling, Jennifer; Basyal, Bikash; Freeman, Thomas F; Gehner, Jessica R; Keyes, Linda; Levin, Dana R; O'Leary, Catherine J; Stuart, Katherine E; Thapa, Ghan B; Tiwari, Aditya; Velgersdyk, Jared L; Zafren, Ken; Basnyat, Buddha

    2017-06-01

    Recent trials have demonstrated the usefulness of ibuprofen in the prevention of acute mountain sickness (AMS), yet the proposed anti-inflammatory mechanism remains unconfirmed. Acetaminophen and ibuprofen were tested for AMS prevention. We hypothesized that a greater clinical effect would be seen from ibuprofen due to its anti-inflammatory effects compared with acetaminophen's mechanism of possible symptom reduction by predominantly mediating nociception in the brain. A double-blind, randomized trial was conducted testing acetaminophen vs ibuprofen for the prevention of AMS. A total of 332 non-Nepali participants were recruited at Pheriche (4371 m) and Dingboche (4410 m) on the Everest Base Camp trek. The participants were randomized to either acetaminophen 1000 mg or ibuprofen 600 mg 3 times a day until they reached Lobuche (4940 m), where they were reassessed. The primary outcome was AMS incidence measured by the Lake Louise Questionnaire score. Data from 225 participants who met inclusion criteria were analyzed. Twenty-five participants (22.1%) in the acetaminophen group and 18 (16.1%) in the ibuprofen group developed AMS (P = .235). The combined AMS incidence was 19.1% (43 participants), 14 percentage points lower than the expected AMS incidence of untreated trekkers in prior studies at this location, suggesting that both interventions reduced the incidence of AMS. We found little evidence of any difference between acetaminophen and ibuprofen groups in AMS incidence. This suggests that AMS prevention may be multifactorial, affected by anti-inflammatory inhibition of the arachidonic-acid pathway as well as other analgesic mechanisms that mediate nociception. Additional study is needed. Copyright © 2017 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  12. Management of acute paracetamol (acetaminophen) toxicity: a standardised proforma improves risk assessment and overall risk stratification by emergency medicine doctors.

    Science.gov (United States)

    McQuade, David J; Aknuri, Srikanth; Dargan, Paul I; Wood, David M

    2012-12-01

    Paracetamol (acetaminophen) poisoning is the most common toxicological presentation in the UK. Doctors managing patients with paracetamol poisoning need to assess the risk of their patient developing hepatotoxicity before determining appropriate treatment. Patients deemed to be at 'high risk' of hepatotoxicity have lower treatment thresholds than those deemed to be at 'normal risk'. Errors in this process can lead to harmful or potentially fatal under or over treatment. To determine how well treating doctors assess risk factor status and whether a standardised proforma is useful in the risk stratification process. Retrospective 12-month case note review of all patients presenting with paracetamol poisoning to our large inner-city emergency department. Data were collected on the documentation of risk factors, the presence of a local hospital proforma and treatment outcomes. 249 presentations were analysed and only 59 (23.7%) had full documentation of all the risk factors required to make a complete risk assessment. 56 of the 59 (94.9%) had the local hospital proforma included in the notes; the remaining 3 (5.1%) had full documentation of risk factors despite the absence of a proforma. A local hospital proforma was more likely to be included in the emergency department notes in those with 'adequate documentation' (78 out of 120 (65%)) than for those with 'inadequate documentation' (16 out of 129 (12.4%)); X(2), pparacetamol poisoning.

  13. Risk Factors, Clinical Presentation, and Outcomes in Overdose With Acetaminophen Alone or With Combination Products: Results From the Acute Liver Failure Study Group.

    Science.gov (United States)

    Serper, Marina; Wolf, Michael S; Parikh, Nikhil A; Tillman, Holly; Lee, William M; Ganger, Daniel R

    2016-01-01

    Acetaminophen (APAP) is the most common cause of acute liver failure (ALF) in the west. It is unknown if APAP overdose in combination with diphenhydramine or opioids confers a different clinical presentation or prognosis. Study objectives were to compare (1) baseline patient characteristics; (2) initial clinical presentation; and (3) clinical outcomes among patients with ALF due to APAP alone or in combination with diphenhydramine or opioids. We analyzed 666 cases of APAP-related liver failure using the Acute Liver Failure Study Group database from 1998 to 2012. The database contains detailed demographic, laboratory, and clinical outcome data, including hemodialysis, transplantation, and death and in-hospital complications such as arrhythmia and infection. The final sample included 666 patients with APAP liver injury. A total 30.3% of patients were overdosed with APAP alone, 14.1% with APAP/diphenhydramine, and 56.6% with APAP/opioids. Patients taking APAP with opioids were older, had more comorbidities, and were more likely to have unintentional overdose (all Ppresentation, 58% in the APAP/opioid group had advanced encephalopathy as compared with 43% with APAP alone (P=0.001) The APAP/diphenhydramine group presented with the highest serum aminotransferase levels, no differences in laboratory values were noted at 3 days postenrollment. No significant differences were observed in clinical outcomes among the groups. Most patients with APAP-induced ALF were taking APAP combination products. There were significant differences in patient characteristics and clinical presentation based on the type of product ingested, however, there were no differences noted in delayed hepatotoxicity or clinical outcomes.

  14. 20(R)-ginsenoside Rg3, a rare saponin from red ginseng, ameliorates acetaminophen-induced hepatotoxicity by suppressing PI3K/AKT pathway-mediated inflammation and apoptosis.

    Science.gov (United States)

    Zhou, Yan-Dan; Hou, Jin-Gang; Liu, Wei; Ren, Shen; Wang, Ying-Ping; Zhang, Rui; Chen, Chen; Wang, Zi; Li, Wei

    2018-06-01

    Although ginsenoside Rg3 was isolated as a major component of Korea red ginseng and confirmed to exert potential hepatoprotective effect on acetaminophen (APAP)-induced liver injury via induction of glutathione S-transferase (GST) in vitro, thein vivo hepatoprotective effect of Rg3 and the underlying molecular mechanism of action remain unclear. The current study was aimed to explore whether 20(R)-Ginsenoside Rg3 (20(R)-Rg3) could alleviate acetaminophen-induced liver injury in mice and to determine the involvement of PI3K/AKT signaling pathway. Our findings demonstrated that a single injection of APAP (250 mg/kg) increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β); such increases were attenuated by pretreatment of mice with 20(R)-Rg3 for seven days. The depletion of glutathione (GSH), generation of malondialdehyde (MDA) and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP exposure were also inhibited by 20(R)-Rg3 pretreatment. Moreover, 20(R)-Rg3 pretreatment significantly alleviated APAP-induced apoptosis, necrosis, and inflammatory infiltration in liver tissues. Importantly, 20(R)-Rg3 effectively attenuated APAP-induced liver injury in part via activating PI3K/AKT signaling pathway. In summary, 20(R)-Rg3 exerted liver protection against APAP-caused hepatotoxicity evidenced by inhibition of oxidative stress and inflammatory response, alleviation of hepatocellular necrosis and apoptosis via activation of PI3K/AKT signaling pathway, showing potential as a novel therapeutic agent to prevent liver damage. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy.

    Science.gov (United States)

    Brusilow, Saul W; Cooper, Arthur J L

    2011-11-01

    Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen. Case report. Johns Hopkins Hospital. A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated. She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter. Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began

  16. Hepatoprotective effect of ethanol extract from Berchemia lineate against CCl4-induced acute hepatotoxicity in mice.

    Science.gov (United States)

    Li, Cong; Yi, Li-Tao; Geng, Di; Han, Yuan-Yuan; Weng, Lian-Jin

    2015-05-01

    The roots of Berchemia lineate (L.) DC. (Rhamnaceae) have been long used as a remedy for the treatment of some diseases in Guangxi Province, China. The present study investigates the hepatoprotective effect of Berchemia lineate ethanol extract (BELE) on CCl4-induced acute liver damage in mice. Effect of BELE administrated for 7 consecutive days was evaluated in mice by the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), albulin (ALB), globulin (GLB), and total protein (TP) levels, as well as liver superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Moreover, histopathological examinations were also taken. Compared with the model group, administration of 400 mg/kg BELE for 7 d in mice significantly decreased the serum ALT (56.25 U/L), AST (297.67 U/L), ALP (188.20 U/L), and TBIL (17.90 mol/L), along with the elevation of TP (64.67 g/L). In addition, BELE (100, 200, and 400 mg/kg, i.g.) treated mice recorded a dose-dependent increment of SOD (291.17, 310.32, and 325.67 U/mg prot) and reduction of MDA (7.27, 6.77, and 5.33 nmol/mg prot) levels. Histopathological examinations also confirmed that BELE can ameliorate CCl4-induced liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. The results indicated that BELE possessed remarkable protective effect against acute hepatotoxicity and oxidative injuries induced by CCl4, and that the hepatoprotective effects of BELE may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity.

  17. Influence of sex and developmental stage on acute hepatotoxic and inflammatory responses to liver procarcinogens in the mouse

    International Nuclear Information System (INIS)

    Hanna, Daniel; Riedmaier, Ariane Emami; Sugamori, Kim S.; Grant, Denis M.

    2016-01-01

    The incidence of liver cancer is higher in men than in women. This sex difference is also observed in murine tumor induction models that result in the appearance of liver tumors in adult mice following their exposure on postnatal days 8 and/or 15 to carcinogens such as 4-aminobiphenyl (ABP) or diethylnitrosamine (DEN). Previous studies performed in adult mice showed that acute hepatotoxic and inflammatory responses to high-dose DEN exposure were greater in males than in females, leading to the suggestion that these responses could account for the sex difference in tumor development. We also recently observed that female but not male mice exposed postnatally to ABP had slightly increased expression of the antioxidant defense genes Nqo1 and Ggt1, which are regulated by the oxidative stress response protein nuclear factor erythroid 2-related factor 2 (NRF2), while expression of Hmox1 was increased in both sexes. The goal of the present study was therefore to compare selected acute hepatotoxic, inflammatory and oxidative stress defense responses to ABP, DEN, or the prototype hepatotoxicant carbon tetrachloride (CCl 4 ), in male and female mice exposed to these chemicals either postnatally or as adults. Exposure of adult mice to ABP, DEN or CCl 4 produced a 2-fold greater acute elevation in serum levels of the hepatotoxicity biomarker alanine aminotransferase (ALT) in males than in females, while levels of the inflammatory biomarker interleukin-6 (IL-6) showed no sex difference. However, treatment of immature mice with either ABP or DEN using standard tumor-inducing postnatal exposure protocols produced no increase in serum ALT or IL-6 levels in either males or females, while CCl 4 produced a 40-fold ALT elevation but with no sex difference. Basal expression of the NRF2-responsive gene Nqo1 was higher in adult females than in males, but there was no sex difference in basal expression of Ggt1 or Hmox1. Sexually immature animals showed no sex difference in basal

  18. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    Directory of Open Access Journals (Sweden)

    Herson Antonio González-Ponce

    2016-10-01

    Full Text Available Acetaminophen (APAP-induced acute liver failure (ALF is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC, the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally. Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF.

  19. Effect of Acetaminophen on the Prevention of Acute Kidney Injury in Patients With Sepsis.

    Science.gov (United States)

    Patanwala, Asad E; Aljuhani, Ohoud; Bakhsh, Hussain; Erstad, Brian L

    2018-01-01

    Acute kidney injury (AKI) commonly occurs in patients with sepsis. Acetaminophen (APAP) has been shown to inhibit lipid peroxidation and, thus, may be renal protective in patients with sepsis. The objective of this study was to determine the effect of APAP on AKI in patients with sepsis. This was a retrospective cohort study conducted at 2 affiliated academic medical centers in the United States. Adult patients who were admitted to the intensive care unit with a diagnosis of severe sepsis were included. Patients were categorized based on whether APAP was received within the first 7 days of hospitalization (APAP or no APAP groups). The primary outcome measure was occurrence or increase in AKI stage from admission. Multivariate logistic regression analyses were used to adjust for potential confounders. There were 238 patients who were included in the study cohort. Of these, 122 received APAP and 116 did not receive APAP. AKI or exacerbation occurred in 16.4% (n = 20) of patients in the APAP group and 19.8% (n = 23) of patients in the no APAP group ( P = 0.505). After adjusting for the most important confounders, there was no significant association between APAP use and AKI (odds ratio = 1.2; 95% CI = 0.6-2.4; P = 0.639). APAP use in critically ill patients with sepsis may not reduce the occurrence or exacerbation of AKI.

  20. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen

    International Nuclear Information System (INIS)

    Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA −/− ). We found that MsrA −/− mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA +/+ ). The central lobule area of the MsrA −/− liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA −/− than in MsrA +/+ mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA −/− than in MsrA +/+ livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA −/− than in MsrA +/+ livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. - Highlights: • MsrA deficiency increases APAP-induced liver damage. • MsrA deletion enhances APAP-induced hepatic GSH depletion and oxidative stress. • MsrA deficiency induces more profound activation of Nrf2 in response to APAP. • MsrA protects the liver from APAP-induced toxicity.

  1. Acute pain management: acetaminophen and ibuprofen are often under-dosed.

    Science.gov (United States)

    Milani, Gregorio P; Benini, Franca; Dell'Era, Laura; Silvagni, Davide; Podestà, Alberto F; Mancusi, Rossella Letizia; Fossali, Emilio F

    2017-07-01

    Most children with pain are managed by either acetaminophen or ibuprofen. However, no study has so far investigated if children are prescribed adequate doses of acetaminophen or ibuprofen in emergency department. Aim of this retrospective study was to investigate the prevalence of under-dosage of these drugs in children presenting with pain in emergency department. Children initially prescribed with acetaminophen or ibuprofen for pain management were included. The χ 2 automatic interaction detection method was used considering the percentage variation from the minimum of the appropriate dose as dependent variable while prescribed drug, age, gender, body weight, type of hospital (pediatric or general), and availability of internal guidelines on pediatric pain management in the emergency department as independent variables. Data on 1471 children managed for pain were available. Under-dosage was prescribed in 893 subjects (61%), of whom 577 were prescribed acetaminophen and 316 ibuprofen. The use of acetaminophen suppositories, body weight 40 kg, and the use of oral ibuprofen identified clusters of children associated with under-dosage prescription. Prescription of acetaminophen and ibuprofen was frequently under-dosed. The use of suppositories, lower and higher body weight, and the use of ibuprofen were associated with under-dosage. Under-dosing may reflect prescription of anti-pyretic doses. Agenzia Italiana del Farmaco-Observational Study Register (RSO). Registration code: PIERRE/1 What is Known: • Pain is frequent in children presented to emergency department. • International recommendations on pain management are often not implemented. What is New: • Acetaminophen and ibuprofen were frequently underdosed in children prescribed for pain in the Italian emergency departments. • Under-dosage may be related to the habit of using acetaminophen and ibuprofen in the recommended range for fever treatment.

  2. Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690].

    NARCIS (Netherlands)

    D.W.J. Dippel (Diederik); E.J. van Breda (Eric); H.B. van der Worp (Bart); H.M.A. van Gemert (Maarten); R.J. Meijer (Ron); L.J. Kappelle (Jaap); P.J. Koudstaal (Peter Jan)

    2003-01-01

    textabstractBACKGROUND: Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when

  3. Targeted Metabolomics of Serum Acylcarnitines Evaluates Hepatoprotective Effect of Wuzhi Tablet (Schisandra sphenanthera Extract against Acute Acetaminophen Toxicity

    Directory of Open Access Journals (Sweden)

    Huichang Bi

    2013-01-01

    Full Text Available Possible prevention and therapeutic intervention strategies to counteract acetaminophen (APAP hepatotoxicity would be of great value. Wuzhi tablet (WZ, extract of Schisandrae sphenanthera possesses hepatoprotective effects against hepatitis and the hepatic dysfunction induced by various chemical hepatotoxins. In this study, the protective effect of WZ on APAP-induced hepatic injury was evaluated and targeted metabolomics by LC-MS-based metabolomics was used to examine whether WZ influences hepatic metabolism. The results demonstrated significant hepatoprotection of WZ against APAP-induced liver injury; pretreatment with WZ prior to APAP administration blocks the increase in serum palmitoylcarnitine and oleoylcarnitine and thus restores the APAP-impaired fatty acid β-oxidation to normal levels. These studies further revealed a significant and prolonged upregulation of the PPARα target genes Cpt1 and Acot1 by WZ mainly contributing to the maintenance of normal fatty acid metabolism and thus potentially contributing to the hepatic protection of WZ against APAP-induced hepatic toxicity. Taken together, the current study provides new insights into understanding the hepatoprotective effect of WZ against APAP-induced liver toxicity.

  4. Effect of paracetamol (acetaminophen and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690

    Directory of Open Access Journals (Sweden)

    Meijer Ron J

    2003-02-01

    Full Text Available Abstract Background Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect. Methods Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter. Results No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C. Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period. Conclusions Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.

  5. Acute ethanol administration reduces the antidote effect of N-acetylcysteine after acetaminophen overdose in mice

    DEFF Research Database (Denmark)

    Dalhoff, K; Hansen, P B; Ott, P

    1991-01-01

    given ethanol or saline alone only 7% and 3%, respectively, survived 96 h. 4. The data suggest that the protective effect of N-acetylcysteine on acetaminophen-induced toxicity in fed mice is reduced by concomitant administration of ethanol. This may explain the clinical observation that ingestion...

  6. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults.

    Science.gov (United States)

    Derry, Sheena; Moore, R Andrew

    2013-04-30

    This is an updated version of the original Cochrane review published in Issue 11, 2010 (Derry 2010). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting, which are commonly associated with migraine. To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010 for the original review, and to 13 February 2013 for the update. Two clinical trials registers (ClinicalTrials.gov and gsk-clinicalstudyregister.com) were also searched on both occasions. We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm. Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared with placebo or other active treatment. Searches for the update identified one additional study for inclusion. Eleven studies (2942 participants, 5109 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12 (19% response with paracetamol, 10% with placebo), 5.0 (56% response with paracetamol, 36% with placebo) and 5.2 (39% response with paracetamol, 20% with placebo) for 2-hour pain-free and 2- and 1

  7. DYNAMICS OF CLINICAL AND BIOCHEMICAL PARAMETERS AND FUNCTIONAL STATE OF THE AUTONOMIC NERVOUS SYSTEM IN PATIENTS WITH ACUTE HEPATITIS B WITH CHRONIC ALCOHOL USE IN HEPATOTOXIC DOSES

    Directory of Open Access Journals (Sweden)

    O. O. Furyk

    2014-02-01

    Full Text Available Relevance of hepatitis B due to the high incidence complexity of pathogenesis, ineffective treatment, severe consequences of the disease. Among combined lesions of the liver, special attention is paid to viral-alcoholic type. One of the mechanisms of chronic hepatitis of different etiology is violation of the functional activity of the autonomic nervous system. The aim of this work- to determine the dynamics of spectral indices of heart rate variability in patients with acute hepatitis B from chronic use of alcohol in hepatotoxic doses. Materials and methods. 133 patients with acute hepatitis B were under observation. Patients were divided into groups taking account the presence or absence of chronic use of alcohol in hepatotoxic doses and using the classification of alcohol consumption based on the frequency and dose of consumed alcohol. I group comprised 52 patients with chronic use of alcohol in the hepatotoxic doses, II group consisted of 81 patient without this factor. Heart rate variability was diagnosed using computer cardiointervalometry performed by electrocardiographic diagnostic system CardioLab-2000. 20 healthy individuals were in the control group. Results and discussion. Prodromal period in patients of the I group was longer (p0,05. However, only patients in group I had marked hemorrhagic manifestations (5,8 % and itching (7.7%. Average serum total bilirubin level was higher (p<0,05 in patients from the I group than in patients from II group. Functional state of autonomic nervous system in patients of both groups were decreased in acute period (vagotonia. Period of convalescence in patients from the I group was accompanied by more severe autonomic dysfunction in 33,6 % (p<0,05. Conclusions. 1. Acute hepatitis B in patients with chronic alcohol use in hepatotoxic doses is characterized by longer (p<0,05 prodrome, cholestatic (7,7% and hemorrhagic manifestations (5,8%, higher levels of hyperbilirubinemia (p<0,05, and during

  8. Protective effect of zinc aspartate against acetaminophen induced hepato-renal toxicity in albino rats

    International Nuclear Information System (INIS)

    Mohamed, E.T.; Said, A.I.; El-Sayed, S.A.

    2011-01-01

    Zinc is an essential nutrient that is required in humans and animals for many physiological functions, including antioxidant functions. The evidence to date indicates that zinc is an important element that links antioxidant system and tissue damage. Acetaminophen (AP), a widely used analgesic and antipyretic, produces hepatocyte and renal tubular necrosis in human and animals following overdose. In human, AP is one of the most common causes of acute liver failure as a result of accidental or deliberate overdose. Moreover, the initial event in AP toxicity is a toxic metabolic injury with the release of free radicals and subsequent cellular death by necrosis and apoptosis. This study was designed to evaluate the potential protective role of zinc aspartate in case of acetaminophen induced hepato-renal toxicity in rats. A total number of 32 adult male albino rats were divided into 4 equal groups: group I (control group), group II (zinc aspartate treated group), group III (acetaminophen treated group; by a single oral dose of 750 mg/kg body weight) and group IV acetaminophen plus zinc treated group; (zinc aspartate was intraperitoneally given one hour after acetaminophen administration in a dose of 30 mg/kg body weight). Serum levels of: alanine aminotransferase, aspartate aminotransferase, direct bilirubin, blood urea nitrogen, creatinine, uric acid, xanthine oxidase (XO), glutathione (GSH), malonaldehyde (MDA) and nitric oxide (NO) were assessed in all groups. The results of this study showed that treatment with acetaminophen alone (group III) produced a significant increase in serum levels of the liver enzymes and direct bilirubin. Moreover, in the same group there was a significant increase in the blood urea nitrogen and serum creatinine compared to the control group. In addition, there was a significant increase in XO and MDA and a significant decrease in GSH and NO level. Injection of rats with zinc aspartate after acetaminophen treatment could produce a

  9. Paracetamol (acetaminophen) for acute treatment of episodic tension-type headache in adults.

    Science.gov (United States)

    Stephens, Guy; Derry, Sheena; Moore, R Andrew

    2016-06-16

    Tension-type headache (TTH) affects about 1 person in 5 worldwide. It is divided into infrequent episodic TTH (fewer than one headache per month), frequent episodic TTH (two to 14 headaches per month), and chronic TTH (15 headache days a month or more). Paracetamol (acetaminophen) is one of a number of analgesics suggested for acute treatment of headaches in frequent episodic TTH. To assess the efficacy and safety of paracetamol for the acute treatment of frequent episodic TTH in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (CRSO), MEDLINE, EMBASE, and the Oxford Pain Relief Database to October 2015, and also reference lists of relevant published studies and reviews. We sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' websites. We included randomised, double-blind, placebo-controlled studies (parallel-group or cross-over) using oral paracetamol for symptomatic relief of an acute episode of TTH. Studies had to be prospective, with participants aged 18 years or over, and include at least 10 participants per treatment arm. Two review authors independently assessed studies for inclusion and extracted data. We used the numbers of participants achieving each outcome to calculate the risk ratio (RR) and number needed to treat for one additional beneficial outcome (NNT) or one additional harmful outcome (NNH) for oral paracetamol compared to placebo or an active intervention for a range of outcomes, predominantly those recommended by the International Headache Society (IHS).We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables. We included 23 studies, all of which enrolled adults with frequent episodic TTH. Twelve studies used the IHS diagnostic criteria or similar, six used the older classification of the Ad Hoc Committee, and five did not describe specific diagnostic criteria

  10. Protective Effects of Cultivated Ginseng, Cultivated Wild Ginseng of Korean and Chinese Against CCl4 and t-BHP Induced Acute Hepatotoxicity in ICR Mice

    Directory of Open Access Journals (Sweden)

    Kim, Young-Jin

    2007-02-01

    Full Text Available Objectives : This study was aimed at investigating live protection mechanism of Cultivated Ginseng and Cultivated Wild Ginseng of Korean and Chinese by inducing liver toxicity through and t-BHP in mice and evaluated serological findings. Methods : Experiment groups was categorized into untreated normal group, treated control group, and orally administered Cultivated Ginseng and Cultivated Wild Ginseng of Korean and Chinese experimental groups. At the termination of experiment, gross examination of the liver as well as Total bilirubin, AST, and ALT contents in the serum were evaluated. Results : 1. In the induced acute hepatotoxicity test, total bilirubin, AST and ALT didn't show significant differences between the control and experimental groups. 2. In the t-BHP induced acute hepatotoxicity test, total bilirubin, AST and ALT didn't show significant differences between the control and experimental groups. Conclusion : Taken together, Cultivated Ginseng and Cultivated Wild Ginseng of Korean and Chinese cannot be effectively used for recovering the liver functions in acute hepatotoxicity tests using and t-BHP. Further researches, for example treated long period, must be tried to verify the efficacies.

  11. Serum neopterin and soluble CD163 as markers of macrophage activation in paracetamol (acetaminophen)-induced human acute liver injury.

    Science.gov (United States)

    Craig, D G; Lee, P; Pryde, E A; Hayes, P C; Simpson, K J

    2013-12-01

    Macrophage activation is implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS) following paracetamol (acetaminophen) overdose (POD). Neopterin is synthesised from macrophages and reflects the intensity of monocyte/macrophage activation. Soluble CD163 (sCD163) is a marker of alternatively activated M2 macrophages. To examine neopterin and sCD163 levels in a cohort of acute liver injury patients. Consecutive patients (n = 41, (18 (43.9%) male) with acute liver injury were enrolled. Neopterin and sCD163 levels were measured by ELISA. A total of 24/33 (72.7%) POD patients developed hepatic encephalopathy (HE), and therefore acute liver failure. Both neopterin and sCD163 levels were significantly higher in PODs compared with chronic liver disease (neopterin P paracetamol overdose, and reflect the degree of macrophage activation in this condition. Serum neopterin in particular may have value as an early proxy marker of macrophage activation following paracetamol overdose. © 2013 John Wiley & Sons Ltd.

  12. Chronic acetaminophen overdosing in children: risk assessment and management.

    Science.gov (United States)

    Sztajnkrycer, M J; Bond, G R

    2001-04-01

    Acetaminophen is currently the pediatric analgesic and antipyretic of choice. Although children appear to tolerate single, high-dose ingestions well, the literature is replete with reports of significant morbidity and mortality after repeated supra-therapeutic dosing. Proposed risk factors for injury with chronic use include age, total dose, duration, presence of intercurrent febrile illness, starvation, co-administration of cytochrome P450-inducing drugs, underlying hepatic disease, and unique genetic makeup. Evaluation of these children should include serum acetaminophen concentration, prothrombin time, and serum bilirubin and transaminase concentrations. The Rumack-Mathew nomogram should not be used to estimate the risk of hepatotoxicity in cases of chronic ingestion. Based on history, clinical examination, and laboratory findings, patients may be placed in three categories: those without hepatic injury and with no residual acetaminophen to be metabolized, those without injury but with some acetaminophen to be metabolized, and those with hepatotoxicity. Those without injury and no residual acetaminophen need not be treated or followed. Patients with hepatotoxicity or potential for hepatotoxicity based on residual acetaminophen should be treated with N-acetylcysteine. Most importantly, because so many parents are unaware of the potential risk of inappropriate dosing, education is the key to preventing future cases.

  13. Study of acute hepatotoxicity of Equisetum arvense L. in rats Estudo da hepatotoxicidade aguda da Equisetum arvense L. em ratos

    Directory of Open Access Journals (Sweden)

    Nilo César do Vale Baracho

    2009-12-01

    Full Text Available PURPOSE: To evaluate the acute hepatotoxicity of Equisentum arvense L. in rats. METHODS: Fifty Wistar rats were used, these being divided in four groups, one being the control (receiving only water and the other groups receiving graded doses of Equisentum arvense L. (30, 50, and 100mg/kg respectively for 14 days. Blood samples were obtained to determine TGO, TGP, FA, DHL and GT-gamma activities. After that, hepatic tissue samples were collected for the anatomopathologic analysis. RESULTS: The anatomopathologic exam of the hepatic tissue showed organ with preserved lobular structure. In the same way, there was no significant change in the seric activities of the hepatic enzymes when compared to control group. CONCLUSION: The oral treatment with graded doses of Equisentum arvense L. was not able to produce hepatic changes. Further studies are necessary to evaluate the chronic hepatotoxicity of Equisentum arvense L. in rats.OBJETIVO: Investigar a hepatotoxicidade aguda da Equisetum arvense L. em ratos. MÉTODOS: foram utilizados 50 ratos Wistar, os quais foram divididos em quatro grupos, sendo um controle (recebendo apenas água e os outros grupos recebendo doses crescentes de cavalinha (30, 50 e 100mg/Kg, respectivamente por 14 dias. Foram coletadas amostras de sangue para determinação da atividade sérica de TGO, TGP, FA, DHL e gama-GT. Em seguida, foram obtidas amostras de tecido hepático para análise anatomopatológica. RESULTADOS: O exame anatomopatológico de tecido hepático demonstrou órgão com estrutura lobular preservada. Da mesma forma, não houve alteração significativa na atividade sérica das enzimas hepáticas, quando comparado ao grupo controle. CONCLUSÃO: O tratamento com doses crescentes de Equisetum arvense L., não induziu hepatotoxicidade aguda em ratos. Novos estudos são necessários para avaliar a hepatoxicidade crônica de Equisetum arvense L. em ratos.

  14. Acetaminophen (Paracetamol) induced acute liver failure - A social problem in an era of increasing tendency to self-treatment.

    Science.gov (United States)

    Wróblewski, Tadeusz; Kobryń, Konrad; Kozieł, Sławomir; Ołdakowska-Jedynak, Urszula; Pinkas, Jarosław; Danielewicz, Roman; Ziarkiewicz-Wróblewska, Bogna; Krawczyk, Marek

    2015-01-01

    The widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure. In 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx). 26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant. Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

  15. Acetaminophen overdose

    Science.gov (United States)

    ... of Drugs . 16th ed. Waltham, MA: Elsevier; 2016:474-493. Hendrickson RG, McKeown, MJ. Acetaminophen. In: Marx ... RSS Follow us Disclaimers Copyright Privacy Accessibility Quality Guidelines Viewers & Players MedlinePlus Connect for EHRs For Developers ...

  16. N-Methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: Oxidative stress after acute and chronic administration

    Directory of Open Access Journals (Sweden)

    Ninković Milica

    2004-01-01

    Full Text Available Background. The underlying mechanisms of N-Methyl-3,4-methylenedioxyamphetamine-MDMA-induced hepatotoxicity are still unknown. The aim of this study was to evaluate hepatic oxido-reductive status in the rats liver after the single and repeated administration of MDMA. Methods. MDMA was dissolved in distilled water and administered in the doses of 5 mg, 10 mg, 20 mg, and 40 mg/kg. The animals from the acute experiment were treated per os with the single dose of the appropriate solution, through the orogastric tube. The animals from the chronic experiment were treated per os, with the doses of 5, 10, or 20 mg/kg of MDMA every day during 14 days. The control groups were treated with water only. Eight hours after the last dose, the animals were sacrificed, dissected their livers were rapidly removed, frozen and stored at -70°C until the moment of analysis. The parameters of oxidative stress in the crude mitochondrial fractions of the livers were analyzed. Results. Superoxide dismutase (SOD activity increased in the livers of the animals that were treated with single doses of MDMA. Chronically treated animals showed the increased SOD activity only after the highest dose (20 mg/kg. The content of reduced glutathione decreased in both groups, but the depletion was much more expressed after the single administration. Lipid peroxidation index increased in dose-dependent manner in both groups, being much higher after the single administration. Conclusion. The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

  17. [Risk of acute hepatic insufficiency in children due to chronic accidental overdose of paracetamol (acetaminophen)

    NARCIS (Netherlands)

    Hameleers-Snijders, P.; Hogeveen, M.; Smeitink, J.A.M.; Kramers, C.; Draaisma, J.M.T.

    2007-01-01

    Two girls aged 4 and 3 years, respectively, experienced acute liver failure due to accidental ingestion of supratherapeutic doses of paracetamol (90 mg/kg/day or more). Recognition of chronic paracetamol intoxication as a cause of acute hepatic failure is often delayed. It is important to consider

  18. A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose

    Directory of Open Access Journals (Sweden)

    Kalsi SS

    2011-12-01

    Full Text Available Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen poisoning is common throughout the world. The management of nonstaggered (acute paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although

  19. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain

    NARCIS (Netherlands)

    Ong, Cliff K. S.; Seymour, Robin A.; Lirk, Phillip; Merry, Alan F.

    2010-01-01

    BACKGROUND: There has been a trend over recent years for combining a nonsteroidal antiinflammatory drug (NSAID) with paracetamol (acetaminophen) for pain management. However, therapeutic superiority of the combination of paracetamol and an NSAID over either drug alone remains controversial. We

  20. Understanding lactic acidosis in paracetamol (acetaminophen) poisoning.

    Science.gov (United States)

    Shah, Anoop D; Wood, David M; Dargan, Paul I

    2011-01-01

    Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure. © 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.

  1. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.

    Science.gov (United States)

    Gulmez, Sinem Ezgi; Larrey, Dominique; Pageaux, Georges-Philippe; Lignot, Severine; Lassalle, Régis; Jové, Jérémy; Gatta, Angelo; McCormick, P Aiden; Metselaar, Harold J; Monteiro, Estela; Thorburn, Douglas; Bernal, William; Zouboulis-Vafiadis, Irene; de Vries, Corinne; Perez-Gutthann, Susana; Sturkenboom, Miriam; Bénichou, Jacques; Montastruc, Jean-Louis; Horsmans, Yves; Salvo, Francesco; Hamoud, Fatima; Micon, Sophie; Droz-Perroteau, Cécile; Blin, Patrick; Moore, Nicholas

    2013-02-01

    Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.

  2. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain.

    Science.gov (United States)

    Ong, Cliff K S; Seymour, Robin A; Lirk, Phillip; Merry, Alan F

    2010-04-01

    There has been a trend over recent years for combining a nonsteroidal antiinflammatory drug (NSAID) with paracetamol (acetaminophen) for pain management. However, therapeutic superiority of the combination of paracetamol and an NSAID over either drug alone remains controversial. We evaluated the efficacy of the combination of paracetamol and an NSAID versus either drug alone in various acute pain models. A systematic literature search of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and PubMed covering the period from January 1988 to June 2009 was performed to identify randomized controlled trials in humans that specifically compared combinations of paracetamol with various NSAIDs versus at least 1 of these constituent drugs. Identified studies were stratified into 2 groups: paracetamol/NSAID combinations versus paracetamol or NSAIDs. We analyzed pain intensity scores and supplemental analgesic requirements as primary outcome measures. In addition, each study was graded for quality using a validated scale. Twenty-one human studies enrolling 1909 patients were analyzed. The NSAIDs used were ibuprofen (n = 6), diclofenac (n = 8), ketoprofen (n = 3), ketorolac (n = 1), aspirin (n = 1), tenoxicam (n = 1), and rofecoxib (n = 1). The combination of paracetamol and NSAID was more effective than paracetamol or NSAID alone in 85% and 64% of relevant studies, respectively. The pain intensity and analgesic supplementation was 35.0% +/- 10.9% and 38.8% +/- 13.1% lesser, respectively, in the positive studies for the combination versus paracetamol group, and 37.7% +/- 26.6% and 31.3% +/- 13.4% lesser, respectively, in the positive studies for the combination versus the NSAID group. No statistical difference in median quality scores was found between experimental groups. Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone.

  3. Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions.

    Science.gov (United States)

    Moore, R A; Derry, S; Wiffen, P J; Straube, S; Aldington, D J

    2015-10-01

    Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to ≥50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions. © 2014 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFICC®.

  4. Acetaminophen overdose associated with double serum concentration peaks

    Directory of Open Access Journals (Sweden)

    Cristian Papazoglu

    2015-12-01

    Full Text Available Acetaminophen is the most commonly used analgesic–antipyretic medication in the United States. Acetaminophen overdose, a frequent cause of drug toxicity, has been recognized as the leading cause of fatal and non-fatal hepatic necrosis. N-Acetylcysteine is the recommended antidote for acetaminophen poisoning. Despite evidence on the efficacy of N-acetylcysteine for prevention of hepatic injury, controversy persists about the optimal duration of the therapy. Here, we describe the case of a 65-year-old male with acetaminophen overdose and opioid co-ingestion who developed a second peak in acetaminophen serum levels after completing the recommended 21-hour intravenous N-acetylcysteine protocol and when the standard criteria for monitoring drug levels was achieved. Prolongation of N-acetylcysteine infusion beyond the standard protocol, despite a significant gap in treatment, was critical for successful avoidance of hepatotoxicity. Delay in acetaminophen absorption may be associated with a second peak in serum concentration following an initial declining trend, especially in cases of concomitant ingestion of opioids. In patients with acetaminophen toxicity who co-ingest other medications that may potentially delay gastric emptying or in those with risk factors for delayed absorption of acetaminophen, we recommend close monitoring of aminotransferase enzyme levels, as well as trending acetaminophen concentrations until undetectable before discontinuing the antidote therapy.

  5. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  6. Short day photoperiod protects against acetaminophen-induced ...

    African Journals Online (AJOL)

    Prof. Ogunji

    blood was collected by cardiac puncture for the estimation of liver enzymes activities. Liver ... revealed the protective effects of short photoperiod against acetaminophen-induced hepatotoxicity and lipid .... homogenized in ice cold KCl (100mM) containing. 0.003M ... This was followed by the addition of 1.0ml water and 5.0ml ...

  7. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain.

    Science.gov (United States)

    Derry, Christopher J; Derry, Sheena; Moore, R Andrew

    2013-06-24

    Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Some combinations of ibuprofen and paracetamol are available for use without prescription in some acute pain situations. To assess the efficacy and adverse effects of single dose oral ibuprofen plus paracetamol for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4 of 12, 2013), MEDLINE (1950 to May 21st 2013), EMBASE (1974 to May 21st 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. Randomised, double-blind clinical trials of single dose, oral ibuprofen plus paracetamol compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults. Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used validated equations to calculate the area under the pain relief versus time curve and derive the proportion of participants with at least 50% of maximum pain relief over six hours. We calculated relative risk (RR) and number needed to treat to benefit (NNT) for ibuprofen plus paracetamol, ibuprofen alone, or placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. Searches identified three studies involving 1647 participants. Each of them examined several dose combinations. Included studies provided data from 508 participants for the comparison of ibuprofen 200 mg + paracetamol 500 mg with placebo, 543

  8. Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen

    Directory of Open Access Journals (Sweden)

    Tomáš Zárybnický

    2018-06-01

    Full Text Available Monoterpenes R-pulegone (PUL and R-menthofuran (MF, abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was to test the effects of PUL, MF and acetaminophen (APAP, as a reference compound on cell viability and microRNA (miRNA expression in human precision-cut liver slices. Slices from five patients were used to follow up on the inter-individual variability. PUL was toxic in all liver samples (the half-maximal effective concentration was 4.0 µg/mg of tissue, while MF and surprisingly APAP only in two and three liver samples, respectively. PUL also changed miRNA expression more significantly than MF and APAP. The most pronounced effect was a marked decrease of miR-155-5p expression caused by PUL even in non-toxic concentrations in all five liver samples. Our results showed that PUL is much more toxic than MF and APAP in human liver and that miR-155-5p could be a good marker of PUL early hepatotoxicity. Marked inter-individual variabilities in all our results demonstrate the high probability of significant differences in the hepatotoxicity of tested compounds among people.

  9. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

    Directory of Open Access Journals (Sweden)

    Nancy Sayuri Uchida

    2017-01-01

    Full Text Available High doses of acetaminophen (APAP lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, and gamma-glutamyl transferase (γGT were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO activity and nitric oxide (NO production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

  10. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    Science.gov (United States)

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Review article: herbal and dietary supplement hepatotoxicity.

    Science.gov (United States)

    Bunchorntavakul, C; Reddy, K R

    2013-01-01

    Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety. © 2012 Blackwell Publishing Ltd.

  12. Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe?

    OpenAIRE

    Mohamed Abdel-Daim; Abdelrahman Ibrahim Abushouk; Raffaella Reggi; Nagendra Sastry Yarla; Maura Palmery; Ilaria Peluso

    2018-01-01

    Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of...

  13. The role of intrahepatic CD3 +/CD4 −/CD8 − double negative T (DN T) cells in enhanced acetaminophen toxicity

    International Nuclear Information System (INIS)

    Getachew, Yonas; Cusimano, Frank A.; James, Laura P.; Thiele, Dwain L.

    2014-01-01

    The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB −/−) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB −/−) mice. Analysis revealed that GrB −/− mice had an increased population of intrahepatic CD3 (+), CD4 (−), and CD8 (−) lymphocytes expressing the CD69 activation marker and Fas ligand. Depletion of these cells in the GrB −/− and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB −/− IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. Conclusions: Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (−), CD8 (−), NK1.1 (−) T cells. Depletion of these cells from GrB −/− mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery. - Highlights: • Intrahepatic lymphocytes (IHLs) from GrB −/− mice harbor activated DNT cells. • IHLs from GrB −/− mice exhibit enhanced Fas ligand expression. • Acetaminophen toxicity is enhanced by activated, FasL expressing DNT cells

  14. The role of intrahepatic CD3 +/CD4 −/CD8 − double negative T (DN T) cells in enhanced acetaminophen toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Getachew, Yonas, E-mail: yonas.getachew@utsouthwestern.edu [Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151 (United States); Cusimano, Frank A. [Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151 (United States); James, Laura P. [Department of Pediatrics, University of Arkansas, Little Rock, AR (United States); Thiele, Dwain L. [Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151 (United States)

    2014-10-15

    The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB −/−) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB −/−) mice. Analysis revealed that GrB −/− mice had an increased population of intrahepatic CD3 (+), CD4 (−), and CD8 (−) lymphocytes expressing the CD69 activation marker and Fas ligand. Depletion of these cells in the GrB −/− and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB −/− IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. Conclusions: Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (−), CD8 (−), NK1.1 (−) T cells. Depletion of these cells from GrB −/− mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery. - Highlights: • Intrahepatic lymphocytes (IHLs) from GrB −/− mice harbor activated DNT cells. • IHLs from GrB −/− mice exhibit enhanced Fas ligand expression. • Acetaminophen toxicity is enhanced by activated, FasL expressing DNT cells.

  15. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

    Directory of Open Access Journals (Sweden)

    Judge Bryan S

    2011-03-01

    Full Text Available Abstract Background Acetaminophen-cysteine adducts (APAP-CYS are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Methods Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated. Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. Results Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20 nmol/ml, Trial 2- 0.1 (0.09 nmol/ml and Trial 3- 0.3 (0.12 nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml. No subject had detectable APAP

  16. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    Science.gov (United States)

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  17. Hydrazine inhalation hepatotoxicity.

    Science.gov (United States)

    Kao, Yung Hsiang; Chong, C H; Ng, W T; Lim, D

    2007-10-01

    Abstract Hydrazine is a hazardous chemical commonly used as a reactant in rocket and jet fuel cells. Animal studies have demonstrated hepatic changes after hydrazine inhalation. Human case reports of hydrazine inhalation hepatotoxicity are rare. We report a case of mild hepatotoxicity following brief hydrazine vapour inhalation in a healthy young man, which resolved completely on expectant management.

  18. Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study.

    Science.gov (United States)

    Cook, Sarah F; King, Amber D; van den Anker, John N; Wilkins, Diana G

    2015-12-15

    Drug metabolism plays a key role in acetaminophen (paracetamol)-induced hepatotoxicity, and quantification of acetaminophen metabolites provides critical information about factors influencing susceptibility to acetaminophen-induced hepatotoxicity in clinical and experimental settings. The aims of this study were to develop, validate, and apply high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) methods for simultaneous quantification of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulfate, acetaminophen-glutathione, acetaminophen-cysteine, and acetaminophen-N-acetylcysteine in small volumes of human plasma and urine. In the reported procedures, acetaminophen-d4 and acetaminophen-d3-sulfate were utilized as internal standards (IS). Analytes and IS were recovered from human plasma (10μL) by protein precipitation with acetonitrile. Human urine (10μL) was prepared by fortification with IS followed only by sample dilution. Calibration concentration ranges were tailored to literature values for each analyte in each biological matrix. Prepared samples from plasma and urine were analyzed under the same HPLC-ESI-MS/MS conditions, and chromatographic separation was achieved through use of an Agilent Poroshell 120 EC-C18 column with a 20-min run time per injected sample. The analytes could be accurately and precisely quantified over 2.0-3.5 orders of magnitude. Across both matrices, mean intra- and inter-assay accuracies ranged from 85% to 112%, and intra- and inter-assay imprecision did not exceed 15%. Validation experiments included tests for specificity, recovery and ionization efficiency, inter-individual variability in matrix effects, stock solution stability, and sample stability under a variety of storage and handling conditions (room temperature, freezer, freeze-thaw, and post-preparative). The utility and suitability of the reported procedures were illustrated by analysis of pharmacokinetic samples

  19. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  20. Acetaminophen-induced Liver Injury is Attenuated in Transgenic fat-1 Mice Endogenously Synthesizing Long-chain n-3 Fatty Acids.

    Science.gov (United States)

    Feng, Ruibing; Wang, Yang; Liu, Conghui; Yan, Chunyan; Zhang, Hang; Su, Huanxing; Kang, Jing X; Shang, Chang-Zhen; Wan, Jian-Bo

    2018-04-18

    Acetaminophen (APAP) overdose-caused hepatotoxicity is the most commonly cause of drugs-induced liver failurecharacterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1) / mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-κB) - mediated inflammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. [Acetaminophen (paracetamol) causing renal failure: report on 3 pediatric cases].

    Science.gov (United States)

    Le Vaillant, J; Pellerin, L; Brouard, J; Eckart, P

    2013-06-01

    Renal failure secondary to acetaminophen poisoning is rare and occurs in approximately 1-2 % of patients with acetaminophen overdose. The pathophysiology is still being debated, and renal acetaminophen toxicity consists of acute tubular necrosis, without complication if treated promptly. Renal involvement can sometimes occur without prior liver disease, and early renal manifestations usually occur between the 2nd and 7th day after the acute acetaminophen poisoning. While therapy is exclusively symptomatic, sometimes serious metabolic complications can be observed. The monitoring of renal function should therefore be considered as an integral part of the management of children with acute, severe acetaminophen intoxication. We report 3 cases of adolescents who presented with acute renal failure as a result of voluntary drug intoxication with acetaminophen. One of these 3 girls developed severe renal injury without elevated hepatic transaminases. None of the 3 girls' renal function required hemodialysis, but one of the 3 patients had metabolic complications after her acetaminophen poisoning. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  2. Acetaminophen use during pregnancy

    DEFF Research Database (Denmark)

    Rebordosa, Cristina; Kogevinas, Manolis; Horváth-Puhó, Erzsébet

    2008-01-01

    information on acetaminophen use during the first trimester of pregnancy. We used the National Hospital Registry to identify 3784 (4.3%) children from the cohort diagnosed with 5847 congenital abnormalities. RESULTS: Children exposed to acetaminophen during the first trimester of pregnancy (n = 26,424) did...

  3. Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Hereti, Rosa I.; Alexandropoulou, Katerina N.; Basayannis, Aristidis C.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi, Attiki 151 27 (Greece)

    2003-12-01

    Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin-eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of {sup 3}H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis

  4. Hepatoprotective, antioxidant, and ameliorative effects of ginger (Zingiber officinale Roscoe) and vitamin E in acetaminophen treated rats.

    Science.gov (United States)

    Abdel-Azeem, Amal S; Hegazy, Amany M; Ibrahim, Khadiga S; Farrag, Abdel-Razik H; El-Sayed, Eman M

    2013-09-01

    Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required.

  5. Acetaminophen and codeine overdose

    Science.gov (United States)

    ... and is not helped by other types of painkillers. Acetaminophen and codeine overdose occurs when someone takes ... a vein) A laxative Medicine to reverse the effects of the poison and treat symptoms Tube through ...

  6. PISA. The effect of paracetamol (acetaminophen and ibuprofen on body temperature in acute stroke: Protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690

    Directory of Open Access Journals (Sweden)

    Kappelle Jaap

    2002-03-01

    Full Text Available Abstract Background During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their functional outcome. Previously, we studied the effect of high dose (6 g daily and low dose (3 g daily paracetamol (acetaminophen in a randomised placebo-controlled trial of 75 patients with acute ischemic stroke. In the high-dose paracetamol group, mean body temperature at 12 and 24 hours after start of treatment was 0.4°C lower than in the placebo group. The effect of ibuprofen, another potent antipyretic drug, on body-core temperature in normothermic patients has not been studied. Aim The aim of the present trial is to study the effects of high-dose paracetamol and ibuprofen on body temperature in patients with acute ischaemic stroke, and to study the safety of these treatments. Design Seventy-five (3 × 25 patients with acute ischaemic stroke confined to the anterior circulation will be randomised to treatment with either: 400 mg ibuprofen, 1000 mg acetaminophen, or with placebo 6 times daily during 5 days. Body-temperatures will be measured with a rectal electronic thermometer at the start of treatment and after 24 hours. An infrared tympanic thermometer will be used to monitor body temperature at 2-hour intervals during the first 24 hours and at 12-hour intervals thereafter. The primary outcome measure will be rectal temperature at 24 hours after the start of treatment. The study results will be analysed on an intent-to-treat basis, but an on-treatment analysis will also be performed. No formal interim analysis will be carried out.

  7. Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children.

    Science.gov (United States)

    Sjoukes, Alies; Venekamp, Roderick P; van de Pol, Alma C; Hay, Alastair D; Little, Paul; Schilder, Anne Gm; Damoiseaux, Roger Amj

    2016-12-15

    Acute otitis media (AOM) is one of the most common childhood infectious diseases and a significant reason for antibiotic prescriptions in children worldwide. Pain from middle ear infection and pressure behind the eardrum is the key symptom of AOM. Ear pain is central to children's and parents' experience of the illness. Because antibiotics provide only marginal benefits, analgesic treatment including paracetamol (acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs) is regarded as the cornerstone of AOM management in children. Our primary objective was to assess the effectiveness of paracetamol (acetaminophen) or NSAIDs, alone or combined, compared with placebo or no treatment in relieving pain in children with AOM. Our secondary objective was to assess the effectiveness of NSAIDs compared with paracetamol in children with AOM. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 7, July 2016; MEDLINE (Ovid, from 1946 to August 2016), Embase (from 1947 to August 2016), CINAHL (from 1981 to August 2016), LILACS (from 1982 to August 2016) and Web of Science (from 1955 to August 2016) for published trials. We screened reference lists of included studies and relevant systematic reviews for additional trials. We searched WHO ICTRP, ClinicalTrials.gov, and the Netherlands Trial Registry (NTR) for completed and ongoing trials (search date 19 August 2016). We included randomised controlled trials (RCTs) comparing the effectiveness of paracetamol or NSAIDs, alone or combined, for pain relief in children with AOM. We also included trials of paracetamol or NSAIDs, alone or combined, for children with fever or upper respiratory tract infections (URTIs) if we were able to extract subgroup data on pain relief in children with AOM either directly or after obtaining additional data from study authors. Two review authors independently assessed methodological quality of the included trials and extracted data. We used the GRADE approach to rate

  8. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    International Nuclear Information System (INIS)

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-01-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  9. Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

    NARCIS (Netherlands)

    Jetten, M.J.A.; Gaj, S.; Ruiz-Aracama, A.; Kok, T.M. de; Delft, J.H.M. van; Lommen, A.; Someren, E.P. van; Jennen, D.G.J.; Claessen, S.M.; Peijnenburg, A.A.C.M.; Stierum, R.H.; Kleinjans, J.C.S.

    2012-01-01

    Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure

  10. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

    NARCIS (Netherlands)

    Jetten, M.J.A.; Gaj, S.; Ruiz Aracama, A.; Kok, de T.M.; Delft, van J.H.M.; Lommen, A.; Someren, van E.P.; Jennen, D.; Claessen, S.M.; Peijnenburg, A.A.C.M.; Stierum, R.; Kleinjans, J.C.S.

    2012-01-01

    Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure

  11. Regulation of alternative macrophage activation in the liver following acetaminophen intoxication by stem cell-derived tyrosine kinase

    Energy Technology Data Exchange (ETDEWEB)

    Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Hankey, Pamela [Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802 (United States); Mishin, Vladimir; Francis, Mary [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Yu, Shan [Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

    2012-07-15

    Stem cell-derived tyrosine kinase (STK) is a transmembrane receptor reported to play a role in macrophage switching from a classically activated/proinflammatory phenotype to an alternatively activated/wound repair phenotype. In the present studies, STK{sup −/−} mice were used to assess the role of STK in acetaminophen-induced hepatotoxicity as evidence suggests that the pathogenic process involves both of these macrophage subpopulations. In wild type mice, centrilobular hepatic necrosis and increases in serum transaminase levels were observed within 6 h of acetaminophen administration (300 mg/kg, i.p.). Loss of STK resulted in a significant increase in sensitivity of mice to the hepatotoxic effects of acetaminophen and increased mortality, effects independent of its metabolism. This was associated with reduced levels of hepatic glutathione, rapid upregulation of inducible nitric oxide synthase, and prolonged induction of heme oxygenase-1, suggesting excessive oxidative stress in STK{sup −/−} mice. F4/80, a marker of mature macrophages, was highly expressed on subpopulations of Kupffer cells in livers of wild type, but not STK{sup −/−} mice. Whereas F4/80{sup +} macrophages rapidly declined in the livers of wild type mice following acetaminophen intoxication, they increased in STK{sup −/−} mice. In wild type mice hepatic expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-12, products of classically activated macrophages, increased after acetaminophen administration. Monocyte chemotactic protein-1 (MCP-1) and its receptor, CCR2, as well as IL-10, mediators involved in recruiting and activating anti-inflammatory/wound repair macrophages, also increased in wild type mice after acetaminophen. Loss of STK blunted the effects of acetaminophen on expression of TNFα, IL-1β, IL-12, MCP-1 and CCR2, while expression of IL-10 increased. Hepatic expression of CX3CL1, and its receptor, CX3CR1 also increased in STK{sup −/−} mice

  12. Interventions for paracetamol (acetaminophen) overdose

    DEFF Research Database (Denmark)

    Chiew, Angela L; Gluud, Christian; Brok, Jesper

    2018-01-01

    BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various...... of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best...... was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol...

  13. Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

    Directory of Open Access Journals (Sweden)

    Luciano Rezende Vilela

    2015-01-01

    Full Text Available Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD, protects against cocaine toxicity. URB597 (1.0 mg/kg abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

  14. Hepatoprotective Effects of Met-enkephalin on Acetaminophen-Induced Liver Lesions in Male CBA Mice

    OpenAIRE

    Martinić, Roko; Šošić, Hrvoje; Turčić, Petra; Konjevoda, Paško; Fučić, Aleksandra; Stojković, Ranko; Aralica, Gorana; Gabričević, Mario; Weitner, Tin; Štambuk, Nikola

    2014-01-01

    Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for se...

  15. Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury.

    Science.gov (United States)

    Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Aguiar, Rafael Pazinatto; Wiirzler, Luiz Alexandre Marques; Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Silva-Comar, Francielli Maria de Souza; Becker, Tânia Cristina Alexandrino; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2017-01-01

    To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

  16. Properties of the radicals formed by one-electron oxidation of acetaminophen - a pulse radiolysis study

    International Nuclear Information System (INIS)

    Bisby, R.H.; Tabassum, N.

    1988-01-01

    The semi-iminoquinone radical of acetaminophen, which has previously been proposed as a possible hepatotoxic intermediate in the cytochrome P-450 catalysed oxidation of acetaminophen, has been generated and studied by pulse radiolysis. In the absence of other reactive solutes, the radical decays rapidly by second order kinetics with a rate constant (2k 2 ) of (2.2 ± 0.4) x 10 9 M -1 sec -1 . In alkaline solutions the radical deprotonates with a pK of 11.1 ± 0.1 to form a radical-anion. The acetaminophen radical-anion reacts with resorcinol at high pH values, leading to the formation of a transient equilibrium from which the one-electron reduction potential of the semi-iminoquinone radical of acetaminophen is estimated to be + 0.707 ± 0.01 V at pH 7. This value predicts that acetaminophen should be oxidised by thiyl radicals. This was confirmed by pulse radiolysis experiments for reaction of the cysteinyl radical, for which rate constants of 7 x 10 6 M -1 sec -1 at pH7 and 2.7 x 10 8 M -1 sec -1 at pH 11.3 were obtained. The reaction of O 2 with the acetaminophen semi-iminoquinone radical could not be detected by pulse radiolysis, and alternative mechanisms for superoxide radical formation are discussed. (author)

  17. TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

    Directory of Open Access Journals (Sweden)

    Madison Davis

    2016-01-01

    Full Text Available In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor-α transgenic mouse hepatocyte (TAMH cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK. The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP, tetrafluoroethylcysteine (TFEC, flutamide, PD0325901, lapatinib, and flupirtine.

  18. Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

    Science.gov (United States)

    Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

    2016-08-01

    Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

  19. Spondias mombin L. (Anacardiaceae) enhances detoxification of hepatic and macromolecular oxidants in acetaminophen-intoxicated rats.

    Science.gov (United States)

    Saheed, Sabiu; Taofik, Sunmonu Olatunde; Oladipo, Ajani Emmanuel; Tom, Ashafa Anofi Omotayo

    2017-11-01

    Oxidative stress is a common pathological condition associated with drug-induced hepatotoxicity. This study investigated Spondias mombin L. aqueous leaf extract on reactive oxygen species and acetaminophen-mediated oxidative onslaught in rats' hepatocytes. Hepatotoxic rats were orally administered with the extract and vitamin C for 4 weeks. The extract dose-dependently scavenged DPPH, hydrogen peroxide and hydroxyl radicals, with IC 50 values of 0.13, 0.66, and 0.64 mg/mL, and corresponding % inhibitions of 89, 80, and 90%, respectively at 1.0 mg/mL. Ferric ion was also significantly reduced. The marked (p<0.05) increases in the activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were reduced following treatment with the extract. The extract also significantly (p<0.05) induced the activities of antioxidant enzymes. These inductions reversed the acetaminophen-enhanced reduction in the specific activities of these enzymes as well as attenuated the observed elevated concentrations of autooxidized products and rived DNA in the acetaminophen-intoxicated animals. The observed effects competed with those of vitamin C and are suggestive of hepatoprotective and antioxidative attributes of the extract. Overall, the data from the present findings suggest that S. Mombin aqueous leaf extract is capable of ameliorating acetaminophen-mediated oxidative hepatic damage via enhancement of antioxidant defense systems.

  20. Hepatotoxicity of amiodarone

    DEFF Research Database (Denmark)

    Rumessen, J J

    1986-01-01

    of the hepatotoxicity of amiodarone is given. It is concluded that solid evidence exists of hepatic injury due to amiodarone treatment, including steatosis, alterations resembling alcoholic hepatitis, cholestatic hepatitis and micronodular cirrhosis of the liver. Patients receiving amiodarone should be regularly......Amiodarone has proved very effective in the treatment of otherwise resistant cardiac tachyarrhythmias. The use of amiodarone has, however, been limited due to its serious side-effects. A patient with cholestatic hepatitis due to amiodarone treatment is presented below and a review...... screened with respect to hepatic enzyme levels. Therapy should be discontinued on the suspicion of cholestatic injury or hepatomegaly....

  1. Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwater fish (Oreochromis mossambicus).

    Science.gov (United States)

    Kavitha, P; Ramesh, R; Bupesh, G; Stalin, A; Subramanian, P

    2011-12-01

    The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus.

  2. Association of antioxidant nutraceuticals and acetaminophen (paracetamol: Friend or foe?

    Directory of Open Access Journals (Sweden)

    Mohamed Abdel-Daim

    2018-04-01

    Full Text Available Acetaminophen (paracetamol or APAP is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT. Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP. Keywords: Acetaminophen, Antioxidants, Food-drug interaction, Nutraceuticals, Paracetamol

  3. The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Huseinovic, A.; van Leeuwen, Jolanda; van Welsem, Tibor; Stulemeijer, Iris; van Leeuwen, Fred; Vermeulen, N.P.E.; Kooter, J.M.; Vos, J.C.

    2017-01-01

    Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity,

  4. Effect of Acetaminophen Ingestion on Thermoregulation of Normothermic, Non-Febrile Humans.

    Directory of Open Access Journals (Sweden)

    Josh eFoster

    2016-03-01

    Full Text Available In non-febrile mouse models, high dose acetaminophen administration causes profound hypothermia. However, this potentially hazardous side-effect has not been confirmed in non-febrile humans. Thus, we sought to ascertain whether an acute therapeutic dose (20 mg·kg lean body mass of acetaminophen would reduce non-febrile human core temperature in a sub-neutral environment. Ten apparently healthy (normal core temperature, no musculoskeletal injury, no evidence of acute illness Caucasian males participated in a preliminary study (Study one to determine plasma acetaminophen concentration following oral ingestion of 20 mg·kg lean body mass acetaminophen. Plasma samples (every 20 minutes up to 2-hours post ingestion were analysed via enzyme linked immunosorbent assay. Thirteen (eight recruited from Study one apparently healthy Caucasian males participated in Study two, and were passively exposed to 20°C, 40% r.h. for 120 minutes on two occasions in a randomised, repeated measures, crossover design. In a double blind manner, participants ingested acetaminophen (20 mg·kg lean body mass or a placebo (dextrose immediately prior to entering the environmental chamber. Rectal temperature, skin temperature, heart rate, and thermal sensation were monitored continuously and recorded every ten minutes. In Study one, the peak concentration of acetaminophen (14 ± 4 µg/ml in plasma arose between 80 and 100 minutes following oral ingestion. In Study two, acetaminophen ingestion reduced the core temperature of all participants, whereas there was no significant change in core temperature over time in the placebo trial. Mean core temperature was significantly lower in the acetaminophen trial compared with that of a placebo (p 0.05. The results indicate oral acetaminophen reduces core temperature of humans exposed to an environment beneath the thermal neutral zone. These results suggest that acetaminophen may inhibit the thermogenic mechanisms required to regulate

  5. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

    International Nuclear Information System (INIS)

    McGill, Mitchell R.; Lebofsky, Margitta; Norris, Hye-Ryun K.; Slawson, Matthew H.; Bajt, Mary Lynn; Xie, Yuchao; Williams, C. David; Wilkins, Diana G.; Rollins, Douglas E.; Jaeschke, Hartmut

    2013-01-01

    At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose–response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia–reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter. - Highlights: • Extensive GSH depletion is not required for APAP-protein binding in the liver. • APAP-protein adducts appear in plasma at subtoxic doses. • Proteins are adducted in the cell and secreted out. • Coincidental liver injury increases plasma APAP-protein adducts at subtoxic doses

  6. Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury

    DEFF Research Database (Denmark)

    Schmelzle, Moritz; Splith, Katrin; Wiuff Andersen, Lars

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... sacrificed and plasma MP were isolated by ultracentrifugation. HSC and CD133 MP levels were analyzed by fluorescence-activated cell sorting. Patients were enrolled with acute (n=5) and acute on chronic (n=5) liver injury with matched controls (n=7). Blood was collected at admission and plasma CD133 and CD39...... MP subsets were analyzed by fluorescence-activated cell sorting. RESULTS: HSC and CD133 MP levels were significantly increased only in the plasma of wild-type mice with acetaminophen hepatotoxicity (P

  7. Serum metabonomics study of the hepatoprotective effect of Corydalis saxicola Bunting on carbon tetrachloride-induced acute hepatotoxicity in rats by (1)H NMR analysis.

    Science.gov (United States)

    Liang, Yong-Hong; Tang, Chao-Ling; Lu, Shi-Yin; Cheng, Bang; Wu, Fang; Chen, Zhao-Ni; Song, Fangming; Ruan, Jun-Xiang; Zhang, Hong-Ye; Song, Hui; Zheng, Hua; Su, Zhi-Heng

    2016-09-10

    Corydalis saxicola Bunting (CS), a traditional Chinese folk medicine, has been effectively used for treating liver disease in Zhuang nationality in South China. However, the exact hepatoprotective mechanism of CS was still looking forward to further elucidation by far. In present work, metabonomic study of biochemical changes in the serum of carbon tetrachloride (CCl4)-induced acute liver injury rats after CS treatment were performed using proton nuclear magnetic resonance ((1)H-NMR) analysis. Metabolic profiling by means of principal components analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation caused by CCl4 was reduced by CS treatment. A total of 9 metabolites including isoleucine (1), lactate (2), alanine (3), glutamine (4), acetone (5), succinate (6), phosphocholine (7), d-glucose (8) and glycerol (9) were considered as potential biomarkers involved in the development of CCl4-induced acute liver injury. According to pathway analysis by metabolites identified and correlation network construction by Pearson's correlation coefficency matrix, alanine, aspartate and glutamate metabolism and glycerolipid metabolism were recognized as the most influenced metabolic pathways associated with CCl4 injury. As a result, notably, deviations of metabolites 1, 3, 4, 7 and 9 in the process of CCl4-induced acute liver injury were improved by CS treatment, which suggested that CS mediated synergistically abnormalities of the metabolic pathways, composed of alanine, aspartate and glutamate metabolism and glycerolipid metabolism. In this study, it was the first report to investigate the hepatoprotective effect of the CS based on metabonomics strategy, which may be a potentially powerful tool to interpret the action mechanism of traditional Chinese folk medicines. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    M. Kasi Reddy

    2017-01-01

    Full Text Available Aim: The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN in comparison to silymarin (SLM against acetaminophen (APAP-induced hepatotoxicity in rats. Materials and Methods: Male Wistar albino rats (n=24 of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity, and 15 (at the end of treatment. Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Results: Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. Conclusion: The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

  9. Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial.

    Directory of Open Access Journals (Sweden)

    Frederic T Billings

    Full Text Available Cardiopulmonary bypass (CPB lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 ± 0.6 μg/mL (78.9 ± 3.9 μM and 8.7 ± 0.3 μg/mL (57.6 ± 2.0 μM, respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05, and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03. Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation.Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.ClinicalTrials.gov NCT

  10. Acetaminophen Toxicosis in a Cat

    OpenAIRE

    Özkan, Burçak

    2017-01-01

    Acetaminophen causes serious problems as toxication in cats in spite of being an effective and reliable analgesic and antipyretic in humans. A six months-old female cat suffering from cough was presented to examination to International Pet Hospital/Tirana/Albania when no result was obtained after one  acetaminophen tablet had been administered in order to heal the disease. Depression, grey and cyanotic mucous membranes and tongue, tachypnea, tachycardia, hypothermia were primary clinical sign...

  11. Transition between acute and chronic hepatotoxicity in mice is associated with impaired energy metabolism and induction of mitochondrial heme oxygenase-1.

    Directory of Open Access Journals (Sweden)

    Aniket Nikam

    Full Text Available The formation of protein inclusions is frequently associated with chronic metabolic diseases. In mice, short-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC leads to hepatocellular damage indicated by elevated serum liver enzyme activities, whereas only minor morphological changes are observed. Conversely, chronic administration of DDC for several weeks results in severe morphological damage, characterized by hepatocellular ballooning, disruption of the intermediate filament cytoskeleton, and formation of Mallory-Denk bodies consisting predominantly of misfolded keratins, Sqstm1/p62, and heat shock proteins. To evaluate the mechanistic underpinnings for this dichotomy we dissected the time-course of DDC intoxication for up to 10 weeks. We determined body weight change, serum liver enzyme activities, morphologic alterations, induction of antioxidant response (heme oxygenase-1, HO-1, oxidative damage and ATP content in livers as well as respiration, oxidative damage and the presence and activity of HO-1 in endoplasmic reticulum and mitochondria (mtHO-1. Elevated serum liver enzyme activity and oxidative liver damage were already present at early intoxication stages without further subsequent increase. After 2 weeks of intoxication, mice had transiently lost 9% of their body weight, liver ATP-content was reduced to 58% of controls, succinate-driven respiration was uncoupled from ATP-production and antioxidant response was associated with the appearance of catalytically active mtHO-1. Oxidative damage was associated with both acute and chronic DDC toxicity whereas the onset of chronic intoxication was specifically associated with mitochondrial dysfunction which was maximal after 2 weeks of intoxication. At this transition stage, adaptive responses involving mtHO-1 were induced, indirectly leading to improved respiration and preventing further drop of ATP levels. Our observations clearly demonstrate principally different

  12. Hepatoprotective effect of Crocus sativus (saffron petals extract against acetaminophen toxicity in male Wistar rats

    Directory of Open Access Journals (Sweden)

    Arash Omidi

    2014-09-01

    Full Text Available Objectives: Acetaminophen (APAP toxicity is known to be common and potentially fatal. This study aims to investigate the protective effects of hydroalcoholic extract, remaining from Crocus sativus petals (CSP against APAP-induced hepatotoxicity by measuring the blood parameters and studying the histopathology of liver in male rats. Materials and Methods: Wister rats (24 were randomly assigned into four groups including: I healthy, receiving normal saline; II Intoxicated, receiving only APAP (600 mg/kg; III pre-treated with low dose of CSP (10 mg /kg and receiving APAP (600 mg/kg; IV pre-treated with high dose of CSP (20 mg/kg and receiving APAP (600 mg/kg. Results: The APAP treatment resulted in higher levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and bilirubin, along with lower total protein and albumin concentration than the control group. The administration of CSP with a dose of 20 mg/kg was found to result in lower levels of AST, ALT and bilirubin, with a significant higher concentration of total protein and albumin. The histopathological results regarding liver pathology, revealed sever conditions including cell swelling, severe inflammation and necrosis in APAP-exposed rats, which was quiet contrasting compared to the control group. The pre-treated rats with low doses of ‍CSP showed hydropic degeneration with mild necrosis in centrilobular areas of the liver, while the same subjects with high doses of ‍CSP appeared to have only mild hepatocyte degeneration. Conclusions: Doses of 20 mg/kg of CSP ameliorates APAP–induced acute liver injury in rats. It was concluded that the antioxidant property of CSP resulted in reducing the oxidative stress complications of toxic levels of APAP in intoxicated rats.

  13. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

    International Nuclear Information System (INIS)

    Williams, C. David; Antoine, Daniel J.; Shaw, Patrick J.; Benson, Craig; Farhood, Anwar; Williams, Dominic P.; Kanneganti, Thirumala-Devi; Park, B. Kevin; Jaeschke, Hartmut

    2011-01-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.

  14. Properties of the radicals formed by one-electron oxidation of acetaminophen - a pulse radiolysis study

    Energy Technology Data Exchange (ETDEWEB)

    Bisby, R H; Tabassum, N

    1988-07-15

    The semi-iminoquinone radical of acetaminophen, which has previously been proposed as a possible hepatotoxic intermediate in the cytochrome P-450 catalysed oxidation of acetaminophen, has been generated and studied by pulse radiolysis. In the absence of other reactive solutes, the radical decays rapidly by second order kinetics with a rate constant (2k/sub 2/) of (2.2 +- 0.4) x 10/sup 9/ M/sup -1/ sec/sup -1/. In alkaline solutions the radical deprotonates with a pK of 11.1 +- 0.1 to form a radical-anion. The acetaminophen radical-anion reacts with resorcinol at high pH values, leading to the formation of a transient equilibrium from which the one-electron reduction potential of the semi-iminoquinone radical of acetaminophen is estimated to be + 0.707 +- 0.01 V at pH 7. This value predicts that acetaminophen should be oxidised by thiyl radicals. This was confirmed by pulse radiolysis experiments for reaction of the cysteinyl radical, for which rate constants of 7 x 10/sup 6/ M/sup -1/ sec/sup -1/ at pH7 and 2.7 x 10/sup 8/ M/sup -1/ sec/sup -1/ at pH 11.3 were obtained. The reaction of O/sub 2/ with the acetaminophen semi-iminoquinone radical could not be detected by pulse radiolysis, and alternative mechanisms for superoxide radical formation are discussed.

  15. A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement.

    Science.gov (United States)

    Park, Yong-Beom; Ha, Chul-Won; Cho, Sung-Do; Lee, Myung-Chul; Lee, Ju-Hong; Seo, Seung-Suk; Kang, Seung-Baik; Kyung, Hee-Soo; Choi, Choong-Hyeok; Chang, NaYoon; Rhim, Hyou Young Helen; Bin, Seong-Il

    2015-01-01

    To evaluate the relative efficacy and safety of extended-release tramadol HCl 75 mg/acetaminophen 650 mg (TA-ER) and immediate-release tramadol HCl 37.5 mg/acetaminophen 325 mg (TA-IR) for the treatment of moderate to severe acute pain following total knee replacement. This phase III, double-blind, placebo-controlled, parallel-group study randomized 320 patients with moderate to severe pain (≥4 intensity on an 11 point numeric rating scale) following total knee replacement arthroplasty to receive oral TA-ER (every 12 hours) or TA-IR (every 6 hours) over a period of 48 hours. In the primary analysis, TA-ER was evaluated for efficacy non-inferior to that of TA-IR based on the sum of pain intensity difference (SPID) at 48 hours after the first dose of study drug (SPID48). Secondary endpoints included SPID at additional time points, total pain relief at all on-therapy time points (TOTPAR), sum of SPID and TOTPAR at all on-therapy time points (SPID + TOTPAR), use of rescue medication, subjective pain assessment (PGIC, Patient Global Impression of Change), and adverse events (AEs). Analysis of the primary efficacy endpoint (SPID48) could not establish the non-inferiority of TA-ER to TA-IR. However, a post hoc analysis with a re-defined non-inferiority margin did demonstrate the non-inferiority of TA-ER to TA-IR. No statistically significant difference in SPID at 6, 12, or 24 hours was observed between the TA-ER and TA-IR groups. Similarly, analysis of TOTPAR showed that there were no significant differences between groups at any on-therapy time point, and SPID + TOTPAR at 6 and 48 hours were similar among groups. There was no difference in the mean frequency or dosage of rescue medication required by both groups, and the majority of patients in both the TA-ER and TA-IR groups rated their pain improvement as 'much' or 'somewhat better'. The overall incidence of ≥1 AEs was similar among the TA-ER (88.8%) and TA-IR (89.5%) groups. The most commonly

  16. Hepatoprotective potential of three sargassum species from Karachi coast against carbon tetrachloride and acetaminophen intoxication

    Directory of Open Access Journals (Sweden)

    Khan Hira

    2016-01-01

    Full Text Available Objective: To assess the hepatoprotective effect of ethanol extracts of Sargassum variegatum (S. variegatum, Sargassum tenerrimum (S. tenerrimum and Sargassum binderi occurring at Karachi coast against carbon tetrachloride (CCl4 and acetaminophen intoxication in rats. Methods: Sargassum species were collected at low tide from Buleji beach at Karachi coast. Effect of ethanol extracts of Sargassum spp., on lipid parameter, serum glucose and kidney function was examined. Liver damage in rats was induced by CCl4 or acetaminophen. Rats were administered with ethanol extracts of S. tenerrimum, S. variegatum and Sargassum binderi at 200 mg/kg body weight daily for 14 days separately. Hepatotoxicity was determined in terms of cardiac and liver enzymes and other biochemical parameters. Results: S. variegatum showed highest activity by reducing the elevated level of hepatic enzymes, bilirubin, serum glucose, triglyceride with restoration of cholesterol. Urea and creatinine concentrations were also significantly (P < 0.05 reduced as compared to acetaminophen intoxicated rats. S. tenerrimum and S. variegatum showed moderate activity against CCl4 hepatic toxicity. Conclusions: The protective role of S. variegatum against acetaminophen liver damage and its positive impact on disturbed lipid, glucose metabolism, kidney dysfunction and S. tenerrimum against CCl4 liver toxicity suggest that Sargassum species offer a non-chemical means for the treatment of toxicity mediated liver damage.

  17. Effects of acetaminophen and ibuprofen in children with migraine receiving preventive treatment with magnesium.

    Science.gov (United States)

    Gallelli, Luca; Avenoso, Tiziana; Falcone, Daniela; Palleria, Caterina; Peltrone, Francesco; Esposito, Maria; De Sarro, Giovambattista; Carotenuto, Marco; Guidetti, Vincenzo

    2014-02-01

    The purpose of this study was to evaluate both the effects of ibuprofen and/or acetaminophen for the acute treatment of primary migraine in children in or out prophylactic treatment with magnesium. Children ranging from the ages of 5 to 16 years with at least 4 attack/month of primary migraine were eligible for participation the study. A visual analog scale was used to evaluate pain intensity at the moment of admission to the study (start of the study) and every month up to 18 months later (end of the study). One hundred sixty children of both sexes aged 5-16 years were enrolled and assigned in 4 groups to receive a treatment with acetaminophen or ibuprofen without or with magnesium. Migraine pain endurance and monthly frequency were similar in the 4 groups. Both acetaminophen and ibuprofen induced a significant decrease in pain intensity (P < .01), without a time-dependent correlation, but did not modify its frequency. Magnesium pretreatment induced a significant decrease in pain intensity (P < .01) without a time-dependent correlation in both acetaminophen- and ibuprofen-treated children and also significantly reduced (P < .01) the pain relief timing during acetaminophen but not during ibuprofen treatment (P < .01). In both acetaminophen and ibuprofen groups, magnesium pretreatment significantly reduced the pain frequency (P < .01). Magnesium increased the efficacy of ibuprofen and acetaminophen with not age-related effects. © 2013 American Headache Society.

  18. Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children

    NARCIS (Netherlands)

    Sjoukes, Alies; Venekamp, Roderick P; van de Pol, Alma C; Hay, Alastair D; Little, Paul; Schilder, Anne GM; Damoiseaux, Roger Amj

    2016-01-01

    BACKGROUND: Acute otitis media (AOM) is one of the most common childhood infectious diseases and a significant reason for antibiotic prescriptions in children worldwide. Pain from middle ear infection and pressure behind the eardrum is the key symptom of AOM. Ear pain is central to children's and

  19. Caffeine and acetaminophen association: Effects on mitochondrial bioenergetics.

    Science.gov (United States)

    Gonçalves, Débora F; de Carvalho, Nelson R; Leite, Martim B; Courtes, Aline A; Hartmann, Diane D; Stefanello, Sílvio T; da Silva, Ingrid K; Franco, Jéferson L; Soares, Félix A A; Dalla Corte, Cristiane L

    2018-01-15

    Many studies have been demonstrating the role of mitochondrial function in acetaminophen (APAP) hepatotoxicity. Since APAP is commonly consumed with caffeine, this work evaluated the effects of the combination of APAP and caffeine on hepatic mitochondrial bioenergetic function in mice. Mice were treated with caffeine (20mg/kg, intraperitoneal (i.p.)) or its vehicle and, after 30minutes, APAP (250mg/kg, i.p.) or its vehicle. Four hours later, livers were removed, and the parameters associated with mitochondrial function and oxidative stress were evaluated. Hepatic cellular oxygen consumption was evaluated by high-resolution respirometry (HRR). APAP treatment decreased cellular oxygen consumption and mitochondrial complex activities in the livers of mice. Additionally, treatment with APAP increased swelling of isolated mitochondria from mice livers. On the other hand, caffeine administered with APAP was able to improve hepatic mitochondrial bioenergetic function. Treatment with APAP increased lipid peroxidation and reactive oxygen species (ROS) production and decreased glutathione levels in the livers of mice. Caffeine administered with APAP was able to prevent lipid peroxidation and the ROS production in mice livers, which may be associated with the improvement of mitochondrial function caused by caffeine treatment. We suggest that the antioxidant effects of caffeine and/or its interactions with mitochondrial bioenergetics may be involved in its beneficial effects against APAP hepatotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe?

    Science.gov (United States)

    Abdel-Daim, Mohamed; Abushouk, Abdelrahman Ibrahim; Reggi, Raffaella; Yarla, Nagendra Sastry; Palmery, Maura; Peluso, Ilaria

    2018-04-01

    Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT). Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP. Copyright © 2017. Published by Elsevier B.V.

  1. The Possible Efficacy of Artichoke in Fluconazole Related Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hüseyin Kurt

    2014-01-01

    Full Text Available Although fluconazole related hepatotoxicity (FRH is rare, mortal acute hepatic necrosis and jaundice were reported in immunocompromised states such as acquired immunodeficiency syndrome (AIDS and bone marrow transplant (BMT. We present a case of a patient with multiple sclerosis who developed hepatotoxicity with the use of a single 150 mg fluconazole tablet for fungal vaginitis, 10 days after methylprednisolone pulse treatment. Our patient’s alanine aminotransferase (ALT and aspartate aminotransferase (AST levels were decreased, 1200 U/L and 800 U/L, respectively, and bilirubin levels were consistent at 37 mg/dL. Artichoke which has anticholestatic and antioxidant properties was used by our patient. She consumed a 30 mg artichoke leaf extract tea 3 times a day. The bilirubin levels significantly declined at the end of the first week and all liver function tests were normalized within 2 months.

  2. Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Das S

    2011-06-01

    Full Text Available Suvadra Das, Partha Roy, Runa Ghosh Auddy, Arup MukherjeeDepartment of Chemical Technology, University of Calcutta, Kolkata, West Bengal, IndiaAbstract: Silymarin (Sm is a polyphenolic component extracted from Silybum marianum. It is an antioxidant, traditionally used as an immunostimulant, hepatoprotectant, and dietary supplement. Relatively recently, Sm has proved to be a valuable chemopreventive and a useful antineoplastic agent. Medical success for Sm is, however, constrained by very low aqueous solubility and associated biopharmaceutical limitations. Sm flavonolignans are also susceptible to ion-catalyzed degradation in the gut. Proven antihepatotoxic activity of Sm cannot therefore be fully exploited in acute chemical poisoning conditions like that in paracetamol overdose. Moreover, a synchronous delivery that is required for hepatic regeneration is difficult to achieve by itself. This work is meant to circumvent the inherent limitations of Sm through the use of nanotechnology. Sm nanoparticles (Smnps were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100® polymer (Rohm Pharma GmbH, Darmstadt, Germany. Process parameter optimization provided 67.39% entrapment efficiency and a Gaussian particle distribution of average size 120.37 nm. Sm release from the nanoparticles was considerably sustained for all formulations. Smnps were strongly protective against hepatic damage when tested in a paracetamol overdose hepatotoxicity model. Nanoparticles recorded no animal death even when administered after an established paracetamol-induced hepatic necrosis. Preventing progress of paracetamol hepatic damage was traced for an efficient glutathione regeneration to a level of 11.3 µmol/g in hepatic tissue due to Smnps.Keywords: silymarin, paracetamol, nanoparticle, glutathione, mouse hepatotoxicity

  3. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2012-01-01

    AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P = 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P = 0.009). CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres. PMID:22106945

  4. Extracorporeal treatment for acetaminophen poisoning

    DEFF Research Database (Denmark)

    Gosselin, S; Juurlink, D N; Kielstein, J T

    2014-01-01

    BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP). METHODS: After a systematic review of the litera...... of NAC has not been definitively demonstrated....

  5. Ethanol extract from portulaca oleracea L. attenuated acetaminophen-induced mice liver injury

    Science.gov (United States)

    Liu, Xue-Feng; Zheng, Cheng-Gang; Shi, Hong-Guang; Tang, Gu-Sheng; Wang, Wan-Yin; Zhou, Juan; Dong, Li-Wei

    2015-01-01

    Acetaminophen-induced liver injury represents the most frequent cause of drug-induced liver failure in the world. Portulaca oleracea L., a widely distributed weed, has been used as a folk medicine in many countries. Previously, we reported that the ethanol extracts of Portulaca oleracea L. (PO) exhibited significant anti-hypoxic activity. In the present study, we investigated the role of PO on acetaminophen (APAP) induced hepatotoxicity. The results demonstrated that PO was an effective anti-oxidative agent, which could, to some extent, reverse APAP-induced hepatotoxicity by regulating the reactive oxygen species (ROS) in the liver of mice. At the same time, PO treatment significantly decreased mice serum levels of IL-6 and TNFα and their mRNA expression in liver tissue IL-α and TNFα play an important role during APAP-induced liver injury. Furthermore, PO inhibited APAP and TNFα-induced activation of JNK, whose activation play an important effect during APAP induced liver injury. These findings suggested that administration of PO may be an effective strategy to prevent or treat liver injury induced by APAP. PMID:25901199

  6. Experimental type 2 diabetes mellitus and acetaminophen toxic lesions: glutathione system indices changes

    Directory of Open Access Journals (Sweden)

    Olga Furka

    2017-11-01

    Full Text Available Background. The goal of the research was to study the effect of acetaminophen on major glutathione part of antioxidant system indices in liver homogenate of rats with type 2 diabetes mellitus in time dynamics. Materials and methods. We conducted two series of experiments. In the first series toxic lesion was caused by a single intragastric administration of acetaminophen suspension in 2 % starch solution to animals in a dose of 1250 mg/kg (1/2 LD50. In the second series  the suspension of acetaminophen in 2 % starch solution in a dose of 55 mg/kg was given, which corresponds to the highest therapeutic dose during 7 days. Non-genetic form of experimental type 2 diabetes mellitus was modeled by Islam S., Choi H. method (2007. Activity of glutathione peroxidase (GPx and glutathione reductase (GR, and contents of reduced glutathione (GSH were determined in liver homogenate. Results. The obtained results have shown that GR and GPx activity actively decreased after acetaminophen administration in higher therapeutic doses to rats with type 2 DM. However, the changes were less pronounced than in rats with type 2 DM and acute acetaminophen toxic lesions. Conclusion. Results of the research have shown that acetaminophen administration to rats with type 2 DM causes a significant violation of compensatory mechanisms, especially of the enzyme and nonenzyme parts of antioxidant system.

  7. Pre-emptive analgesia with paracetamol (acetaminophen) in postoperative pain

    International Nuclear Information System (INIS)

    Afhami, M.R.; Hassanzadeh, J.P.; Panahea, J.R.

    2007-01-01

    To evaluate efficacy and safety of preoperative paracetamol for postoperative pain relief. The study population consisted of 40 adult female patients scheduled for tubectomy as an elective surgery who were in ASA class I. Patients were allocated randomly to receive 325mg of acetaminophen orally half an hour before surgery. Pain was assessed by verbal rating scale in three situations (resting, moving and coughing). Data was collection done using the questionnaire and data analysis done using descriptive statistical methods. The patients who received oral paracetamol experienced moderate and mild pain in 50% of the cases when they were in resting position. Feeling mild and moderate pain with movement was in 40% and 60% respectively. While coughing, 100% of the cases felt only moderate pain and none experienced severe pain. Administration of a single dose of acetaminophen in preoperative period is effective for acute postoperative pain relief. (author)

  8. Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36.5 °C or above.

    Science.gov (United States)

    de Ridder, Inger R; de Jong, Frank Jan; den Hertog, Heleen M; Lingsma, Hester F; van Gemert, H Maarten A; Schreuder, A H C M L Tobien; Ruitenberg, Annemieke; Maasland, E Lisette; Saxena, Ritu; Oomes, Peter; van Tuijl, Jordie; Koudstaal, Peter J; Kappelle, L Jaap; Algra, Ale; van der Worp, H Bart; Dippel, Diederik W J

    2015-04-01

    In the first hours after stroke onset, subfebrile temperatures and fever have been associated with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a randomized clinical trial of 1400 patients with acute stroke, patients who were treated with high-dose paracetamol showed more improvement on the modified Rankin Scale at three-months than patients treated with placebo, but this difference was not statistically significant. In the 661 patients with a baseline body temperature of 37.0 °C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 1.43; 95% confidence interval: 1.02-1.97). This relation was also found in the patients with a body temperature of 36.5 °C or higher (odds ratio 1.31; 95% confidence interval 1.01-1.68). These findings need confirmation. The study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 36.5 °C or above on functional outcome. The Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial. We use a power of 85% to detect a significant difference in the scores on the modified Rankin Scale of the paracetamol group compared with the placebo group at a level of significance of 0.05 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 36.5 °C or above will be included within 12 h of symptom onset. Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been registered as NTR2365 in The Netherlands Trial Register. The primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression. If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be

  9. Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.

    Directory of Open Access Journals (Sweden)

    Laura James

    Full Text Available Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001, glycodeoxycholic acid (R=0.581; p<0.001, and glycochenodeoxycholic acid (R=0.571; p<0.001. Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.

  10. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Andreas Buness

    Full Text Available Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI using transcriptomics, metabolite profiling (metabolomics and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine, classical clinical chemistry markers like AST (aspartate aminotransferase, ALT (alanine aminotransferase, and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1 and Egr1 (early growth response protein 1. The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  11. Liver inflammation during monocrotaline hepatotoxicity

    International Nuclear Information System (INIS)

    Copple, Bryan L.; Ganey, Patricia E.; Roth, Robert A.

    2003-01-01

    Monocrotaline (MCT) is a pyrrolizidine alkaloid (PA) plant toxin that causes hepatotoxicity in humans and animals. Human exposure occurs from consumption of contaminated grains and herbal teas and medicines. Intraperitoneal injection (i.p.) of 300 mg/kg MCT in rats produced time-dependent hepatic parenchymal cell (HPC) injury beginning at 12 h. At this time, an inflammatory infiltrate consisting of neutrophils (PMNs) appeared in areas of hepatocellular injury, and activation of the coagulation system occurred. PMN accumulation was preceded by up-regulation of the PMN chemokines cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) in the liver. The monocyte chemokine, monocyte chemoattractant protein-1 (MCP-1), was also upregulated. Inhibition of Kupffer cell function with gadolinium chloride (GdCl 3 ) significantly reduced CINC-1 protein in plasma after MCT treatment but had no effect on hepatic PMN accumulation. Since inflammation can contribute to either pathogenesis or resolution of tissue injury, we explored inflammatory factors as a contributor to MCT hepatotoxicity. To test the hypothesis that PMNs contribute to MCT-induced HPC injury, rats were depleted of PMNs with a rabbit anti-PMN serum prior to MCT treatment. Anti-PMN treatment reduced hepatic PMN accumulation by 80% but had no effect on MCT-induced HPC injury or activation of the coagulation system. To test the hypothesis that Kupffer cells and/or tumor necrosis factor-α (TNF-α) are required for MCT-induced HPC injury, rats were treated with either GdCl 3 to inhibit Kupffer cell function or pentoxifylline (PTX) to prevent synthesis of TNF-α. Neither treatment prevented MCT-induced HPC injury. Results from these studies suggest that PMNs, Kupffer cells and TNF-α are not critical mediators of MCT hepatotoxicity. Accordingly, although inflammation occurs in the liver after MCT treatment, it is not required for HPC injury and possibly occurs secondary to

  12. Comparison of Intravenous Metoclopramide and Acetaminophen in Primary Headaches: a Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Gholamreza Faridaalaee

    2015-05-01

    Full Text Available Introduction: Headache is the most common neurologic symptom among referees to the emergency department (ED, while the best treatment has not yet been found. Therefore, in the present study pain relief effects of metoclopramide and acetaminophen were compared in patients suffered acute primary headache. Methods: This study was a double-blind randomized clinical trial performed in Imam Khomeini Hospital, Urmia, Iran, through July to October 2014.  All adult patients, with acute primary (migraine, tension type and cluster headache referred to the ED were included in this study. Pain Severity was measured with 10 centimeters numeric rating scales. The patients were randomized in to two groups of intravenous (IV metoclopramide (10 milligrams and acetaminophen (1 gram. Pain score, success rate, and complication of drugs were compared within administration time and 15, 30, 60, as well as 120 minutes after medication. Results: 100 patients were equally categorized in to two groups (mean age of 32 ± 13.2 years; 51.2% male. Initial pain score in metoclopramide and acetaminophen groups were 9.1 and 9.4, respectively (p=0.46. IV metoclopramide did not have any analgesic effect at 15 minutes, but had good effect at 30 minutes. While, the analgesic effect of acetaminophen initiated after 15 minutes. After 2 hours, both drugs had good treatment effect on primary headaches (p<0.001. Conclusion: The present study demonstrated that efficacy of metoclopramide for pain relief in primary headaches is lower than acetaminophen.  In this regard, success rate of acetaminophen was 42.0% versus 0% for metoclopramide within 15 minutes. The efficacy of acetaminophen continued until 60 minutes.

  13. Acetaminophen Toxicosis in a Cat

    OpenAIRE

    Anvik, J. O.

    1984-01-01

    A seven month old domestic shorthaired male cat was presented with a known history of acetaminophen ingestion. Clinical findings included icterus, depression, hypothermia, tachypnea and pronounced edema of the head and neck. Treatment was aimed at providing substrate to assist in conjugation of the drug and reversing methemoglobinemia. Administration of oral acetylcysteine, ascorbic acid and IV fluids was insufficient in this case due to a delay in initiation of treatment. The salient postmor...

  14. Discrepancies between N-Acetyl Cysteine Prescription based on Patient’s History and Plasma Acetaminophen Level

    Directory of Open Access Journals (Sweden)

    Fakhreddin Taghaddosi-Nejad

    2012-11-01

    Full Text Available Background: Fatalities from acetaminophen poisoning are common, but they are preventable by timely treatment with N-acetyl cysteine (NAC. In many medical centers, NAC is prescribed in keeping with the ingested dose of the drug as revealed through medical history. It seems to significantly differ from the real indications of NAC administration based on plasma level of acetaminophen. Overtreatment increases adverse drug reactions and it is time- consuming and costly. Methods: Acetaminophen plasma level was checked by HPLC method in 170 admitted patients who had history of acute ingestion of more than 7.5 g acetaminophen within 4 to 24 hours prior to hospital admission. Indications for NAC prescription according to patient’s history and adaptation from acetaminophen plasma level in Romack-Mathew nomogram were matched. Data were analyzed by SPSS software version 16.0. Results: Mean age of the patients was 21.8±6.05 years. In 75.8% of the patients, poisoning had occurred after suicidal attempts. Acetaminophen plasma level was between less than 2 and 265 μg/ml (18.7±28.88, mean± SD. Only in 18 (10.6% cases, overtreatment had been performed. Multiple logistic regression analysis showed that the number of suicidal attempts, number of ingested pills, and time of referral had positive relationships with acetaminophen plasma level. Conclusion: If NAC is prescribed only based on patient's medical history, overtreatment may take place.

  15. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial : a multicentre, randomised, placebo-controlled, phase III trial

    NARCIS (Netherlands)

    den Hertog, Heleen M.; van der Worp, H. Bart; van Gemert, H. Maarten A.; Algra, Ate; Kappelle, L. Jaap; Van Gijn, Jan; Koudstaal, Peter J.; Dippel, Diederik W. J.

    Background High body temperature in the first 12-24 h after stroke onset is associated with poor functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial aimed to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing

  16. [Hepatox: database on hepatotoxic drugs].

    Science.gov (United States)

    Quinton, A; Latry, P; Biour, M

    1993-01-01

    Hepatox is a data base on the hepatotoxic drugs file published every year in Gastroentérologie Clinique et Biologique. The program was developed under Omnis 7 for Apple computers, and under Visual Basic Professional Toolkit and Code Base for IBM PC and compatibles computers. The data base includes forms of 866 drugs identified by their approved name and those of their 1,300 corresponding proprietary names in France; drugs are distributed among 104 pharmacological classes. It is possible to have instantaneously access to the card of a drug identified by its approved name. Acceding to a drug identified by its proprietary name gives a list of the approved name of its components; going from a name of this list to the correspondent card of hepatoxicity is immediate. It is easy to extract lists of drugs responsible of a type of hepatic injury, and a table of types of hepatic injuries induced by the drugs of a pharmacological class.

  17. Identification of identical transcript changes in liver and whole blood during acetaminophen toxicity

    Directory of Open Access Journals (Sweden)

    Liwen eZhang

    2012-09-01

    Full Text Available Abstract The ability to identify mechanisms underlying drug-induced liver injury (DILI in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a noninvasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP. In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose with similar patterns of expression in blood and liver during APAP induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only thirty eight genes were common to both the 6 and 24h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined.

  18. Hepatotoxicity and the present herbal hepatoprotective scenario

    OpenAIRE

    Priyankar Dey; Manas Ranjan Saha; Arnab Sen

    2013-01-01

    Most of the metabolic and physiological processes of our body as well as the detoxification of various drugs and xenobiotic chemicals occur in the liver. During this detoxification process, the reactive chemical intermediates damage the liver severely. There are several commercially available drugs, consumption of which results in idiosyncratic drug reaction mediated hepatotoxicity. Drug induced hepatotoxicity is a burning problem in this regard and several drugs are withdrawn from the market...

  19. Paracetamol (acetaminophen) poisoning.

    Science.gov (United States)

    Park, B Kevin; Dear, James W; Antoine, Daniel J

    2015-10-19

    Paracetamol directly causes around 150 deaths per year in UK. We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). At this update, searching of electronic databases retrieved 127 studies. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 46 studies and the further review of 18 full publications. Of the 18 full articles evaluated, one systematic review was updated and one RCT was added at this update. In addition, two systematic reviews and three RCTs not meeting our inclusion criteria were added to the Comment sections. We performed a GRADE evaluation for three PICO combinations. In this systematic overview we categorised the efficacy for six interventions, based on information about the effectiveness and safety of activated charcoal (single or multiple dose), gastric lavage, haemodialysis, liver transplant, methionine, and acetylcysteine.

  20. Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

    Science.gov (United States)

    Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

    2017-06-01

    The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

  1. The Social Side Effects of Acetaminophen

    Science.gov (United States)

    Mischkowski, Dominik

    About 23% of all adults in the US take acetaminophen during an average week (Kaufman, Kelly, Rosenberg, Anderson, & Mitchell, 2002) because acetaminophen is an effective physical painkiller and easily accessible over the counter. The physiological side effects of acetaminophen are well documented and generally mild when acetaminophen is consumed in the appropriate dosage. In contrast, the psychological and social side effects of acetaminophen are largely unknown. Recent functional neuroimaging research suggests that the experience of physical pain is fundamentally related to the experience of empathy for the pain of other people, indicating that pharmacologically reducing responsiveness to physical pain also reduces cognitive, affective, and behavioral responsiveness to the pain of others. I tested this hypothesis across three double-blind between-subjects drug intervention studies. Two experiments showed that acetaminophen had moderate effects on empathic affect, specifically personal distress and empathic concern, and a small effect on empathic cognition, specifically perceived pain, when facing physical and social pain of others. The same two experiments and a third experiment also showed that acetaminophen can increase the willingness to inflict pain on other people, i.e., actual aggressive behavior. This effect was especially pronounced among people low in dispositional empathic concern. Together, these findings suggest that the physical pain system is more involved in the regulation of social cognition, affect, and behavior than previously assumed and that the experience of physical pain and responsiveness to the pain of others share a common neurochemical basis. Furthermore, these findings suggest that acetaminophen has unappreciated but serious social side effects, and that these side effects may depend on psychological characteristics of the drug consumer. This idea is consistent with recent theory and research on the context-dependency of neurochemical

  2. Compound list: acetaminophen [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available acetaminophen APAP 00001 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/acetam...inophen.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/acetam...inophen.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/i...cedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/acetaminophen.Rat.in_vivo.Liver.Repeat.zip ftp...://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Single/acetaminophen.Rat.in_vivo.Kidn

  3. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

    Directory of Open Access Journals (Sweden)

    Christian Frenzel

    2016-04-01

    Full Text Available Herb induced liver injury (HILI and drug induced liver injury (DILI share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM rarely causes elevated liver tests (LT. However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

  4. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

    Directory of Open Access Journals (Sweden)

    Nora Freyer

    2018-03-01

    Full Text Available The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05 and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001, indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05, suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

  5. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions.

    Science.gov (United States)

    Freyer, Nora; Greuel, Selina; Knöspel, Fanny; Gerstmann, Florian; Storch, Lisa; Damm, Georg; Seehofer, Daniel; Foster Harris, Jennifer; Iyer, Rashi; Schubert, Frank; Zeilinger, Katrin

    2018-03-15

    The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP ( p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

  6. Towards non-invasive 3D hepatotoxicity assays with optical coherence phase microscopy

    Science.gov (United States)

    Nelson, Leonard J.; Koulovasilopoulos, Andreas; Treskes, Philipp; Hayes, Peter C.; Plevris, John N.; Bagnaninchi, Pierre O.

    2015-03-01

    Three-dimensional tissue-engineered models are increasingly recognised as more physiologically-relevant than standard 2D cell culture for pre-clinical drug toxicity testing. However, many types of conventional toxicity assays are incompatible with dense 3D tissues. This study investigated the use of optical coherence phase microscopy (OCPM) as a novel approach to assess cell death in 3D tissue culture. For 3D micro-spheroid formation Human hepatic C3A cells were encapsulated in hyaluronic acid gels and cultured in 100μl MEME/10%FBS in 96-well plates. After spheroid formation the 3D liver constructs were exposed to acetaminophen on culture day 8. Acetaminophen hepatotoxicity in 3D cultures was evaluated using standard biochemical assays. An inverted OCPM in common path configuration was developed with a Callisto OCT engine (Thorlabs), centred at 930nm and a custom scanning head. Intensity data were used to perform in-depth microstructural imaging. In addition, phase fluctuations were measured by collecting several successive B scans at the same location, and statistics on the first time derivative of the phase, i.e. time fluctuations, were analysed over the acquisition time interval to retrieve overall cell viability. OCPM intensity (cell cluster size) and phase fluctuation statistics were directly compared with biochemical assays. In this study, we investigated optical coherence phase tomography to assess cell death in a 3d liver model after exposure to a prototypical hepatotoxin, acetaminophen. We showed that OCPM has the potential to assess noninvasively and label-free drug toxicity in 3D tissue models.

  7. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  8. Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

    International Nuclear Information System (INIS)

    Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.; Kosyk, Oksana; Sandot, Amelia; Witek, Rafal; Kaiser, Robert; Stewart, Todd; Amaral, Kirsten; Freeman, Kimberly; Black, Chris; LeCluyse, Edward L.; Ferguson, Stephen S.; Rusyn, Ivan

    2010-01-01

    Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

  9. Hepatoprotective Effects of Met-enkephalin on Acetaminophen-Induced Liver Lesions in Male CBA Mice

    Directory of Open Access Journals (Sweden)

    Roko Martinić

    2014-08-01

    Full Text Available Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for several different animal disease models. In this group plasma alanine aminotransferase and aspartate aminotransferase enzyme activities, as well as liver necrosis score were significantly reduced in comparison to control animals treated with physiological saline (p > 0.01. The specificity of the peptide hepatoprotection was investigated from the standpoint of the receptor and peptide blockade. It was concluded that Met-enkephalin effects on the liver were mediated via δ and ζ opioid receptors. Genotoxic testing of Met-enkephalin confirmed the safety of the peptide.

  10. Interventions for paracetamol (acetaminophen) overdose.

    Science.gov (United States)

    Chiew, Angela L; Gluud, Christian; Brok, Jesper; Buckley, Nick A

    2018-02-23

    Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of

  11. Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study

    OpenAIRE

    Wondwossen Abera,; Waqtola Cheneke,; Gemeda Abebe,

    2016-01-01

    Background: Antituberculosis drugs cause hepatotoxicity in some individuals leading to acute liver failure, which results in death. Such phenomena limit the clinical use of drugs, contributing to treatment failure that possibly causes drug resistance. Furthermore, associated risk factors for the development of antituberculosis-drug-induced hepatotoxicity (anti-TB-DIH) are found to be controversial among different study findings. Methods: A prospective cohort study was conducted from May 20...

  12. Dipyrone and acetaminophen: correct dosing by parents?

    Directory of Open Access Journals (Sweden)

    João Guilherme Bezerra Alves

    Full Text Available CONTEXT AND OBJECTIVE: Several studies in developed countries have documented that a significant percentage of children are given inappropriate doses of acetaminophen and ibuprofen. The objective of this paper was to investigate parents’ accuracy in giving dipyrone and acetaminophen to their children, in a poor region. DESIGN AND SETTING: Cross-sectional study at the pediatric emergency department of Instituto Materno-Infantil Prof. Fernando Figueira, a teaching hospital in Pernambuco. METHODS: The inclusion criteria were age between 3 and 36 months, main complaint of fever and at least one dose of dipyrone or acetaminophen given to the child during the 24 hours preceding their arrival at the emergency department. The mothers were asked for demographic information and about the antipyretic doses given, which were compared with the recommended dosage. RESULTS: Among the 200 patients studied, 117 received dipyrone and 83 received acetaminophen. Overall, 75 % received an incorrect dose of antipyretic. Of the patients who received dipyrone, 105 (89.7% were given an incorrect dose; 16 (15.2% received too little dipyrone, and 89 (84.8% received too much. Of the patients who received acetaminophen, 45 (54.2% were given an incorrect dose; 38 (84.4% received too little acetaminophen, and 7 (15.6% received too much. There were no differences in maternal and child characteristics between the groups receiving correct and incorrect doses of medication, except for the type of medication (dipyrone versus acetaminophen. CONCLUSIONS: Most of the children treated were given inappropriate doses, mainly dipyrone overdosing and acetaminophen underdosing.

  13. Hepatotoxicity in hyperthyroid patient after consecutive methimazole and propylthiouracil therapies

    Directory of Open Access Journals (Sweden)

    Fernando Gomez-Peralta

    2018-01-01

    Full Text Available Methimazole (MMI and propylthiouracil (PTU are widely used antithyroid drugs (ATD that have been approved for the treatment of hyperthyroidism. Hepatotoxicity may be induced by these drugs, though they exert dissimilar incidence rates of hepatotoxicity and, possibly, with different underlying pathogenic mechanisms. We report the case of a 55-year-old woman with no relevant medical history diagnosed with hyperthyroidism due to Graves’ disease, who developed two episodes of acute hepatitis concurrent with the consecutive administration of two different ATDs, first MMI and then PTU. Given the impossibility of administering ATDs, it was decided to perform a total thyroidectomy because the patient was found to be euthyroid at that point. Pathological anatomy showed diffuse hyperplasia and a papillary thyroid microcarcinoma of 2 mm in diameter. Subsequent clinical check-ups were normal. This case suggests the importance of regular monitoring of liver function for hyperthyroid patients. Due to the potential severity of this side effect, it is recommended to determine baseline liver function prior to initiation of treatment.

  14. Acetaminophen (paracetamol) oral absorption and clinical influences.

    Science.gov (United States)

    Raffa, Robert B; Pergolizzi, Joseph V; Taylor, Robert; Decker, John F; Patrick, Jeffrey T

    2014-09-01

    Acetaminophen (paracetamol) is a widely used nonopioid, non-NSAID analgesic that is effective against a variety of pain types, but the consequences of overdose can be severe. Because acetaminophen is so widely available as a single agent and is increasingly being formulated in fixed-ratio combination analgesic products for the potential additive or synergistic analgesic effect and/or reduced adverse effects, accidental cumulative overdose is an emergent concern. This has rekindled interest in the sites, processes, and pharmacokinetics of acetaminophen oral absorption and the clinical factors that can influence these. The absorption of oral acetaminophen occurs primarily along the small intestine by passive diffusion. Therefore, the rate-limiting step is the rate of gastric emptying into the intestines. Several clinical factors can affect absorption per se or the rate of gastric emptying, such as diet, concomitant medication, surgery, pregnancy, and others. Although acetaminophen does not have the abuse potential of opioids or the gastrointestinal bleeding or organ adverse effects of NSAIDs, excess amounts can produce serious hepatic injury. Thus, an understanding of the sites and features of acetaminophen absorption--and how they might be influenced by factors encountered in clinical practice--is important for pain management using this agent. It can also provide insight for design of formulations that would be less susceptible to clinical variables. © 2013 World Institute of Pain.

  15. Factors influencing circadian rhythms in acetaminophen lethality.

    Science.gov (United States)

    Schnell, R C; Bozigian, H P; Davies, M H; Merrick, B A; Park, K S; McMillan, D A

    1984-01-01

    Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.

  16. [Hepatotoxicity associated with the use of Herbalife].

    Science.gov (United States)

    Jóhannsson, Magnús; Ormarsdóttir, Sif; Olafsson, Sigurdur

    2010-03-01

    Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

  17. Treatment strategies for early presenting acetaminophen overdose: a survey of medical directors of poison centers in North America and Europe.

    Science.gov (United States)

    Kozer, E; McGuigan, M

    2002-03-01

    Acetaminophen is frequently used in self-poisoning in Western countries. Although treatment with N-acetylcysteine (NAC) reduces liver injury, no consensus exists on the preferred management of acetaminophen toxicity. To describe the approach taken by toxicologists in North America and Europe toward the management of acetaminophen toxicity. Medical directors of poison centers in the US, Canada, and Europe were surveyed by means of a questionnaire presenting two clinical scenarios of acetaminophen overdose: a healthy adolescent with no risk factors who had an acute ingestion of acetaminophen, and an adult with both acute ingestion and possible risk factors. For each case, several questions about the management of these patients were asked. Questionnaires were sent to medical directors of 76 poison centers in North America and 48 in Europe, with response rates of 62% and 44%, respectively. Forty percent of responders suggested using charcoal 4 hours after ingestion of a potential toxic dose of acetaminophen, and 90% recommended treatment with NAC when levels were above 150 microg/mL but below 200 microg/mL 4 hours after ingestion. Duration of treatment with oral NAC ranged from 24 to 96 hours; 38 responders suggested a duration of 72 hours. Of 49 centers recommending oral NAC, 18 (36.7%) said they might consider treatment for less than 72 hours. Eleven of 29 (37.9%) responders suggested treatment with intravenous NAC for more than 20 hours as their usual protocol or a protocol for specific circumstances. Our study showed large variability in the management of acetaminophen overdose. Variations in treatment protocols should be addressed in clinical trials to optimize the treatment for this common problem.

  18. Hepatotoxicity with antituberculosis drugs: the risk factors

    International Nuclear Information System (INIS)

    Mahmood, K.; Samo, A.H.; Jairamani, K.L.; Talib, A.

    2007-01-01

    To assess the severity and frequency of hepatotoxicity caused by different antituberculosis (ATT) drugs and to evaluate whether concurrence of risk factors influence the antituberculosis drug induced hepatotoxicity. This prospective cohort study was conducted in Medical Unit-V and OPD department of Civil Hospital Karachi from July 2004 to July 2005. A total of 339 patients diagnosed of active tuberculosis infection with normal pretreatment liver function were monitored clinically as well as biochemically. Their data were collected on proforma and patients were treated with Isoniazid, Rifampicin and Pyrazinamide. Duration after which derangement in function, if any, occurred and time taken for normalization was noted. Treatment was altered as needed, with exclusion of culprit drug. Finally data was analyzed by SPSS version 10.0. ATT induced hepatotoxicity was seen in 67 (19.76%) out of 339 patients. Females were more affected as compared to males (26.3% vs. 19.7%). BMI (kg/m2) of 91% of diseased group were less than 18.5 (p<0.01) most of them were anemic having low albumin level suggestive of lean body mass. Hepatotoxicity was more severe in AFB smear positive patients. Concomitant use of alcohol, paracetamol and low serum cholesterol were proved as predisposing factors. Isoniazid (37 patients (55.21%), p<0.01) was the main culprit followed by Rifampicin (23 patients, 34.21%) and Pyrazinamide (7 patients, 10.5%). Most of the patients (61%) developed the hepatotoxicity within two weeks of starting antituberculosis therapy with mild to moderate alteration in ALT and AST. ATT-induced hepatitis is significantly more frequent and more severe in patients with hepatotoxicity risk factors. (author)

  19. Application of toxicogenomics in hepatic systems toxicology for risk assessment: Acetaminophen as a case study

    International Nuclear Information System (INIS)

    Kienhuis, Anne S.; Bessems, Jos G.M.; Pennings, Jeroen L.A.; Driessen, Marja; Luijten, Mirjam; Delft, Joost H.M. van

    2011-01-01

    Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as a model compound to discuss the application of toxicogenomics in hepatic systems toxicology for its potential role in the risk assessment process, to progress from hazard identification towards hazard characterization. The toxicogenomics-based parallelogram is used to identify current achievements and limitations of acetaminophen toxicogenomic in vivo and in vitro studies for in vitro-to-in vivo and interspecies comparisons, with the ultimate aim to extrapolate animal studies to humans in vivo. This article provides a model for comparison of more species and more in vitro models enhancing the robustness of common toxicogenomic responses and their relevance to human risk assessment. To progress to quantitative dose-response analysis needed for hazard characterization, in hepatic systems toxicology studies, generation of toxicogenomic data of multiple doses/concentrations and time points is required. Newly developed bioinformatics tools for quantitative analysis of toxicogenomic data can aid in the elucidation of dose-responsive effects. The challenge herein is to assess which toxicogenomic responses are relevant for induction of the apical effect and whether perturbations are sufficient for the induction of downstream events, eventually causing toxicity.

  20. Antioxidant properties of Taraxacum officinale leaf extract are involved in the protective effect against hepatoxicity induced by acetaminophen in mice.

    Science.gov (United States)

    Colle, Dirleise; Arantes, Leticia Priscilla; Gubert, Priscila; da Luz, Sônia Cristina Almeida; Athayde, Margareth Linde; Teixeira Rocha, João Batista; Soares, Félix Alexandre Antunes

    2012-06-01

    Acetaminophen (APAP) hepatotoxicity has been related to several cases of hepatitis, cirrhosis, and hepatic transplant. As APAP hepatotoxicity is related to reactive oxygen species (ROS) formation and excessive oxidative stress, natural antioxidant compounds have been tested as an alternative therapy to diminish the hepatic dysfunction induced by APAP. Taraxacum officinale Weber (Family Asteraceae), commonly known as dandelion, is used for medicinal purposes because of its choleretic, diuretic, antioxidant, anti-inflammatory, and hepatoprotective properties. This study evaluated the hepatoprotective activity of T. officinale leaf extract against APAP-induced hepatotoxicity. T. officinale was able to decrease thiobarbituric acid-reactive substance levels induced by 200 mg/kg APAP (p.o.), as well as prevent the decrease in sulfhydryl levels caused by APAP treatment. Furthermore, histopathological alterations, as well as the increased levels of serum aspartate and alanine aminotransferases caused by APAP, were prevented by T. officinale (0.1 and 0.5 mg/mL). In addition, T. officinale extract also demonstrated antioxidant activity in vitro, as well as scavenger activity against 2,2-diphenyl-1-picrylhydrazyl and nitric oxide radicals. Our results clearly demonstrate the hepatoprotective effect of T. officinale against the toxicity induced by APAP. The possible mechanisms involved include its scavenger activities against ROS and reactive nitrogen species, which are attributed to the content of phenolic compounds in the extract.

  1. DILI (drug induced liver injury in a 9-month-old infant: a rare case of phenobarbital-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Anna Paola Pinna

    2013-04-01

    Full Text Available Phenobarbital is one of the most commonly prescribed antiepileptic drugs in childhood, but it can rarely cause serious adverse effects, such as hepatotoxicity that includes a broad clinical spectrum (from isolate hypertransaminasemia to acute liver failure. We describe a case of DILI in a 9-month-old infant caused by chronic therapy with phenobarbital.

  2. Missed paracetamol (acetaminophen) overdose due to confusion regarding drug names.

    Science.gov (United States)

    Hewett, David G; Shields, Jennifer; Waring, W Stephen

    2013-07-01

    Immediate management of drug overdose relies upon the patient account of what was ingested and how much. Paracetamol (acetaminophen) is involved in around 40% of intentional overdose episodes, and remains the leading cause of acute liver failure in many countries including the United Kingdom. In recent years, consumers have had increasing access to medications supplied by international retailers via the internet, which may have different proprietary or generic names than in the country of purchase. We describe a patient that presented to hospital after intentional overdose involving 'acetaminophen' purchased via the internet. The patient had difficulty recalling the drug name, which was inadvertently attributed to 'Advil', a proprietary non-steroidal anti-inflammatory drug. The error was later recognised when the drug packaging became available, but the diagnosis of paracetamol overdose and initiation of acetylcysteine antidote were delayed. This case illustrates the benefit of routinely measuring paracetamol concentrations in all patients with suspected poisoning, although this is not universally accepted in practice. Moreover, it highlights the importance of the internet as a source of medications for intentional overdose, and emphasises the need for harmonisation of international drug names to improve patient safety.

  3. Effect of surfactants on the mechanical properties of acetaminophen ...

    African Journals Online (AJOL)

    The purpose of this study was to investigate the effect of non ionic surfactant on the mechanical properties of acetaminophen-wax matrix tablet and hence its implication on dissolution profile. Acetaminophen-wax matrix granules were prepared by melt granulation technique. This was formed by triturating acetaminophen ...

  4. Correction: PAIS: paracetamol (acetaminophen in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480

    Directory of Open Access Journals (Sweden)

    Kappelle L Jaap

    2008-11-01

    Full Text Available Abstract Background The Paracetamol (Acetaminophen In Stroke (PAIS study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever. The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis. Methods Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial. Conclusion The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power. Trial Registration Current Controlled Trials [ISCRTN74418480

  5. Biochemical and standard toxic effects of acetaminophen on the macrophyte species Lemna minor and Lemna gibba.

    Science.gov (United States)

    Nunes, Bruno; Pinto, Glória; Martins, Liliana; Gonçalves, Fernando; Antunes, Sara C

    2014-09-01

    Acetaminophen is globally one of the most prescribed drugs due to its antipyretic and analgesic properties. However, it is highly toxic when the dosage surpasses the detoxification capability of an exposed organism, with involvement of an already described oxidative stress pathway. To address the issue of the ecotoxicity of acetaminophen, we performed acute exposures of two aquatic plant species, Lemna gibba and Lemna minor, to this compound. The selected biomarkers were number of fronds, biomass, chlorophyll content, lipid peroxidation (TBARS assay), and proline content. Our results showed marked differences between the two species. Acetaminophen caused a significant decrease in the number of fronds (EC50 = 446.6 mg/L), and the establishment of a dose-dependent peroxidative damage in L. minor, but not in L. gibba. No effects were reported in both species for the indicative parameters chlorophyll content and total biomass. However, the proline content in L. gibba was substantially reduced. The overall conclusions point to the occurrence of an oxidative stress scenario more prominent for L. minor. However, the mechanisms that allowed L. gibba to cope with acetaminophen exposure were distinct from those reported for L. minor, with the likely involvement of proline as antioxidant.

  6. Paracetamol (acetaminophen) efficacy and safety in the newborn.

    Science.gov (United States)

    Cuzzolin, Laura; Antonucci, Roberto; Fanos, Vassilios

    2013-02-01

    Neonates can perceive pain, therefore an adequate analgesic therapy is a major issue not only from an ethical perspective but also to improve short- and long-term outcome. Fever during the neonatal period requires hospitalization and needs a treatment with an antipyretic agent because of the high risk of severe complications. Paracetamol (acetaminophen), the most commonly prescribed drug in paediatric patients for its analgesic and antipyretic effects, is the only agent recommended for use as an antipyretic in the newborn and has been recently proposed as a supplement therapy to opioids for postoperative analgesia. This article aims to give an updated overview on the use of paracetamol in newborns by presenting its pharmacological profile (mechanism of action, pharmacokinetics), recommendations for dosing regimens (oral or rectal administration: 25-30 mg/kg/day in preterm neonates of 30 weeks' gestation, 45 mg/kg/day in preterm neonates of 34 weeks' gestation, 60 mg/kg/day in term neonates; i.v. administration: indicatively 20-40 mg/kg/day depending on gestational age, with some differences among various guidelines) and clinical uses (more commonly as analgesic/antipyretic by oral or rectal route, but also i.v. in anaesthesia for postoperative analgesia and painful procedures in Neonatal Intensive Care Units). Moreover, drug tolerability is discussed in the light of its potential hepatotoxicity and the unique characteristics of the newborn patient. By analyzing the available literature and the dosing guidelines, a mismatch exists between the current clinical use of paracetamol and the recommendations, suggesting a cautious approach particularly in extremely preterm neonates.

  7. Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver.

    Science.gov (United States)

    Papageorgiou, Ioannis; Freytsis, Marina; Court, Michael H

    2016-10-01

    Acetaminophen is the leading cause of acute liver failure (ALF) in many countries including the United States. Hepatic glucuronidation by UDP-glucuronosyltransferase (UGT) 1A subfamily enzymes is the major route of acetaminophen elimination. Reduced glucuronidation may predispose some individuals to acetaminophen-induced ALF, but mechanisms underlying reduced glucuronidation are poorly understood. We hypothesized that specific microRNAs (miRNAs) may reduce UGT1A activity by direct effects on the UGT1A 3'-UTR shared by all UGT1A enzyme transcripts, or by indirect effects on transcription factors regulating UGT1A expression. We performed an unbiased miRNA whole transcriptome association analysis using a bank of human livers with known acetaminophen glucuronidation activities. Of 754 miRNAs evaluated, 9 miRNAs were identified that were significantly overexpressed (p2-fold) in livers with low acetaminophen glucuronidation activities compared with those with high activities. miR-375 showed the highest difference (>10-fold), and was chosen for further mechanistic validation. We demonstrated using in silico analysis and luciferase reporter assays that miR-375 has a unique functional binding site in the 3'-UTR of the aryl hydrocarbon receptor (AhR) gene. Furthermore overexpression of miR-375 in LS180 cells demonstrated significant repression of endogenous AhR protein (by 40%) and mRNA (by 10%), as well as enzyme activity and/or mRNA of AhR regulated enzymes including UGT1A1, UGT1A6, and CYP1A2, without affecting UGT2B7, which is not regulated by AhR. Thus miR-375 is identified as a novel repressor of UGT1A-mediated hepatic acetaminophen glucuronidation through reduced AhR expression, which could predispose some individuals to increased risk for acetaminophen-induced ALF. Published by Elsevier Inc.

  8. Tramadol and acetaminophen tablets for dental pain.

    OpenAIRE

    Medve, R. A.; Wang, J.; Karim, R.

    2001-01-01

    The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 40...

  9. Quercitrin from Toona sinensis (Juss. M.Roem. Attenuates Acetaminophen-Induced Acute Liver Toxicity in HepG2 Cells and Mice through Induction of Antioxidant Machinery and Inhibition of Inflammation

    Directory of Open Access Journals (Sweden)

    Van-Long Truong

    2016-07-01

    Full Text Available Quercitrin is found in many kinds of vegetables and fruits, and possesses various bioactive properties. The aim of the present study was to elucidate hepatoprotective mechanisms of quercitrin isolated from Toona sinensis (Juss. M.Roem. (syn. Cedrela sinensis Juss., using acetaminophen (APAP-treated HepG2 cell and animal models. In an in vitro study, quercitrin suppressed the production of reactive oxygen species and enhanced expression of nuclear factor E2-related factor 2 (Nrf2, activity of antioxidant response element (ARE-reporter gene, and protein levels of NADPH: quinone oxidoreductase 1 (NQO1, catalase (CAT, glutathione peroxidase (GPx, and superoxide dismutase 2 (SOD-2 in APAP-treated HepG2 cells. In an in vivo study, Balb/c mice were orally administered with 10 or 50 mg/kg of quercitrin for 7 days and followed by the injection with single dose of 300 mg/kg APAP. Quercitrin decreased APAP-caused elevation of alanine aminotransferase and aspartate aminotransferase levels, liver necrosis, the expression of pro-inflammatory factors including inducible nitric oxide synthase, cyclooxygenase 2 and inerleukin-1β, and phosphorylation of kinases including c-Jun N-terminal kinase and p38. Quercitrin restored protein levels of Nrf2, NQO1 and activities and expressions of CAT, GPx, SOD-2. The results suggested that quercitrin attenuates APAP-induced liver damage by the activation of defensive genes and the inhibition of pro-inflammatory genes via the suppressions of JNK and p38 signaling.

  10. Gemfibrozil hepatotoxicity: a case report.

    Science.gov (United States)

    Domínguez Tordera, Patricia; Comellas Alabern, José Francisco; Ronda Rivero, Félix

    2011-10-01

    A 55-year-old woman was admitted to our hospital for management of thoracic trauma and bone fractures. One month after admission she started to receive gemfibrozil for hypertriglyceridemia. In the second month of admission, the patient complained of nausea and malaise. Laboratory value showed an acute hepatitis with raised AST, ALT. The abdominal ultrasound scan was normal, and viral serologic tests were negative. Gemfibrozil was discontinued and in a few days AST and ALT levels returned to normal. Gemfibrozil-induced hepatitis is a rare event but should be considered in the differential diagnoses of hepatitis in which no other obvious alternative cause is found.

  11. Protection afforded by pre- or post-treatment with 4-phenylbutyrate against liver injury induced by acetaminophen overdose in mice.

    Science.gov (United States)

    Shimizu, Daisuke; Ishitsuka, Yoichi; Miyata, Keishi; Tomishima, Yoshiro; Kondo, Yuki; Irikura, Mitsuru; Iwawaki, Takao; Oike, Yuichi; Irie, Tetsumi

    2014-09-01

    Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is a widely used analgesic/antipyretic drug with few adverse effects at therapeutic doses; suicidal or unintentional overdose of APAP frequently induces severe hepatotoxicity. To explore a new and effective antidote for APAP hepatotoxicity, this study examined the effects of sodium 4-phenylbutyrate (4-PBA) on liver injury induced by APAP overdose in mice. Liver injury was induced in C57BL/6 male mice by intraperitoneal injection of APAP (400mg/kg). The effects of 4-PBA (100-200mg/kg) treatment at 1h before the APAP injection were evaluated with serum alanine aminotransferase (ALT) and blood ammonia levels, hepatic pathological changes, including histopathology, DNA damage, nitrotyrosine formation, and mRNA or protein expression involved in the development of hepatotoxicity, such as X-box binding protein-1 (XBP1), c-Jun N-terminal kinase (JNK), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 interacting mediator of cell death (Bim). In addition, glutathione depletion and CYP2E1 protein expression, which are measures of the metabolic conversion of APAP to a toxic metabolite, were examined. Furthermore, we examined the effects of post-treatment with 4-PBA against APAP-induced hepatotoxicity in mice. When administered at 1h before APAP injection, 4-PBA significantly prevented the increase in serum ALT and blood ammonia levels, centrilobular necrosis of hepatocytes, DNA fragmentation, and nitrotyrosine formation induced by APAP in mice. 4-PBA also inhibited hepatic Xbp1 mRNA splicing and JNK phosphorylation induced by APAP, but did not suppress CHOP and Bim mRNA and protein expression. In addition, 4-PBA had little effect on hepatic glutathione depletion and CYP2E1 expression, parameters of toxic APAP metabolite production. Post-treatment with 4-PBA administration at 1 or 2h after APAP injection also attenuated the increase in serum ALT and blood ammonia levels and hepatic pathological changes in APAP

  12. The current state of serum biomarkers of hepatotoxicity.

    Science.gov (United States)

    Ozer, Josef; Ratner, Marcia; Shaw, Martin; Bailey, Wendy; Schomaker, Shelli

    2008-03-20

    The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTalpha) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in

  13. The current state of serum biomarkers of hepatotoxicity

    International Nuclear Information System (INIS)

    Ozer, Josef; Ratner, Marcia; Shaw, Martin; Bailey, Wendy; Schomaker, Shelli

    2008-01-01

    The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTα) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in early

  14. Autoprotection in acetaminophen intoxication in rats

    DEFF Research Database (Denmark)

    Dalhoff, K; Laursen, H; Bangert, K

    2001-01-01

    and liver tissue were collected before and 12, 24, 36, and 48 hr after the toxic dose and were analysed for hepatic glutathione and cysteine contents, hepatic glutathione-S-transferase and blood alanine aminotransferase activity, as well as acetaminophen concentration in plasma. Steady-state mRNA levels......Autoprotection by acetaminophen, i.e. increased resistance to toxic effects caused by pretreatment, is a well-known phenomenon. The purpose of the present work was to identify mechanisms for increased acetaminophen tolerance induced by pretreatment of rats. One group of female Wistar rats...... (pretreated rats) received acetaminophen orally in increasing doses (1 to 4.3 g/kg) twice a week for 3 weeks, one group (naïve rats) received the vehicle. At time zero pretreated rats received a toxic dose of 7.5 g/kg (100% lethal in naïve rats), and naïve rats received a toxic dose of 4.3 g/kg. Blood...

  15. Don't Double Up on Acetaminophen

    Science.gov (United States)

    ... re at the store deciding which product to buy, check the 'Drug Facts' label of OTC cold, cough and flu ... If you’re still not sure which to buy, ask the pharmacist for advice. FDA has an ... medicines containing acetaminophen accounted for nearly half of all ...

  16. Transplacental Passage of Acetaminophen in Term Pregnancy.

    Science.gov (United States)

    Nitsche, Joshua F; Patil, Avinash S; Langman, Loralie J; Penn, Hannah J; Derleth, Douglas; Watson, William J; Brost, Brian C

    2017-05-01

    Objective  The objective of this study was to determine the maternal and fetal pharmacokinetic (PK) profiles of acetaminophen after administration of a therapeutic oral dose. Study Design  After obtaining Institutional Review Board approval and their written informed consent, pregnant women were given a single oral dose (1,000 mg) of acetaminophen upon admission for scheduled cesarean delivery. Maternal venous blood and fetal cord blood were obtained at the time of delivery and acetaminophen levels were measured using gas chromatography-mass spectroscopy. PK parameters were calculated by noncompartmental analysis. Nonparametric correlation of maternal/fetal acetaminophen levels and PK curves were calculated. Results  In this study, 34 subjects were enrolled (median, 32 years; range, 25-39 years). The median maternal weight was 82 kg (range, 62-100 kg). All but two subjects were delivered beyond 39 weeks' gestation. The median newborn birth weight was 3,590 g (interquartile range, 3,403-3,848 g). Noncompartmental analysis described similar PK parameters in the maternal ( T 1/2 , 84 minutes; apparent clearance [Cl/F], 28.8 L/h; apparent volume of distribution [V d /F], 57.5 L) and fetal compartments ( T 1/2 , 82 minutes; Cl/F, 31.2 L/h; V d /F, 61.2 L). Paired maternal/fetal acetaminophen levels were highly correlated ( p  surrogate for fetal exposure. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  17. Toxicoproteomic assessment of liver responses to acute pyrrolizidine alkaloid intoxication in rats.

    Science.gov (United States)

    Li, Yan-Hong; Tai, William Chi-Shing; Khan, Imran; Lu, Cheng; Lu, Yao; Wong, Wing-Yan; Chan, Wood-Yee; Wendy Hsiao, Wen-Luan; Lin, Ge

    2018-04-03

    A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and three toxicity pathways of vascular endothelial cell death, which was further verified by observed sinusoidal endothelial cell losses, were found uniquely associated with retrorsine-induced hepatotoxicity. This toxicoproteomic study of acute pyrrolizidine alkaloid intoxication lays a foundation for future investigation to delineate molecular mechanisms of pyrrolizidine alkaloid-induced hepatotoxicity.

  18. Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

    Science.gov (United States)

    Wong, Anselm; Sivilotti, Marco L A; Gunja, Naren; McNulty, Richard; Graudins, Andis

    2018-03-01

    Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

  19. PISA. The effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute stroke: protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690

    NARCIS (Netherlands)

    E.J. van Breda (Eric); H.B. van der Worp (Bart); H.M.A. van Gemert (Maarten); R. Meijer; L.J. Kappelle (Jaap); P.J. Koudstaal (Peter Jan); D.W.J. Dippel (Diederik)

    2002-01-01

    textabstractBACKGROUND: During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may

  20. PISA. The effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute stroke: Protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690

    NARCIS (Netherlands)

    E.J. van Breda (Eric); B. van der Worp (Bart); M. van Gemert (Maarten); R.J. Meijer (Ron); L.J. Kappelle (Jaap); P.J. Koudstaal (Peter Jan); D.W.J. Dippel (Diederik)

    2002-01-01

    textabstractBackground: During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their

  1. [Good use and knowledge of paracetamol (acetaminophen) among self-medicated patients: Prospective study in community pharmacies].

    Science.gov (United States)

    Severin, Anne-Elise; Petitpain, Nadine; Scala-Bertola, Julien; Latarche, Clotilde; Yelehe-Okouma, Melissa; Di Patrizio, Paolo; Gillet, Pierre

    2016-06-01

    Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P<0.0001) and more surprisingly; (ii) the fact of having no children (parentality: OR=0.1; P=0.006). Responses corresponding to involuntary overdosage were mostly due to a too short interval between drug intakes (3hours). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet. Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity. Package leaflets have also to be more informative. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  2. The modulatory effect of Moringa oleifera leaf extract on endogenous antioxidant systems and inflammatory markers in an acetaminophen-induced nephrotoxic mice model

    Directory of Open Access Journals (Sweden)

    Govindarajan Karthivashan

    2016-07-01

    Full Text Available N-Acetyl-p-Aminophenol (APAP, also known as acetaminophen, is the most commonly used over-the counter analgesic and antipyretic medication. However, its overdose leads to both liver and kidney damage. APAP-induced toxicity is considered as one of the primary causes of acute liver failure; numerous scientific reports have focused majorly on APAP hepatotoxicity. Alternatively, not many works approach APAP nephrotoxicity focusing on both its mechanisms of action and therapeutic exploration. Moringa oleifera (MO is pervasive in nature, is reported to possess a surplus amount of nutrients, and is enriched with several bioactive candidates including trace elements that act as curatives for various clinical conditions. In this study, we evaluated the nephro-protective potential of MO leaf extract against APAP nephrotoxicity in male Balb/c mice. A single-dose acute oral toxicity design was implemented in this study. Group 2, 3, 4 and 5 received a toxic dose of APAP (400 mg/kg of bw, i.p and after an hour, these groups were administered with saline (10 mL/kg, silymarin—positive control (100 mg/kg of bw, i.p, MO leaf extract (100 mg/kg of bw, i.p, and MO leaf extract (200 mg/kg bw, i.p respectively. Group 1 was administered saline (10 mL/kg during both the sessions. APAP-treated mice exhibited a significant elevation of serum creatinine, blood urea nitrogen, sodium, potassium and chloride levels. A remarkable depletion of antioxidant enzymes such as SOD, CAT and GSH-Px with elevated MDA levels has been observed in APAP treated kidney tissues. They also exhibited a significant rise in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and decreased anti-inflammatory (IL-10 cytokine level in the kidney tissues. Disorganized glomerulus and dilated tubules with inflammatory cell infiltration were clearly observed in the histology of APAP treated mice kidneys. All these pathological changes were reversed in a dose-dependent manner after MO leaf extract

  3. [Screening of hepatotoxicity fraction of Genkwa Flos and study on UPLC fingerprint of hepatotoxicity fraction].

    Science.gov (United States)

    Yuan, Yang; Geng, Lu-Lu; Zhuang, He-Fei; Meng, Xia; Peng, Ying; Bi, Kai-Shun; Chen, Xiao-Hui

    2013-01-01

    To look for the active fraction of ethanol extract of Genkwa Flos (EGF) induced hepatotoxicity and develop an UPLC fingerprint of the active fraction. Target fraction of EGF induced hepatotoxicity was guided by the serum biochemical and histopathology methods. The UPLC method was applied to establish the chromatographic fingerprint. The separation was achieved on a BEH C18 column (2.1 mm x 50 mm, 1.7 microm) with a mobile phase consisting of acetonitrile and water containing 0.05% phosphate acid running gradient elution. The detection was carried out at 210 nm and the analysis was finished within 10 min. The chloroform phase of EGF could be responsible for the hepatotoxicity of this herb. The common mode of the UPLC fingerprint was set up under the established condition. There were 17 common peaks in fourteen batches of herbs, eight of which were identified, and the similar degrees of the fourteen batches to the common mode were between 0.890-0.999. It is easy to locate the chloroform extraction of EGF with hepatotoxicity. And the UPLC fingerprint was developed for the above fraction, which could provide valuable references for safe and effective clinical use of EGF.

  4. An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

    African Journals Online (AJOL)

    Background: Hepatic dysfunction in the cancer unit has a significant impact on patient outcomes. The therapeutic application of anthracycline antibiotics are limited by side‑effects mainly myelosuppression, chronic cardiotoxicity, and hepatotoxicity. Aim: To assess the risk of Hepatotoxicity in breast cancer patients receiving ...

  5. Antituberculosis drugs and hepatotoxicity among hospitalized patients in Jos, Nigeria

    Directory of Open Access Journals (Sweden)

    Samson E Isa

    2016-01-01

    Conclusion: Hepatotoxicity due to first-line anti-TBs, whether based on clinical features alone or backed by liver chemistry, is common among hospitalized patients in our environment. Studies to determine the predictors of hepatotoxicity to guide clinical interventions aimed at the prevention or timely identification of cases are needed.

  6. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury - Corrected and republished from: Biomedicine (Taipei). 2016 Jun; 6 (2): 9. doi: 10.7603/s40681-016-0009-1PMCID: PMC4864770.

    Science.gov (United States)

    Chen, Lung-Che; Hu, Li-Hong; Yin, Mei-Chin

    2017-06-01

    Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP up-regulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepato-protective agent. © Author(s) 2017. This article is published with open access by China Medical University.

  7. Acute chloroform ingestion successfully treated with intravenously administered N-acetylcysteine.

    Science.gov (United States)

    Dell'Aglio, Damon M; Sutter, Mark E; Schwartz, Michael D; Koch, David D; Algren, D A; Morgan, Brent W

    2010-06-01

    Chloroform, a halogenated hydrocarbon, causes central nervous system depression, cardiac arrhythmias, and hepatotoxicity. We describe a case of chloroform ingestion with a confirmatory serum level and resultant hepatotoxicity successfully treated with intravenously administered N-acetylcysteine (NAC). A 19-year-old man attempting suicide ingested approximately 75 mL of chloroform. He was unresponsive and intubated upon arrival. Intravenously administered NAC was started after initial stabilization was complete. His vital signs were normal. Admission laboratory values revealed normal serum electrolytes, AST, ALT, PT, BUN, creatinine, and bilirubin. Serum ethanol level was 15 mg/dL, and aspirin and acetaminophen were undetectable. The patient was extubated but developed liver function abnormalities with a peak AST of 224 IU/L, ALT of 583 IU/L, and bilirubin level reaching 16.3 mg/dL. NAC was continued through hospital day 6. Serum chloroform level obtained on admission was 91 μg/mL. The patient was discharged to psychiatry without known sequelae and normal liver function tests. The average serum chloroform level in fatal cases of inhalational chloroform poisoning was 64 μg/mL, significantly lower than our patient. The toxicity is believed to be similar in both inhalation and ingestion routes of exposure, with mortality predominantly resulting from anoxia secondary to central nervous system depression. Hepatocellular toxicity is thought to result from free radical-induced oxidative damage. Previous reports describe survival after treatment with orally administered NAC, we report the first use of intravenously administered NAC for chloroform ingestion. Acute oral ingestion of chloroform is extremely rare. Our case illustrates that with appropriate supportive care, patients can recover from chloroform ingestion, and intravenously administered NAC may be of benefit in such cases.

  8. [Constitutional syndrome associated to metformin induced hepatotoxicity].

    Science.gov (United States)

    de la Poza Gómez, Gema; Rivero Fernández, Miguel; Vázquez Romero, Manuel; Angueira Lapeña, Teresa; Arranz de la Mata, Gemma; Boixeda de Miquel, Daniel

    2008-12-01

    Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.

  9. Possible hepatotoxicity of chronic marijuana usage

    OpenAIRE

    Borini, Paulo; Guimarães, Romeu Cardoso; Borini, Sabrina Bicalho

    2004-01-01

    CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Braz...

  10. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    International Nuclear Information System (INIS)

    Mandal, Mili; Gardner, Carol R.; Sun, Richard; Choi, Hyejeong; Lad, Sonali; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2016-01-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b + infiltrating Ly6G + granulocytic and Ly6G − monocytic cells in the spleen and the liver. The majority of the Ly6G + cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G − cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80 + ) and immature (F4/80 − ) pro-inflammatory Ly6C hi macrophages and mature anti-inflammatory (Ly6C lo ) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3 + macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the bone marrow. • Hepatotoxicity is reduced in

  11. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Mili, E-mail: milimandal@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sun, Richard, E-mail: fishpower52@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Choi, Hyejeong, E-mail: choi@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Lad, Sonali, E-mail: sonurose92@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Mishin, Vladimir, E-mail: mishinv@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2016-08-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b{sup +} infiltrating Ly6G{sup +} granulocytic and Ly6G{sup −} monocytic cells in the spleen and the liver. The majority of the Ly6G{sup +} cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G{sup −} cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80{sup +}) and immature (F4/80{sup −}) pro-inflammatory Ly6C{sup hi} macrophages and mature anti-inflammatory (Ly6C{sup lo}) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3{sup +} macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the

  12. Targeted metabolomic profiling indicates structure-based perturbations in serum phospholipids in children with acetaminophen overdose

    Directory of Open Access Journals (Sweden)

    Sudeepa Bhattacharyya

    Full Text Available Phospholipids are an important class of lipids that act as building blocks of biological cell membranes and participate in a variety of vital cellular functions including cell signaling. Previous studies have reported alterations in phosphatidylcholine (PC and lysophosphatidylcholine (lysoPC metabolism in acetaminophen (APAP-treated animals or cell cultures. However, little is known about phospholipid perturbations in humans with APAP toxicity. In the current study, targeted metabolomic analysis of 180 different metabolites including 14 lysoPCs and 73 PCs was performed in serum samples from children and adolescents hospitalized for APAP overdose. Metabolite profiles in the overdose group were compared to those of healthy controls and hospitalized children receiving low dose APAP for treatment of pain or fever (therapeutic group. PCs and lysoPCs with very long chain fatty acids (VLCFAs were significantly decreased in the overdose group, while those with comparatively shorter chain lengths were increased in the overdose group compared to the therapeutic and control groups. All ether linked PCs were decreased in the overdose group compared to the controls. LysoPC-C26:1 was highly reduced in the overdose group and could discriminate between the overdose and control groups with 100% sensitivity and specificity. The PCs and lysoPCs with VLCFAs showed significant associations with changes in clinical indicators of drug metabolism (APAP protein adducts and liver injury (alanine aminotransferase, or ALT. Thus, a structure-dependent reduction in PCs and lysoPCs was observed in the APAP-overdose group, which may suggest a structure-activity relationship in inhibition of enzymes involved in phospholipid metabolism in APAP toxicity. Keywords: Metabolomics, Phospholipids, Acetaminophen, Hepatotoxicity, Drug

  13. Effect of acetaminophen administration to rats chronically exposed to depleted uranium

    International Nuclear Information System (INIS)

    Gueguen, Y.; Grandcolas, L.; Baudelin, C.; Grison, S.; Tissandie, E.; Jourdain, J.R.; Paquet, F.; Voisin, P.; Aigueperse, J.; Gourmelon, P.; Souidi, M.

    2007-01-01

    The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination

  14. Predictive toxicology using systemic biology and liver microfluidic “on chip” approaches: Application to acetaminophen injury

    International Nuclear Information System (INIS)

    Prot, Jean-Matthieu; Bunescu, Andrei; Elena-Herrmann, Bénédicte; Aninat, Caroline; Snouber, Leila Choucha; Griscom, Laurent; Razan, Florence; Bois, Frederic Y.; Legallais, Cécile

    2012-01-01

    We have analyzed transcriptomic, proteomic and metabolomic profiles of hepatoma cells cultivated inside a microfluidic biochip with or without acetaminophen (APAP). Without APAP, the results show an adaptive cellular response to the microfluidic environment, leading to the induction of anti-oxidative stress and cytoprotective pathways. In presence of APAP, calcium homeostasis perturbation, lipid peroxidation and cell death are observed. These effects can be attributed to APAP metabolism into its highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). That toxicity pathway was confirmed by the detection of GSH-APAP, the large production of 2-hydroxybutyrate and 3-hydroxybutyrate, and methionine, cystine, and histidine consumption in the treated biochips. Those metabolites have been reported as specific biomarkers of hepatotoxicity and glutathione depletion in the literature. In addition, the integration of the metabolomic, transcriptomic and proteomic collected profiles allowed a more complete reconstruction of the APAP injury pathways. To our knowledge, this work is the first example of a global integration of microfluidic biochip data in toxicity assessment. Our results demonstrate the potential of that new approach to predictive toxicology. -- Highlights: ► We cultivated liver cells in microfluidic biochips ► We integrated transcriptomic, proteomic and metabolomics profiles ► Pathways reconstructions were proposed in control and acetaminophen treated cultures ► Biomarkers were identified ► Comparisons with in vivo studies were proposed.

  15. Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

    Science.gov (United States)

    Acheampong, Paul; Thomas, Simon H L

    2016-10-01

    To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI). Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage. In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l(-1) , liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ≤6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US-Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration Paracetamol concentrations <20 mg l(-1) with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases. © 2016 The British Pharmacological Society.

  16. Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration

    Directory of Open Access Journals (Sweden)

    Jack Hinson

    2013-08-01

    Full Text Available High doses of acetaminophen (APAP result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid β-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid β-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2–4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines.

  17. Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies.

    Science.gov (United States)

    Cao, Lei; Kwara, Awewura; Greenblatt, David J

    2017-12-01

    Excessive exposure to acetaminophen (APAP, paracetamol) can cause liver injury through formation of a reactive metabolite that depletes hepatic glutathione and causes hepatocellular oxidative stress and damage. Generation of this metabolite is mediated by Cytochrome-P450 (CYP) isoforms, mainly CYP2E1. A number of naturally occurring flavonoids can mitigate APAP-induced hepatotoxicity in experimental animal models. Our objective was to determine the mechanism of these protective effects and to evaluate possible human applicability. Two flavonoids, luteolin and quercetin, were evaluated as potential inhibitors of eight human CYP isoforms, of six UDP-glucuronosyltransferase (UGT) isoforms and of APAP glucuronidation and sulfation. The experimental model was based on in-vitro metabolism by human liver microsomes, using isoform-specific substrates. Luteolin and quercetin inhibited human CYP isoforms to varying degrees, with greatest potency towards CYP1A2 and CYP2C8. However, 50% inhibitory concentrations (IC 50 values) were generally in the micromolar range. UGT isoforms were minimally inhibited. Both luteolin and quercetin inhibited APAP sulfation but not glucuronidation. Inhibition of human CYP activity by luteolin and quercetin occurred with IC 50 values exceeding customary in-vivo human exposure with tolerable supplemental doses of these compounds. The findings indicate that luteolin and quercetin are not likely to be of clinical value for preventing or treating APAP-induced hepatotoxicity. © 2017 Royal Pharmaceutical Society.

  18. The neuronal nitric oxide synthase inhibitor NANT blocks acetaminophen toxicity and protein nitration in freshly isolated hepatocytes.

    Science.gov (United States)

    Banerjee, Sudip; Melnyk, Stepan B; Krager, Kimberly J; Aykin-Burns, Nukhet; Letzig, Lynda G; James, Laura P; Hinson, Jack A

    2015-12-01

    3-Nitrotyrosine (3NT) in liver proteins of mice treated with hepatotoxic doses of acetaminophen (APAP) has been postulated to be causative in toxicity. Nitration is by a reactive nitrogen species formed from nitric oxide (NO). The source of the NO is unclear. iNOS knockout mice were previously found to be equally susceptible to APAP toxicity as wildtype mice and iNOS inhibitors did not decrease toxicity in mice or in hepatocytes. In this work we examined the potential role of nNOS in APAP toxicity in hepatocytes using the specific nNOS inhibitor NANT (10 µM)(N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N'-nitroguanidinetris (trifluoroacetate)). Primary hepatocytes (1 million/ml) from male B6C3F1 mice were incubated with APAP (1mM). Cells were removed and assayed spectrofluorometrically for reactive nitrogen and oxygen species using diaminofluorescein (DAF) and Mitosox red, respectively. Cytotoxicity was determined by LDH release into media. Glutathione (GSH, GSSG), 3NT, GSNO, acetaminophen-cysteine adducts, NAD, and NADH were measured by HPLC. APAP significantly increased cytotoxicity at 1.5-3.0 h. The increase was blocked by NANT. NANT did not alter APAP mediated GSH depletion or acetaminophen-cysteine adducts in proteins which indicated that NANT did not inhibit metabolism. APAP significantly increased spectroflurometric evidence of reactive nitrogen and oxygen formation at 0.5 and 1.0 h, respectively, and increased 3NT and GSNO at 1.5-3.0 h. These increases were blocked by NANT. APAP dramatically increased NADH from 0.5-3.0 h and this increase was blocked by NANT. Also, APAP decreased the Oxygen Consumption Rate (OCR), decreased ATP production, and caused a loss of mitochondrial membrane potential, which were all blocked by NANT. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Opioid use in knee arthroplasty after receiving intravenous acetaminophen.

    Science.gov (United States)

    Kelly, Jennifer S; Opsha, Yekaterina; Costello, Jennifer; Schiller, Daryl; Hola, Eric T

    2014-12-01

    Intravenous (IV) acetaminophen may be an effective component of multimodal postoperative pain management. The primary objective of this study was to evaluate the impact of IV acetaminophen on total opioid use in postoperative patients. The secondary objective was to evaluate the effect of IV acetaminophen on hospital length of stay. This retrospective, case-control study evaluated the impact of IV acetaminophen on total opioid use in surgical patients. Patients were included if they received at least one perioperative dose of IV acetaminophen and underwent a surgical knee procedure. Controls were matched and randomly selected based on procedure type, age, and severity of illness. Postoperative opioids were converted into oral morphine equivalents, and overall use was compared between groups. One hundred patients were enrolled, with 25 patients receiving IV acetaminophen and 75 matched controls. A total of 135 mg versus 112.5 mg oral morphine equivalents were used in the IV acetaminophen group and control group, respectively (p=0.987). There were 45 mg/day oral morphine equivalents used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). The median hospital length of stay in both groups was 3 days (p=0.799). IV acetaminophen did not significantly decrease postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. There was no significant difference in hospital length of stay between the IV acetaminophen group and the control group. These findings require further study in larger patient populations and in other orthopedic procedures that typically require longer hospital stays. © 2014 Pharmacotherapy Publications, Inc.

  20. Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

    Institute of Scientific and Technical Information of China (English)

    Lily Dare; Jennifer Hewett; Joseph Kartaik Lim

    2008-01-01

    Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxiciLy, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the seLLing of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements,and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted.

  1. Hepatotoxicity of illegal home-made alcohols.

    Science.gov (United States)

    Gökce, Hasan; Akcan, Ramazan; Celikel, Adnan; Zeren, Cem; Ortanca, Ibrahim; Demirkiran, Sumeyra

    2016-10-01

    Alcohol-related hepatotoxicity is not only caused by excessive alcohol consumption but also caused and even accelerated by hepatotoxic ingredients other than ethanol. Concentrations of hepatotoxic substances might be significantly high, particularly in illegally produced home-made alcohols. In this study we aim to analyze the hepatotoxic effects of a home-made alcohol traditionally called "bogma raki" in Turkey. Fifty Wistar albino male rats were used. Five groups were randomly formed with ten animals in each. Besides laboratory diets, groups were fed as follows: Group 1 (control group) distilled water; Group 2 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day); Group 3 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day)+walnut (10 g/kg/day); Group 4 whisky with distilled water (%40 (v/v), 9.2 ml/kg/day); Group 5 distilled water + walnut (10 g/kg/day), for 28 days. The toxicological analysis of The spirits were analyzed using Hewlett-Packard (Palo Alto, CA) GC/MS system with HP 6890 gas chromatograph, an HP 5972 mass selective detector (MSD) and an HP 6890 automatic liquid sampler GC/MS; the pressure of the carrier gas helium was 6.0 bar and the split value with a ratio of 1:100. The injection unit temperature set to 250 °C and MS quadrupole temperature set to 280 °C. The MS quadrupole detector ionization energy set to 70 eV. The initial column temperature was 60 °C (for 4 min) programmed by 6 °C/min to final temperature 160 °C and kept for 8 min at 160 °C. Utilized whisky and bogma raki samples were analyzed for the amounts of trans-anethole, ethanol, methanol, 1-propanolol, butanol, 2-butanol, 2-methyl-1-propanolol (isobutanol) and 3-methylbutanol (isoamyl alcohol). Histopathological changes in liver tissues were graded as follows; normal = 0 (illegally produced raki sample (%v/v) was as follows: trans-anethole %1.93, ethanol %95.70, 2-methyl-1-propanolol (isobutanol) %0.19, asetic acid %0.25, 3-methylbutanol (isoamyl

  2. The effects of indomethacin, diclofenac, and acetaminophen suppository on pain and opioids consumption after cesarean section

    Directory of Open Access Journals (Sweden)

    Godrat Akhavanakbari

    2013-01-01

    Full Text Available Background: Cesarean section is one of the common surgeries of women. Acute post-operative pain is one of the recognized post-operative complications. Aims: This study was planned to compare the effects of suppositories, indomethacin, diclofenac and acetaminophen, on post-operative pain and opioid usage after cesarean section. Materials and Methods: In this double-blind clinical trial study, 120 candidates of cesarean with spinal anesthesia and American Society of Anesthesiologists (ASA I-II were randomly divided into four groups. Acetaminophen, indomethacin, diclofenac, and placebo suppositories were used in groups, respectively, after operation and the dosage was repeated every 6 h and pain score and opioid usage were compared 24 h after the surgery. The severity of pain was recorded on the basis of Visual Analog Scale (VAS and if severe pain (VAS > 5 was observed, 0.5 mg/kg intramuscular pethidine had been used. Statistical Analysis Used: The data were analyzed in SPSS software version 15 and analytical statistics such as ANOVA, Chi-square, and Tukey′s honestly significant difference (HSD post-hoc. Results : Pain score was significantly higher in control group than other groups, and also pain score in acetaminophen group was higher than indomethacin and diclofenac. The three intervention groups received the first dose of pethidine far more than control group and the distance for diclofenac and indomethacin were significantly longer (P < 0.001. The use of indomethacin, diclofenac, and acetaminophen significantly reduces the amount of pethidine usage in 24 h after the surgery relation to control group. Conclusions : Considering the significant decreasing pain score and opioid usage especially in indomethacin and diclofenac groups rather than control group, it is suggested using of indomethacin and diclofenac suppositories for post-cesarean section analgesia.

  3. Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

    Directory of Open Access Journals (Sweden)

    Robim M. Rodrigues

    2016-06-01

    Full Text Available This data set is composed of transcriptomics analyses of (i liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF and (ii hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC. Data from primary human hepatocytes was also added to the data set “Open TG-GATEs: a large-scale toxicogenomics database” (Igarashi et al., 2015 [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI׳s Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article “Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems” (Rodrigues et al., 2016 [2].

  4. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Michaut, Anaïs; Le Guillou, Dounia [INSERM, U991, Université de Rennes 1, Rennes (France); Moreau, Caroline [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Bucher, Simon [INSERM, U991, Université de Rennes 1, Rennes (France); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Martinais, Sophie [INSERM, U991, Université de Rennes 1, Rennes (France); Gicquel, Thomas; Morel, Isabelle [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, Rennes (France); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, Rennes (France)

    2016-02-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1

  5. Evaluation of adsorption capacity of acetaminophen on activated ...

    African Journals Online (AJOL)

    Purpose: To investigate varying dosage forms of activated charcoal obtained from community pharmacy outlets in Nigeria for their adsorption capacity when challenged with acetaminophen. Methods: Equilibruim kinetics of acetaminophen adsorption onto activated charcoal surface was determined via batch studies at ...

  6. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

    Anderson, Brian J; van Lingen, Richard A; Hansen, Tom G

    2002-01-01

    The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens.......The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens....

  7. An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure

    Institute of Scientific and Technical Information of China (English)

    María Jesús Tu(n)ón; Marcelino Alvarez; Jesús M Culebras; Javier González-Gallego

    2009-01-01

    Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by meansof the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

  8. Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity.

    Science.gov (United States)

    Bruckner, James V; Ramanathan, Raghupathy; Lee, K Monica; Muralidhara, Srinivasa

    2002-01-01

    The toxicity of carbon tetrachloride (CCl(4)) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl(4) was rhythmic and coincided in time with maximum susceptibility to CCl(4) hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl(4) metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl(4)/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl(4) near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of (14)CCl(4)/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl(4). Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl(4). Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl(4)-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl(4). These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl(4) chronotoxicity in rats.

  9. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    International Nuclear Information System (INIS)

    Henninger, Christian; Huelsenbeck, Johannes; Huelsenbeck, Stefanie; Grösch, Sabine; Schad, Arno; Lackner, Karl J.; Kaina, Bernd; Fritz, Gerhard

    2012-01-01

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  10. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  11. Ringer's lactate improves liver recovery in a murine model of acetaminophen toxicity

    Directory of Open Access Journals (Sweden)

    Yang Runkuan

    2011-11-01

    Full Text Available Abstract Background Acetaminophen (APAP overdose induces massive hepatocyte necrosis. Liver regeneration is a vital process for survival after a toxic insult. Since hepatocytes are mostly in a quiescent state (G0, the regeneration process requires the priming of hepatocytes by cytokines such as TNF-α and IL-6. Ringer's lactate solution (RLS has been shown to increase serum TNF-α and IL-6 in patients and experimental animals; in addition, RLS also provides lactate, which can be used as an alternative metabolic fuel to meet the higher energy demand by liver regeneration. Therefore, we tested whether RLS therapy improves liver recovery after APAP overdose. Methods C57BL/6 male mice were intraperitoneally injected with a single dose of APAP (300 mg/kg dissolved in 1 mL sterile saline. Following 2 hrs of APAP challenge, the mice were given 1 mL RLS or Saline treatment every 12 hours for a total of 72 hours. Results 72 hrs after APAP challenge, compared to saline-treated group, RLS treatment significantly lowered serum transaminases (ALT/AST and improved liver recovery seen in histopathology. This beneficial effect was associated with increased hepatic tissue TNF-α concentration, enhanced hepatic NF-κB DNA binding and increased expression of cell cycle protein cyclin D1, three important factors in liver regeneration. Conclusion RLS improves liver recovery from APAP hepatotoxicity.

  12. Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

    Science.gov (United States)

    Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

    2009-11-01

    The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

  13. Plasma microRNA profiles distinguish lethal injury in acetaminophen toxicity: A research study

    Institute of Scientific and Technical Information of China (English)

    Jeanine Ward; Shashi Bala; Jan Petrasek; Gyongyi Szabo

    2012-01-01

    AIM:To investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice.METHODS:Using plasma from APAP poisoned mice,either lethally (500 mg/kg) or sublethally (150 mg/kg) dosed,we screened commercially available murine microRNA libraries (SABiosciences,Qiagen Sciences,MD) to evaluate for unique miRNA profiles between these two dosing parameters.RESULTS:We distinguished numerous,unique plasma miRNAs both up- and downregulated in lethally compared to sublethally dosed mice.Of note,many of the greatest up- and downregulated miRNAs,namely 574-5p,466g,466f-3p,375,29c,and 148a,have been shown to be associated with asthma in prior studies.Interestingly,a relationship between APAP and asthma has been previously well described in the literature,with an as yet unknown mechanism of pathology.There was a statistically significant increase in alanine aminotransferase levels in the lethal compared to sublethal APAP dosing groups at the 12 h time point (P <0.001).There was 90% mortality in the lethally compared to sublethally dosed mice at the 48 h time point (P =0.011).CONCLUSION:We identified unique plasma miRNAs both up- and downregulated in APAP poisoning which are correlated to asthma development.

  14. Targeted liquid chromatography–mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children

    Science.gov (United States)

    Bhattacharyya, Sudeepa; Yan, Ke; Pence, Lisa; Simpson, Pippa M; Gill, Pritmohinder; Letzig, Lynda G; Beger, Richard D; Sullivan, Janice E; Kearns, Gregory L; Reed, Michael D; Marshall, James D; Van Den Anker, John N; James, Laura P

    2014-01-01

    Aim Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose (‘overdose’ or toxic ingestion) exposure to APAP. Materials & methods The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography–triple-quadrupole mass spectrometry. Results Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. Conclusion Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity. PMID:24521011

  15. Possible hepatotoxicity of chronic marijuana usage

    Directory of Open Access Journals (Sweden)

    Paulo Borini

    Full Text Available CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Brazil PARTICIPANTS: The study was made among 123 patients interned in the Hospital Espírita de Marília from October 1996 to December 1998, divided into 3 groups: 26 (21% using only marijuana, 83 (67.5% using marijuana and crack, and 14 (11.4% consuming marijuana and alcohol. PROCEDURES AND MAIN MEASUREMENTS: Patients were examined clinically with special emphasis on types of drugs used, drug intake route, age when consumption began, length and pattern of usage, presence of tattooing, jaundice, hepatomegaly and splenomegaly. Serum determinations of total proteins, albumin, globulin, total and fractions of bilirubin, aspartate (AST and alanine (ALT aminotransferases, alkaline phosphatase (AP, gamma-glutamyltransferase and prothrombin activity were performed. RESULTS: Among users of only marijuana, hepatomegaly was observed in 57.7% and splenomegaly in 73.1%, and slightly elevated AST (42.3%, ALT (34.6% and AP (53.8%. The three groups did not differ significantly in the prevalence of hepatomegaly, splenomegaly and hepatosplenomegaly. The group using both marijuana and alcohol showed the highest prevalence of alterations and highest levels of aminotransferases. Mean AP levels were above normal in all groups. CONCLUSIONS: Chronic marijuana usage, on its own or in association with other drugs, was associated with hepatic morphologic and enzymatic alterations. This indicates that cannabinoids are possible hepatotoxic substances.

  16. Acetaminophen (paracetamol) for the common cold in adults.

    Science.gov (United States)

    Li, Siyuan; Yue, Jirong; Dong, Bi Rong; Yang, Ming; Lin, Xiufang; Wu, Taixiang

    2013-07-01

    Acetaminophen is frequently prescribed for treating patients with the common cold, but there is little evidence as to whether it is effective. To determine the efficacy and safety of acetaminophen in the treatment of the common cold in adults. We searched CENTRAL 2013, Issue 1, Ovid MEDLINE (1950 to January week 5, 2013), EMBASE (1980 to February 2013), CINAHL (1982 to February 2013) and LILACS (1985 to February 2013). We included randomised controlled trials (RCTs) comparing acetaminophen to placebo or no treatment in adults with the common cold. Studies were included if the trials used acetaminophen as one ingredient of a combination therapy. We excluded studies in which the participants had complications. Primary outcomes included subjective symptom score and duration of common cold symptoms. Secondary outcomes were overall well being, adverse events and financial costs. Two review authors independently screened studies for inclusion, assessed risk of bias and extracted data. We performed standard statistical analyses. We included four RCTs involving 758 participants. We did not pool data because of heterogeneity in study designs, outcomes and time points. The studies provided sparse information about effects longer than a few hours, as three of four included studies were short trials of only four to six hours. Participants treated with acetaminophen had significant improvements in nasal obstruction in two of the four studies. One study showed that acetaminophen was superior to placebo in decreasing rhinorrhoea severity, but was not superior for treating sneezing and coughing. Acetaminophen did not improve sore throat or malaise in two of the four studies. Results were inconsistent for some symptoms. Two studies showed that headache and achiness improved more in the acetaminophen group than in the placebo group, while one study showed no difference between the acetaminophen and placebo group. None of the included studies reported the duration of common cold

  17. Sub-acute hepatotoxicity of Pausinystalia yohimbe bark extract ...

    African Journals Online (AJOL)

    Corynanthe yohibi) (Family, Rubiaceae) is a true aphrodisiac used as a possible treatment for organic, psychogenic and substance induced erectile impotence and other male sexual dysfunctions. It increases blood flow to erectile tissues and exerts its ...

  18. Protective effect of agmatine in acute chlorpromazine hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Bratislav Dejanovic

    2014-01-01

    Full Text Available The present study focused on potentially beneficial effects of agmatine on oxidative stress development in the liver during chlorpromazine treatment in rats. We wanted to examine the role of reactive oxygen species and efficiency of antioxidant protection through the determination of malondylaldehyde and total glutathione concentrations in rat liver homogenate, as well as plasma concentrations of malonylaldehyde and sulfhydryl groups after the treatment. Also, liver tissue sections were examined to follow histological changes. Chlorpromazine was applied intraperitoneally at a single dose of 38.7 mg/kg b.w. The second group was treated with both chlorpromazine (at a single dose of 38.7 mg/kg b.w. and agmatine (at a single dose of 75 mg/kg b.w.. Agmatine was applied immediately after the chlorpromazine. The control group was treated with 0.9% saline solution in the same manner. Rats were sacrificed by decapitation 24 h after the treatment and biochemical and immunohistochemical examinations were performed. Analysis of data showed that treatment with agmatine significantly attenuated the oxidative stress indicators as evidenced by lowering malonylaldehyde concentrations in the liver and in plasma while not affecting liver concentrations of total glutathione and plasma concentration of sulfhydryl groups. Additionally, histological evaluation revealed the improvement of liver damage in this respect. The presented data indicated that intraperitoneally administered agmatine protects against chlorpromazine-induced liver disease in rats.

  19. Amelioration of lead-induced hepatotoxicity by Allium sativum ...

    African Journals Online (AJOL)

    2010-01-07

    Jan 7, 2010 ... The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by ..... fatty acids having double bonds, largely present in the phospholipids of .... disulfide, and diallyl disulfide, possess antioxidant prop- erties and can ...

  20. Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol ...

    African Journals Online (AJOL)

    DR SULEIMAN

    Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol Attendants in Ibadan, Nigeria. *1A.L. Ogunneye ... inhalation of petrol fumes is associated with adverse effect on the kidney and liver function. ..... neurotoxicity in mice. African ...

  1. Herbal hepatotoxicity: a tabular compilation of reported cases.

    Science.gov (United States)

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-11-01

    Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future. © 2012 John Wiley & Sons A/S.

  2. Underdosing of acetaminophen by parents and emergency department utilization.

    Science.gov (United States)

    Goldman, Ran D; Scolnik, Dennis

    2004-02-01

    Fever is a common reason for parents to seek medical attention for their children. We conducted this study to document accuracy of parental administration of acetaminophen and to identify if parents who did not give an optimal dose would have decided not to come to the emergency department (ED) if the fever had diminished at home. A cross-sectional study including 248 caregivers of children who had a chief complaint of fever and had been given acetaminophen in the preceding 24 hours were interviewed. Enrollment was 86%. One hundred parents (47%) gave acetaminophen in the recommended dose, 26 parents (12%) gave an overdose, and 87 (41%) gave an underdose of acetaminophen. Half of the parents (54%) would not have come to the ED if the fever had subsided after using the antipyretic treatment at home. Children with significantly higher maximal temperature at home would not have been taken to the ED if fever had subsided. Parents who speak English as the primary language at home gave the recommended dose of acetaminophen more frequently than non-English-speaking parents. A significant portion of our population gives an underdose of acetaminophen, reflecting lack of knowledge or misuse. Based on parental reports, the majority of visits for fever might have been prevented, if parents had been successful in their effort to reduce temperature to below of what they considered as fever, but factors other than underdosing of acetaminophen probably encourage parents of febrile children to visit the ED.

  3. Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury: Protection by starch-desferal and minocycline.

    Science.gov (United States)

    Hu, Jiangting; Kholmukhamedov, Andaleb; Lindsey, Christopher C; Beeson, Craig C; Jaeschke, Hartmut; Lemasters, John J

    2016-08-01

    Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and the mitochondrial permeability transition (MPT). Iron is a critical catalyst for ROS formation, and reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity. Previous studies show that APAP disrupts lysosomes, which release ferrous iron (Fe(2+)) into the cytosol to trigger the MPT and cell killing. Here, our aim was to investigate whether iron released from lysosomes after APAP is then taken up into mitochondria via the mitochondrial electrogenic Ca(2+), Fe(2+) uniporter (MCFU) to cause mitochondrial dysfunction and cell death. Hepatocytes were isolated from fasted male C57BL/6 mice. Necrotic cell killing was assessed by propidium iodide fluorimetry. Mitochondrial membrane potential (ΔΨ) was visualized by confocal microscopy of rhodamine 123 (Rh123) and tetramethylrhodamine methylester (TMRM). Chelatable Fe(2+) was monitored by quenching of calcein (cytosol) and mitoferrofluor (MFF, mitochondria). ROS generation was monitored by confocal microscopy of MitoSox Red and plate reader fluorimetry of chloromethyldihydrodichlorofluorescein diacetate (cmH2DCF-DA). Administered 1h before APAP (10mM), the lysosomally targeted iron chelator, starch-desferal (1mM), and the MCFU inhibitors, Ru360 (100nM) and minocycline (4µM), decreased cell killing from 83% to 41%, 57% and 53%, respectively, after 10h. Progressive quenching of calcein and MFF began after ~4h, signifying increased cytosolic and mitochondrial chelatable Fe(2+). Mitochondria then depolarized after ~10h. Dipyridyl, a membrane-permeable iron chelator, dequenched calcein and MFF fluorescence after APAP. Starch-desferal, but not Ru360 and minocycline, suppressed cytosolic calcein quenching, whereas starch-desferal, Ru360 and minocycline all suppressed mitochondrial MFF quenching and mitochondrial depolarization. Starch-desferal, Ru360 and minocycline also each decreased ROS formation. Moreover

  4. Fulltext PDF

    Indian Academy of Sciences (India)

    2016-09-28

    Sep 28, 2016 ... acute toxicity of Triphala Mashi, an Ayurvedic formulation. J. Herb. Pharmacother. ... status in the liver and kidney of young and aged rats. Cell. Biochem. Funct. ... acetaminophen-induced hepatotoxicity in mice. J. Pharmacol.

  5. PULMONARY AND LIVER DAMAGE DURING TREATMENT WITH ACETAMINOPHEN (PARACETAMOL

    Directory of Open Access Journals (Sweden)

    L. I. Dvoretski

    2016-01-01

    Full Text Available This is a case report of pulmonary damage in the form of intestinal pneumonitis with severe respiratory failure during administration of acetaminophen (paracetamol. In addition, significant increase of ALT and AST levels without clinical signs of liver damage was observed in this patient. After glucocorticoids administration regression of radiological abnormal findings in the lungs along with normalization of liver enzymes values were registered. The rarity of interstitial pneumonitis induced by acetaminophen (paracetamol, especially in combination with liver damage, is emphasized. The presented patient history is the first case report of drug-induced hepatopulmonary syndrome during acetaminophen (paracetamol administration.

  6. Parallelogram approach using rat-human In vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans

    NARCIS (Netherlands)

    Kienhuis, A.S.; Poll, M.C.G. van de; Wortelboer, H.; Herwijnen, M. van; Gottschalk, R.; Jong, C.H.C. de; Boorsma, A.; Paules, R.S.; Kleinjans, J.C.S.; Stierum, R.H.; Delft, J.H.M. van

    2009-01-01

    The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these

  7. Nonacetaminophen Drug-Induced Acute Liver Failure.

    Science.gov (United States)

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Pyruvate dehydrogenase complex and lactate dehydrogenase as targets for therapy of acute liver failure.

    Science.gov (United States)

    Ferriero, Rosa; Nusco, Edoardo; De Cegli, Rossella; Carissimo, Annamaria; Manco, Giuseppe; Brunetti-Pierri, Nicola

    2018-03-23

    Acute liver failure is a rapidly progressive deterioration of hepatic function resulting in high mortality and morbidity. Metabolic enzymes can translocate in the nucleus to regulate histone acetylation and gene expression. Levels and activities of pyruvate dehydrogenase complex (PDHC) and lactate dehydrogenase (LDH) were evaluated in nuclear fractions of livers of mice exposed to various hepatotoxins including CD95-Ab, α-amanitin, and acetaminophen. Whole-genome gene expression profiling by RNA-seq was performed in livers of mice with acute liver failure and analyzed by Gene Ontology Enrichment Analysis. Efficacy of histone acetyltransferase inhibitor garcinol and LDH inhibitor galloflavin at reducing liver damage was evaluated in mice with induced hepatotoxicity. Levels and activities of PDHC and LDH were increased in cytoplasmatic and nuclear fractions of livers of mice with acute liver failure. The increase of nuclear PDHC and LDH was associated with increased concentrations of acetyl-coA and lactate in nuclear fractions, and histone H3 hyper-acetylation. Gene expression in livers of mice with acute liver failure suggested that increased histone H3 acetylation induces the expression of genes related to response to damage. Reduced histone acetylation by the histone acetyltransferase inhibitor garcinol decreased liver damage and improved survival in mice with acute liver failure. Knock-down of PDHC or LDH improved viability in cells exposed to a pro-apoptotic stimulus. Treatment with the LDH inhibitor galloflavin that was also found to inhibit PDHC, reduced hepatic necrosis, apoptosis, and expression of pro-inflammatory cytokines in mice with acute liver failure. Mice treated with galloflavin also showed a dose-response increase in survival. PDHC and LDH translocate to the nucleus and are targets for therapy of acute liver failure. Acute liver failure is a rapidly progressive and life-threatening deterioration of liver function resulting in high mortality and

  9. The protection of glycyrrhetinic acid (GA) towards acetaminophen ...

    African Journals Online (AJOL)

    induced toxicity partially through fatty acids metabolic pathway. ... Abstract. Background: Acetaminophen (APAP)-induced liver toxicity remains the key factor limiting the clinical application of APAP, and herbs are the important sources for isolation of ...

  10. the effect of acetaminophen (paracetamol ) on tear production abstract

    African Journals Online (AJOL)

    LIVINGSTON

    cox-1 and cox-2 has long been known to be the mechanism of action ... effects typical of NSAIDS . Chronic excessive alcohol consumption can ... The effect of acetaminophen (paracetamol ) on the tear production of 100 young healthy subjects ...

  11. S-adenosyl-L-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Brown, James Mike [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States); Kuhlman, Christopher [Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, AZ (United States); Terneus, Marcus V. [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States); Labenski, Matthew T. [Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, AZ (United States); Lamyaithong, Andre Benja; Ball, John G. [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States); Lau, Serrine S. [Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, AZ (United States); Valentovic, Monica A., E-mail: Valentov@marshall.edu [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States)

    2014-12-01

    Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-L-methionine (SAMe) treatment 1 hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n = 5/group) were divided into the following groups and treated as indicated: Veh (15 ml/kg water, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg), and SAMe given 1 h after APAP (S + A). APAP toxicity was confirmed by an increase (p < 0.05) in plasma ALT (U/l) and liver weight/10 g body weight relative to the Veh, SAMe and S + A groups 4 h following APAP treatment. SAMe administered 1 h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10 g body weights were lower in the S + A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S + A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1. - Highlights: • Acetaminophen (APAP) toxicity protected by S-adenosylmethionine (SAMe) • 4-Hydroxynonenal adducted to sarcosine dehydrogenase • 4-Hydroxynonenal adducted to carbamoyl phosphate synthetase-1 • SAMe reduced APAP mediated CPS-1 mitochondrial leakage.

  12. S-adenosyl-L-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry

    International Nuclear Information System (INIS)

    Brown, James Mike; Kuhlman, Christopher; Terneus, Marcus V.; Labenski, Matthew T.; Lamyaithong, Andre Benja; Ball, John G.; Lau, Serrine S.; Valentovic, Monica A.

    2014-01-01

    Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-L-methionine (SAMe) treatment 1 hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n = 5/group) were divided into the following groups and treated as indicated: Veh (15 ml/kg water, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg), and SAMe given 1 h after APAP (S + A). APAP toxicity was confirmed by an increase (p < 0.05) in plasma ALT (U/l) and liver weight/10 g body weight relative to the Veh, SAMe and S + A groups 4 h following APAP treatment. SAMe administered 1 h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10 g body weights were lower in the S + A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S + A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1. - Highlights: • Acetaminophen (APAP) toxicity protected by S-adenosylmethionine (SAMe) • 4-Hydroxynonenal adducted to sarcosine dehydrogenase • 4-Hydroxynonenal adducted to carbamoyl phosphate synthetase-1 • SAMe reduced APAP mediated CPS-1 mitochondrial leakage

  13. Infant Sleep After Immunization: Randomized Controlled Trial of Prophylactic Acetaminophen

    Science.gov (United States)

    Gay, Caryl L.; Lynch, Mary; Lee, Kathryn A.

    2011-01-01

    OBJECTIVE: To determine the effects of acetaminophen and axillary temperature responses on infant sleep duration after immunization. METHODS: We conducted a prospective, randomized controlled trial to compare the sleep of 70 infants monitored by using ankle actigraphy for 24 hours before and after their first immunization series at ∼2 months of age. Mothers of infants in the control group received standard care instructions from their infants' health care provider, and mothers of infants in the intervention group were provided with predosed acetaminophen and instructed to administer a dose 30 minutes before the scheduled immunization and every 4 hours thereafter, for a total of 5 doses. Infant age and birth weight and immunization factors, such as acetaminophen use and timing of administration, were evaluated for changes in infant sleep times after immunization. RESULTS: Sleep duration in the first 24 hours after immunization was increased, particularly for infants who received their immunizations after 1:30 pm and for those who experienced elevated temperatures in response to the vaccines. Infants who received acetaminophen at or after immunization had smaller increases in sleep duration than did infants who did not. However, acetaminophen use was not a significant predictor of sleep duration when other factors were controlled. CONCLUSIONS: If further research confirms the relationship between time of day of vaccine administration, increased sleep duration after immunization, and antibody responses, then our findings suggest that afternoon immunizations should be recommended to facilitate increased sleep in the 24 hours after immunization, regardless of acetaminophen administration. PMID:22123869

  14. Childhood suicide attempts with acetaminophen in Denmark

    DEFF Research Database (Denmark)

    Hedeland, Rikke; Jørgensen, Marianne H; Teilmann, Grete

    2013-01-01

    Aims: To explore: (1) The relationship between children admitted to our paediatric department as a result of suicide attempts with acetaminophen and their parents and friends. (2) The extent to which the children had attempted to speak to their parents about their problems before their suicide...... Hospital, Denmark, 2006-2011. Study group: 107 children, 11 to 15 years old. Control group: 59 age- and gender-matched children. Results: 43.5% experienced a dissociated parental relationship characterized by the inability to speak to their parents about any problems, compared with 2% in the control group.......02). Prior to their suicide attempts, 41.5% of the children had attempted to speak to their parents about their problems but felt that they were not heard. There was a significant association among 'the feeling of not being heard' and the purpose of the suicide attempt (p = 0.002) and self-mutilation (p = 0...

  15. Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.

    Science.gov (United States)

    Spruiell, Krisstonia; Gyamfi, Afua A; Yeyeodu, Susan T; Richardson, Ricardo M; Gonzalez, Frank J; Gyamfi, Maxwell A

    2015-09-01

    Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. U.S. Government work not protected by U.S. copyright.

  16. Possible Protective Effect of Low-dose Gamma Irradiation and Certain Natural Products on Chemically Induced Hepatotoxicity in Rats

    International Nuclear Information System (INIS)

    Rashed, R.R.A.

    2015-01-01

    Liver, the largest organ in the human body, is a vital organ that performs more than 500 vital metabolic functions. More than a 1000 drugs of the modern pharmacopoeia can induce liver injury with different clinical presentations. In the most severe cases, drug-induced liver injury may require liver transplantation or lead to death of the patient. Acetaminophen (acetyl-para-amino-phenol, paracetamol, APAP) is safe at therapeutic doses, but accidental or intentional overdose can induce severe hepatotoxicity in both humans and experimental animals. APAP-induced hepatotoxicity is dose related and reproducible in animals, and is thus widely used as a model for experimentally induced hepatotoxicity. Many herbs have been used as natural remedies for the prevention and/or treatment of liver diseases. Herbal drugs gained importance and popularity in recent years because of their safety, efficacy and cost effectiveness. Interestingly, exposure to a small dose or dose rate of radiation was reported to induce stress, perturbing homeostasis. Organisms respond adaptively to such disturbances. The mechanisms by which low-dose radiation (LDR) protects the cells or tissue against subsequent radiation- or drug-induced toxicities have been attributed to its stimulation of various protective molecules such as antioxidants and anti apoptotic. In the light of the above mentioned information, this study was constructed in order to investigate the mechanism(s) of the hepato protective effects offered by each of garlic oil (GO), black seed oil (BO) and sesame oil (SO) each alone or combined with low dose total body gamma (γ)-irradiation against APAP-induced hepatotoxicity in male albino Wistar rats. Preliminary pilot studies were performed prior to the main experimental work; in order to select the effective irradiation dose, the hepato protective natural products and the duration of their administration to be used in the main study. To carry out the main study, 96 rats were randomly

  17. Acute Liver Toxicity due to Efavirenz/Emtricitabine/Tenofovir

    Directory of Open Access Journals (Sweden)

    Rashmee Patil

    2015-01-01

    Full Text Available The fixed-dose combination of Efavirenz/Emtricitabine/Tenofovir is a first-line agent for the treatment of HIV; however few cases have reported hepatotoxicity associated with the drug. We report a case of Efavirenz/Emtricitabine/Tenofovir-associated hepatotoxicity presenting mainly with hepatocellular injury characterized by extremely elevated aminotransferase levels, which resolved without acute liver failure or need for liver transplant referral.

  18. Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L. fruits.

    Science.gov (United States)

    Xue, Li-Ming; Zhang, Qiao-Yan; Han, Ping; Jiang, Yi-Ping; Yan, Rong-Di; Wang, Yang; Rahman, Khalid; Jia, Min; Han, Ting; Qin, Lu-Ping

    2014-03-14

    In the recent years, the international community has attached increasing importance to possible toxicity associated with Traditional Chinese Medicine (TCM). And hepatotoxicity is one of the major concerns, a fundamental pathological process induced by toxicant. This paper is in an attempt to identify the hepatotoxic components in Xanthium strumarium L. fruits (XSF) and interpret the toxicological mechanism induced by XSF. XSF extract was prepared and seven characteristic components were isolated and identified in XSF water extracts. We evaluated their hepatotoxicity effect on cell proliferation and lactate dehydrogenase (LDH) activity in L-02 and BRL liver cell line. An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy combined with multivariate statistical analysis was undertake to elucidate the hepatotoxicity mechanism induced in rats by XSF. The urine and serum metabolites were measured after treatment of rats with XSF (7.5, 15.0 and 30.0 g/kg/day) for 5 days. The results showed that atractyloside, carboxyatractyloside, 4'-desulphate-atractyloside and XSF induced significant cytotoxic effects in both L-02 and BRL liver cell lines, indicating that atractyloside, carboxyatractyloside, and 4'-desulphate-atractyloside were the toxic components of XSF. When rats were treated with XSF at 30.0 g/kg the hepatotoxicity was reflected in the changes observed in serum biochemical profiles and by the histopathological examination of the liver. The levels of VLDL/LDL, 3-HB, lactate, acetate, acetone and glutamate in serum were increased in this group, while d-glucose, choline and valine were decreased. The elevation in the levels of succinate, citrate, 2-oxo-glutamate, glycine, 3-HB, acetate, lactate, hippurate, dimethylglycine, methylamine, dimethylamine, phenylalanine and tryptophan was observed in urine, in contrast a reduction in the intensities of taurine, d-glucose, N-acetyl-glucoprotein and trimethylamine

  19. Evaluation of N-Acetyl Cysteine performance in acetaminophen poisoning using certain liver and renal factors in plasma

    Directory of Open Access Journals (Sweden)

    Armin Salek Maghsoudi

    2014-10-01

    Full Text Available Background: Annually, acetaminophen poisoning causes probable acute liver and renal failures in different societies. N-acetyl cystein (NAC, first suggested as an effective antidote to fight against acetaminophen poisoning in 1970, prevents the binding of NAPQI to hepatic cells. Methods: In the present study 30 patients with the average age of 27 and acetaminophen poisoning who referred to the poisons unit of Sina hospital in Tabriz were selected as the study sample. During the 24 hours of hospitalization, the blood samples of the patients were taken and collected in heparinized tubes. The plasma was separated by centrifuge and kept in tubes in -70°C until it was analyzed by a high performance liquid chromatography method (HPLC and laboratory analytical kits. Results: the glutathione peroxidase (GPX activity difference between the patients and control group was significant at first (P0.05. Conclusion: The activity level of GPX changed before a tangible change in regular liver enzymes. Urea level increased after 24 hours of treatment despite serum therapy and hydration condition.

  20. Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine.

    Science.gov (United States)

    Coulson, James; Thompson, John Paul

    2010-02-01

    The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro. HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA. NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol. Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.

  1. The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Angelina Huseinovic

    Full Text Available Acetaminophen (APAP, although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.

  2. Hepatotoxicity after liver irradiation in children and adolescents. Results from the RiSK

    Energy Technology Data Exchange (ETDEWEB)

    Roesler, Pascal; Christiansen, Hans [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); Kortmann, Rolf-Dieter [University of Leipzig, Department of Radiotherapy, Leipzig (Germany); Martini, Carmen [University Hospital of Freiburg, Department of Radiotherapy, Freiburg im Breisgau (Germany); Matuschek, Christiane [Heinrich-Heine University of Duesseldorf, Department of Radiotherapy, Medical Faculty, Duesseldorf (Germany); Meyer, Frank [Hospital Augsburg, Department of Radiotherapy, Augsburg (Germany); Ruebe, Christian [University Hospital of Homburg/Saar, Department of Radiotherapy, Homburg/Saar (Germany); Langer, Thorsten [University Hospital of Schleswig-Holstein, Department of Pediatrics, Pediatric Oncology, Campus Luebeck (Germany); Koch, Raphael [University of Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany); Eich, Hans Theodor; Willich, Normann [University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany); Steinmann, Diana [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany)

    2015-05-01

    The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose-volume effects and liver function in childhood and adolescence. Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the ''Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)'' using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria. Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1-18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1-4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume-dose correlations showed no statistically noticeable effect on acute or chronic toxicity. Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose-volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It

  3. Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen

    International Nuclear Information System (INIS)

    Moffit, Jeffrey S.; Aleksunes, Lauren M.; Kardas, Michael J.; Slitt, Angela L.; Klaassen, Curtis D.; Manautou, Jose E.

    2007-01-01

    Mice pretreated with the peroxisome proliferator clofibrate (CFB) are resistant to acetaminophen (APAP) hepatotoxicity. Whereas the mechanism of protection is not entirely known, CFB decreases protein adducts formed by the reactive metabolite of APAP, N-acetyl-p-benzoquinone imine (NAPQI). NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme with antioxidant properties that is responsible for the reduction of cellular quinones. We hypothesized that CFB increases NQO1 activity, which in turn enhances the conversion of NAPQI back to the parent APAP. This could explain the decreases in APAP covalent binding and glutathione depletion produced by CFB without affecting APAP bioactivation to NAPQI. Administration of CFB (500 mg/kg, i.p.) to male CD-1 mice for 5 or 10 days increased NQO1 protein and activity levels. To evaluate the capacity of NQO1 to reduce NAPQI back to APAP, we utilized a microsomal activating system. Cytochrome P450 enzymes present in microsomes bioactivate APAP to NAPQI, which binds the electrophile trapping agent, N-acetyl cysteine (NAC). We analyzed the formation of APAP-NAC metabolite in the presence of human recombinant NQO1. Results indicate that NQO1 is capable of reducing NAPQI. The capacity of NQO1 to amelioriate APAP toxicity was then evaluated in primary hepatocytes. Primary hepatocytes isolated from mice dosed with CFB are resistant to APAP toxicity. These hepatocytes were also exposed to ES936, a high affinity, and irreversible inhibitor of NQO1 in the presence of APAP. Concentrations of ES936 that resulted in over 94% inhibition of NQO1 activity did not increase the susceptibility of hepatocytes from CFB treated mice to APAP. Whereas NQO1 is mechanistically capable of reducing NAPQI, CFB-mediated hepatoprotection does not appear to be dependent upon enhanced expression of NQO1

  4. Aminotriazole alleviates acetaminophen poisoning via downregulating P450 2E1 and suppressing inflammation.

    Directory of Open Access Journals (Sweden)

    Yuping Jing

    Full Text Available Aminotriazole (ATZ is commonly used as a catalase (CAT inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2 levels, malondialdehyde (MDA contents, myeloperoxidase (MPO levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1 expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation.

  5. Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

    Directory of Open Access Journals (Sweden)

    Grammas Paula

    2009-03-01

    Full Text Available Abstract Background Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD, have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress. Methods Cerebral cortical cultured neurons are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (5 μM. Cell survival is assessed by MTT assay and inflammatory protein (tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES release quantitated by ELISA. Expression of pro- and anti-apoptotic proteins is assessed by western blots. Results Acetaminophen has pro-survival effects on neurons in culture. Menadione, a superoxide releasing oxidant stressor, causes a significant (p Conclusion These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress.

  6. Activation of Nrf2 protects against triptolide-induced hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Jia Li

    Full Text Available Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF, has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2 in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN, attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

  7. Influence of extraction methods on the hepatotoxicity of Azadirachta ...

    African Journals Online (AJOL)

    The influence of extraction methods: Cold aqueous (CA) hot aqueous (HA) and alcoholic extraction (AE) methods on the hepatotoxic effect of Azadirachta indica bark extract (ABC) was investigated using albino rats. A total of forty eight rats were divided into three groups of sixteen rats equally for the extraction methods.

  8. The Effects of Bitter Kola Supplemented Diet on Hepatotoxicity of ...

    African Journals Online (AJOL)

    MICHAEL

    supplemented rat chow and mercury contaminated water, group V animals were ... hepatotoxic effects of the heavy metal indirectly assessed by measurement of the serum levels of alkaline .... III vs V: Group IV vs V.P-values less than 0.05.

  9. Comparative Hepatotoxicity Test of Cadmium and Lead in Rats ...

    African Journals Online (AJOL)

    Background: Adverse environmental impacts include contamination of water, soil, and phytotoxicity from excessive heavy metals dispersed from mines and smelter sites leading to potential risk to human health. This study investigated the comparative hepatotoxicity test of mining pond waters used for domestic purposes in ...

  10. Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol ...

    African Journals Online (AJOL)

    The present study was conducted to evaluate the hepatotoxic and nephrotoxic effects of petroleum fumes on male and female petrol attendants. Investigations had been carried out on thirty (30) adult petrol attendants from different filling stations in Ibadan metropolis of Nigeria with ten (10) healthy adults as control. All the ...

  11. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

    Directory of Open Access Journals (Sweden)

    Xinmiao Yan

    2016-03-01

    Full Text Available Pyrrolizidine Alkaloids (PAs are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1 and glutathione peroxidase 1 (GPX1 targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  12. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.

    Science.gov (United States)

    Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

    2016-03-07

    Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  13. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ — Hawaii, 2013

    Science.gov (United States)

    Johnston, David I.; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L.; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y.

    2015-01-01

    Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases’ medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and trace back, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. PMID:26538199

  14. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ - Hawaii, 2013.

    Science.gov (United States)

    Johnston, David I; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y

    2016-01-01

    Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases' medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and traceback, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Hepatotoxicity of kaurene glycosides from Xanthium strumarium L. fruits in mice.

    Science.gov (United States)

    Wang, Yang; Han, Ting; Xue, Li-Ming; Han, Ping; Zhang, Qiao-Yan; Huang, Bao-Kang; Zhang, Hong; Ming, Qian-Liang; Peng, Wei; Qin, Lu-Ping

    2011-06-01

    The fruit of Xanthium strumarium L. (Cang-Er-Zi) is a traditional Chinese medicine that is used in curing nasal diseases and headache according to the Chinese Pharmacopoeia. However, clinical utilization of Xanthium strumarium is relatively limited because of its toxicity. The present investigation was carried out to evaluate the toxic effects on acute liver injury in mice of the two kaurene glycosides (atractyloside and carbxyatractyloside), which are main toxic constituents isolated from Fructus Xanthii on acute liver injury in mice. Histopathological examinations revealed that there were not obviously visible injury in lungs, heart, spleen, and the central nervous system in the mice by intraperitoneal injection of atractyloside (ATR, at the doses 50,125 and 200 mg/kg) and carbxyatractyloside (CATR, at the doses 50,100 and 150 mg/kg) for 5 days. However, it revealed extensive liver injuries compared with the normal group. In the determination of enzyme levels in serum, intraperitoneal injection of ATR and CATR resulted in significantly elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the hepatic oxidative stress level, antioxidant-related enzyme activity assays showed that ATR and CATR administration significantly increased hepatic malondialdehyde (MDA) concentration, as well as decreased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) concentration, and this was in good agreement with the results of serum aminotransferase activity and histopathological examinations. Taken together, our results demonstrate that kaurene glycosides induce hepatotoxicity in mice by way of its induction of oxidative stress as lipid peroxidation in liver, which merited further studies. Therefore, these toxic constituents explain, at least in part, the hepatotoxicity of X. strumarium L. in traditional medicine.

  16. Effects of cysteine and acetaminophen on the syntheses of glutathione and adenosine 3'-phosphate 5'-phosphosulfate in isolated rat hepatocytes

    DEFF Research Database (Denmark)

    Dalhoff, K; Poulsen, H E

    1992-01-01

    are dependent on sulphur deriving from cysteine. The effect of cysteine on the syntheses was investigated at non-toxic and toxic concentrations of the hepatotoxic drug acetaminophen (AA). Administration of AA trapped radioactivity (35S) in the pre-labelled PAPS and GSH pools by formation of the metabolites, AA......-sulphate and AA-GSH. Turnover rates were determined from the decline of AA-sulphate and AA-GSH specific activity. Syntheses of PAPS and GSH were calculated by multiplying the rates with the concentrations of the respective co-substrates. Increasing AA concentration from non-toxic to toxic levels resulted.......05) in experiments with non-toxic AA concentrations. In experiments with toxic AA concentrations opposite effects of cysteine were seen, i.e. median PAPS synthesis was reduced (3 to 2 nmol/10(6) cells/min) (P less than 0.05) while median GSH synthesis was unchanged (23 to 16 nmol/10(6) cells/min). The present method...

  17. Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

    Science.gov (United States)

    Sheehan, William J; Mauger, David T; Paul, Ian M; Moy, James N; Boehmer, Susan J; Szefler, Stanley J; Fitzpatrick, Anne M; Jackson, Daniel J; Bacharier, Leonard B; Cabana, Michael D; Covar, Ronina; Holguin, Fernando; Lemanske, Robert F; Martinez, Fernando D; Pongracic, Jacqueline A; Beigelman, Avraham; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Chmiel, James F; Daines, Cori L; Daines, Michael O; Gaffin, Jonathan M; Gentile, Deborah A; Gower, W Adam; Israel, Elliot; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Ly, Ngoc; Marbin, Jyothi; Morgan, Wayne J; Myers, Ross E; Olin, J Tod; Peters, Stephen P; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Thyne, Shannon M; Wechsler, Michael E; Phipatanakul, Wanda

    2016-08-18

    Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. Among

  18. An evaluation on consumers' usage pattern of acetaminophen (paracetamol: A multicenter study from Penang, Malaysia

    Directory of Open Access Journals (Sweden)

    Chee Ping Chong

    2017-01-01

    Full Text Available Background: Acetaminophen poisoning is becoming an increasingly common social problem in Malaysia. An understanding of consumers' usage pattern of acetaminophen is essential in addressing the issue of accidental acetaminophen poisoning. This study was therefore aimed to evaluate the usage pattern of acetaminophen among the consumers in the state of Penang, Malaysia. Methods: A survey using a questionnaire was carried out in Health Clinic of University Sciences Malaysia (USM, Outpatient Clinic of Advance Medical and Dental Institute, USM, and five selected community pharmacies in the state of Penang from February 2013 to April 2013. A convenient sample of 400 Malaysian consumers was involved in this study. Results: Majority (98.0% of the consumers had ever taken acetaminophen. The consumers mostly used acetaminophen for headache (75.0% and fever (72.8%. The 500 mg acetaminophen tablet was more commonly used among the consumers (94.3% then the 650 mg tablet (44.3%. A total of 1.1% of the consumers had taken more than two tablets of acetaminophen 500 mg tablet per intake. Meanwhile, 24.4% of the consumers had taken two tablets or more of acetaminophen 650 mg tablet per intake. The consumers mostly consumed acetaminophen in a frequency of either 4 hourly (29.5%, 8 hourly (17.3% or 6 hourly (14.8%. However, 6.3% and 7.0% of the consumers would increase the dosage or frequency of acetaminophen consumption, respectively, when their conditions or symptoms persisted after taking the acetaminophen. Conclusions: The use of acetaminophen is prevalent among the surveyed consumers. The risks of acetaminophen overdose were found among the consumers.

  19. Careful: Acetaminophen in Pain Relief Medicines Can Cause Liver Damage

    Science.gov (United States)

    ... Pain Relievers and Fever Reducers Careful: Acetaminophen in pain relief medicines can cause liver damage Share Tweet Linkedin Pin it More sharing options Linkedin Pin ... ingredient in many over-the-counter and prescription medicines that help relieve pain and reduce fever. More than 600 over-the- ...

  20. Possible fatal acetaminophen intoxication with atypical clinical presentation

    NARCIS (Netherlands)

    de-Giorgio, Fabio; Lodise, Maria; Chiarotti, Marcello; d'Aloja, Ernesto; Carbone, Arnaldo; Valerio, Luca

    2013-01-01

    Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely,

  1. Study of Nephrotoxic Potential of Acetaminophen in Birds

    Science.gov (United States)

    Jayakumar, K.; Mohan, K.; Swamy, H. D. Narayana; Shridhar, N. B.; Bayer, M. D.

    2010-01-01

    The present study was designed to evaluate the effect of acetaminophen on kidneys of birds by comparison with diclofenac that is used as positive control. The birds of Group I served as negative control and received normal saline, whereas Group II birds received diclofenac injection (2.5 mg/kg IM) and Group III birds received acetaminophen injection (10 mg/kg IM) for a period of seven days daily. The birds treated with diclofenac showed severe clinical signs of toxicity accompanied with high mortality and significant increase (P<0.001) in serum creatinine and uric acid concentration. The creatinine and uric acid concentrations were consistent with gross and histopathological findings. The negative control and acetaminophen-treated groups showed no adverse clinical signs, serum creatinine and uric acid concentrations were normal, and no gross or histopathological changes in kidneys were observed. Thus, it was concluded that acetaminophen can be used for treatment in birds without any adverse effect on kidneys. PMID:21170252

  2. Reducing Fever in Children: Safe Use of Acetaminophen

    Science.gov (United States)

    ... label or you can’t tell how much to give, ask your pharmacist or doctor what to do. Never give more of an acetaminophen-containing medicine than directed. If the medicine doesn’t help your child feel better, talk to your doctor, nurse, or pharmacist. If the ...

  3. Xenobiotics-induced hepatotoxicity and an influence of HLA typisation

    Directory of Open Access Journals (Sweden)

    Žunić Miodrag

    2014-01-01

    Full Text Available Introduction: The increased reporting of cases of drug-induced liver injuries, reflects the growing number of new agents introduced into clinical practice in the last decades. It should be added to the modernization of industries, and new chemicals which it applied. Drug-induced liver injuries make up a persisting and challenging problem for physicians, health agencies and pharmaceutical firms. Research objectives: The aim of the study is the determination of the most common causes of drug-induced liver injury in our surroundings. We compared the importance of hepatotoxic action of drugs in relation to other noxa in human environment. We determinated the importance of the body sensitivity on the acting agents. We also examined the importance of different drugs in the development of hepatotoxicity, regardless the dose. Materials and methods: We analyzed 52 patients with a diagnosis of hepa-totoxic liver injury (medical history, detailed clinical evaluation of patients, histopathological analysis of the liver, abdominal ultra sound, laboratory determination of standard liver function tests and followed up for 12 months. In the period from 01.04. 2005 to 01.04.2009, in these patients of the Institute of Gastroenterology and Hepatology, Clinical Center of Serbia in Belgrade, we monitored liver functional tests and morphological findings. We used biological markers relevant for the differential diagnosis, monitoring of disease progression and response to therapy. The results of the patients with hepatotoxic liver injury were compared with the values of the findings of the 52 patients in the control group, with the diagnosis of chronic viral hepatitis, hospitalized in the same institution during the same time. Results: The causes of toxic liver damage in our study were following agents, classified into groups: Industrial toxins (8 patients, Food and beverages (9 pts, Antirheumatics and analgesics (6 pts, Antiarrhythmic drugs (4 pts Antilipemic (4 pts

  4. Chloroform ingestion causing severe gastrointestinal injury, hepatotoxicity and dermatitis confirmed with plasma chloroform concentrations.

    Science.gov (United States)

    Jayaweera, Dushan; Islam, Shawkat; Gunja, Naren; Cowie, Chris; Broska, James; Poojara, Latesh; Roberts, Michael S; Isbister, Geoffrey K

    2017-02-01

    Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.

  5. Type 2 diabetic rats are sensitive to thioacetamide hepatotoxicity

    International Nuclear Information System (INIS)

    Sawant, Sharmilee P.; Dnyanmote, Ankur V.; Warbritton, Alan; Latendresse, John R.; Mehendale, Harihara M.

    2006-01-01

    Previously, we reported high hepatotoxic sensitivity of type 2 diabetic (DB) rats to three dissimilar hepatotoxicants. Additional work revealed that a normally nonlethal dose of CCl 4 was lethal in DB rats due to inhibited compensatory tissue repair. The present study was conducted to investigate the importance of compensatory tissue repair in determining the final outcome of hepatotoxicity in diabetes, using another structurally and mechanistically dissimilar hepatotoxicant, thioacetamide (TA), to initiate liver injury. A normally nonlethal dose of TA (300 mg/kg, ip), caused 100% mortality in DB rats. Time course studies (0 to 96 h) showed that in the non-DB rats, liver injury initiated by TA as assessed by plasma alanine or aspartate aminotransferase and hepatic necrosis progressed up to 48 h and regressed to normal at 96 h resulting in 100% survival. In the DB rats, liver injury rapidly progressed resulting in progressively deteriorating liver due to rapidly expanding injury, hepatic failure, and 100% mortality between 24 and 48 h post-TA treatment. Covalent binding of 14 C-TA-derived radiolabel to liver tissue did not differ from that observed in the non-DB rats, indicating similar bioactivation-based initiation of hepatotoxicity. S-phase DNA synthesis measured by [ 3 H]-thymidine incorporation, and advancement of cells through the cell division cycle measured by PCNA immunohistochemistry, were substantially inhibited in the DB rats compared to the non-DB rats challenged with TA. Thus, inhibited cell division and compromised tissue repair in the DB rats resulted in progressive expansion of liver injury culminating in mortality. In conclusion, it appears that similar to type 1 diabetes, type 2 diabetes also increases sensitivity to dissimilar hepatotoxicants due to inhibited compensatory tissue repair, suggesting that sensitivity to hepatotoxicity in diabetes occurs in the absence as well as presence of insulin

  6. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    OpenAIRE

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were ad...

  7. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    Science.gov (United States)

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  8. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests.

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-07-27

    To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none. Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.

  9. No evidence demonstrating hepatotoxicity associated with hydroxycitric acid

    Institute of Scientific and Technical Information of China (English)

    Sidney J Stohs; Harry G Preuss; Sunny E Ohia; Gilbert R Kaats; Carl L Keen; Lonnie D Williams; George A Burdock

    2009-01-01

    Although a number of cases of hepatotoxicity are associated with the use of Hydroxycut weight management products,it has been alleged that their effects are primarily due to the presence of hydroxycitric acid (HCA,as Super CitriMax) in the formulations.However,while these products contain up to 20 different ingredients,some do not contain HCA.Case studies reported to date have not considered in depth the literature on the numerous animal and human studies that have been conducted on the safety and efficacy of HCA.No HCAassociated hepatotoxicity or treatment-related adverse effects have been reported in these studies,and thus it is premature to make the assumptions presented in the recent case studies regarding Hydroxycut.If it is established in well controlled studies that the use of these formulations with and/or without HCA can result in the occurrence or progression of hepatotoxicity,additional studies should be conducted to characterize the causative factor(s).

  10. Rocuronium is more hepatotoxic than succinylcholine in vitro.

    Science.gov (United States)

    Sauer, Martin; Piel, Ines; Haubner, Cristof; Richter, Georg; Mann, Miriam; Nöldge-Schomburg, Gabriele; Mencke, Thomas

    2017-09-01

    The development of liver failure is a major problem in critically ill patients. The hepatotoxicity of many drugs, as one important reason for liver failure, is poorly screened for in human models. Rocuronium and succinylcholine are neuromuscular blocking agents used for tracheal intubation and for rapid-sequence induction. We used an in-vitro test with a permanent cell line and compared rocuronium and succinylcholine for hepatotoxicity. In-vitro study. A basic science laboratory, University Hospital Rostock, Germany. The basic test compound is the permanent human liver cell line HepG2/C3A. In a standardised microtitre plate assay the toxicity of different concentrations of rocuronium, succinylcholine and plasma control was tested. After two incubation periods of 3 days, the viability of cells (XTT test, lactate dehydrogenase release and trypan blue staining), micro-albumin synthesis and the cytochrome 1A2 activity (metabolism of ethoxyresorufin) were measured. Differences between rocuronium and succinylcholine were assessed using the Kruskal-Wallis one-way test and two-tailed Mann-Whitney U test. Rocuronium, but not succinylcholine, led to a significant dose-dependent decrease of viability, albumin synthesis and cytochrome 1A2 activity of test cells. An in-vitro test with a cell line showed hepatotoxicity of rocuronium that was dose-dependent. Further studies are needed to investigate the underlying mechanisms of the effects of rocuronium on hepatic cellular integrity. Not suitable.

  11. Histomorphological effects of isoniazid induced hepatotoxicity in male albino mice

    International Nuclear Information System (INIS)

    Humayun, F.; Zareen, N.

    2017-01-01

    To observe the histomorphological changes of isoniazid induced hepatotoxicity in male albino mice. Methodology: This experimental study was carried out at University of Health Sciences, Lahore, Pakistan from January to December 2013. Forty male albino mice selected by simple random technique, were divided into two groups; A-Control, and B-experimental. Group A comprised of 15, while Group B comprised 25 mice. Both the groups were kept under identical conditions and diet. However, experimental group was treated with an additional oral hepatotoxic dose of isoniazid i.e. 100mg/kg bodyweight daily for 30 days. After 30 days, the animals were sacrificed and livers were dissected out. Gross comparison of the organ and stained sections were histologically compared for morphological differences between the groups. Fischer Exact test was used to analyze the qualitative data and a p<0.05 was considered significant. Results: Group A animals showed the normal liver architecture. Whereas, those of Group B showed deranged hepatic histomorphology. Conclusion: Hepatotoxic dose of Isoniazid caused histomorphological alterations in the liver of male albino mice. (author)

  12. Hepatotoxicity induced by methimazole in a previously healthy patient.

    Science.gov (United States)

    Gallelli, Luca; Staltari, Orietta; Palleria, Caterina; De Sarro, Giovambattista; Ferraro, Maria

    2009-09-01

    We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

  13. Gastric emptying in rats with acetaminophen-induced hepatitis

    Directory of Open Access Journals (Sweden)

    G. Hessel

    1998-09-01

    Full Text Available The objective of this work was to study the gastric emptying (GE of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each. Group I was fed a sucrose diet throughout the experiment (66 h while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each. Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg. Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 µg/ml than in group IB (87 µg/ml. The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values. The correlation between gastric retention and AST levels was significant (P<0.05 for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

  14. Hepatotoxic potential of asarones: In vitro evaluation of hepatotoxicity and quantitative determination in herbal products

    Directory of Open Access Journals (Sweden)

    Dhavalkumar Narendrabha Patel

    2015-02-01

    Full Text Available α and β asarones are natural constituents of some aromatic plants, especially species of the genus Acorus. In addition to beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of β-asarone, a limit of exposure from herbal products of approximately 2 μg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of β-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of β-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4 to 25 times greater amounts of β-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE2 cells confirmed the cytotoxicity of -asarone (IC50 = 40.0 ± 2.0 µg/mL which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxicity effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety. Further investigations of the toxicity of asarones are

  15. Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Du, Kuo; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M. [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Ding, Wen-Xing [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2015-12-01

    3′-Hydroxyacetanilide or N-acetyl-meta-aminophenol (AMAP) is generally regarded as a non-hepatotoxic analog of acetaminophen (APAP). Previous studies demonstrated the absence of toxicity after AMAP in mice, hamsters, primary mouse hepatocytes and several cell lines. In contrast, experiments with liver slices suggested that it may be toxic to human hepatocytes; however, the mechanism of toxicity is unclear. To explore this, we treated primary human hepatocytes (PHH) with AMAP or APAP for up to 48 h and measured several parameters to assess metabolism and injury. Although less toxic than APAP, AMAP dose-dependently triggered cell death in PHH as indicated by alanine aminotransferase (ALT) release and propidium iodide (PI) staining. Similar to APAP, AMAP also significantly depleted glutathione (GSH) in PHH and caused mitochondrial damage as indicated by glutamate dehydrogenase (GDH) release and the JC-1 assay. However, unlike APAP, AMAP treatment did not cause relevant c-jun-N-terminal kinase (JNK) activation in the cytosol or phospho-JNK translocation to mitochondria. To compare, AMAP toxicity was assessed in primary mouse hepatocytes (PMH). No cytotoxicity was observed as indicated by the lack of lactate dehydrogenase release and no PI staining. Furthermore, there was no GSH depletion or mitochondrial dysfunction after AMAP treatment in PMH. Immunoblotting for arylated proteins suggested that AMAP treatment caused extensive mitochondrial protein adduct formation in PHH but not in PMH. In conclusion, AMAP is hepatotoxic in PHH and the mechanism involves the formation of mitochondrial protein adducts and mitochondrial dysfunction. - Highlights: • AMAP induces cell death in primary human hepatocytes (PHH). • AMAP does not cause cell death in primary mouse hepatocytes (PMH). • AMAP leads to mitochondria dysfunction in PHH but not PMH. • Protein adduct formation and dysfunction in mitochondria correlate with toxicity.

  16. Mitochondrial protein adducts formation and mitochondrial dysfunction during N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes

    International Nuclear Information System (INIS)

    Xie, Yuchao; McGill, Mitchell R.; Du, Kuo; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Ding, Wen-Xing; Jaeschke, Hartmut

    2015-01-01

    3′-Hydroxyacetanilide or N-acetyl-meta-aminophenol (AMAP) is generally regarded as a non-hepatotoxic analog of acetaminophen (APAP). Previous studies demonstrated the absence of toxicity after AMAP in mice, hamsters, primary mouse hepatocytes and several cell lines. In contrast, experiments with liver slices suggested that it may be toxic to human hepatocytes; however, the mechanism of toxicity is unclear. To explore this, we treated primary human hepatocytes (PHH) with AMAP or APAP for up to 48 h and measured several parameters to assess metabolism and injury. Although less toxic than APAP, AMAP dose-dependently triggered cell death in PHH as indicated by alanine aminotransferase (ALT) release and propidium iodide (PI) staining. Similar to APAP, AMAP also significantly depleted glutathione (GSH) in PHH and caused mitochondrial damage as indicated by glutamate dehydrogenase (GDH) release and the JC-1 assay. However, unlike APAP, AMAP treatment did not cause relevant c-jun-N-terminal kinase (JNK) activation in the cytosol or phospho-JNK translocation to mitochondria. To compare, AMAP toxicity was assessed in primary mouse hepatocytes (PMH). No cytotoxicity was observed as indicated by the lack of lactate dehydrogenase release and no PI staining. Furthermore, there was no GSH depletion or mitochondrial dysfunction after AMAP treatment in PMH. Immunoblotting for arylated proteins suggested that AMAP treatment caused extensive mitochondrial protein adduct formation in PHH but not in PMH. In conclusion, AMAP is hepatotoxic in PHH and the mechanism involves the formation of mitochondrial protein adducts and mitochondrial dysfunction. - Highlights: • AMAP induces cell death in primary human hepatocytes (PHH). • AMAP does not cause cell death in primary mouse hepatocytes (PMH). • AMAP leads to mitochondria dysfunction in PHH but not PMH. • Protein adduct formation and dysfunction in mitochondria correlate with toxicity.

  17. Construction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data

    International Nuclear Information System (INIS)

    Zhu, Xiao; Kruhlak, Naomi L.

    2014-01-01

    Graphical abstract: - Abstract: Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clinical manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quantitative structure–activity relationship (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). In order to determine the optimal classification scheme to partition positive from negative drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicological endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug's potential to cause DILI

  18. The Protective Effect of Liquorice Plant Extract on CCl4-Induced Hepatotoxicity in Common Carp (Cyprinus carpio

    Directory of Open Access Journals (Sweden)

    Hassan Malekinejad

    2010-12-01

    Full Text Available The protective effect of liquorice plant extract (LPE on CCl4-induced hepatotoxicity in common carp was evaluated using fifty adult carps. The fish were cultured in a standard environment in terms of water flow rate, oxygen, pH, food and temperature. The fish were assigned into 5 groups (N = 10 as control, sham, and tests. The test groups were pre-treated for 3 h with various concentrations of LPE, 3 days before CCl4 exposure. The control and sham groups received normal saline before and after CCl4 exposure. To induce hepatotoxicity, animals in the sham and test groups were exposed against 100 l L-1 CCl4 for 45 min. The fish in all groups 1 h after CCl4 exposure were anesthetized and the blood samples were collected. Immediately the liver specimens were dissected out and were stored in 10 % formalin for further pathological studies. Determination of serum level of ALP and SGOT revealed that acute form of CCl4 exposure elevated significantly (P < 0.05 the serum level of either tested hepatic marker enzymes. While 3 days pretreatment with LPE prevented from ALP and SGOT enhancement. The pathological evaluation revealed that the CCl4 exposure resulted in a minor pathologic manifestation such as slight congestion, which the LPE pretreated groups showed the remarkable improvement. The anti-oxidant capacity of LPE was assayed by FRAP and DPPH methods. Both provided techniques showed that LPE exerts an excellent anti-oxidant effect. This data suggest that LPE exerts protective effect against CCl4-induced hepatotoxicity. Moreover, the hepatoprotective effect of LPE may attribute to its antioxidant capacity.

  19. Prior acetaminophen consumption impacts the early adaptive cellular response of human skeletal muscle to resistance exercise.

    Science.gov (United States)

    D'Lugos, Andrew C; Patel, Shivam H; Ormsby, Jordan C; Curtis, Donald P; Fry, Christopher S; Carroll, Chad C; Dickinson, Jared M

    2018-04-01

    Resistance exercise (RE) is a powerful stimulus for skeletal muscle adaptation. Previous data demonstrate that cyclooxygenase (COX)-inhibiting drugs alter the cellular mechanisms regulating the adaptive response of skeletal muscle. The purpose of this study was to determine whether prior consumption of the COX inhibitor acetaminophen (APAP) alters the immediate adaptive cellular response in human skeletal muscle after RE. In a double-blinded, randomized, crossover design, healthy young men ( n = 8, 25 ± 1 yr) performed two trials of unilateral knee extension RE (8 sets, 10 reps, 65% max strength). Subjects ingested either APAP (1,000 mg/6 h) or placebo (PLA) for 24 h before RE (final dose consumed immediately after RE). Muscle biopsies (vastus lateralis) were collected at rest and 1 h and 3 h after exercise. Mammalian target of rapamycin (mTOR) complex 1 signaling was assessed through immunoblot and immunohistochemistry, and mRNA expression of myogenic genes was examined via RT-qPCR. At 1 h p-rpS6 Ser240/244 was increased in both groups but to a greater extent in PLA. At 3 h p-S6K1 Thr389 was elevated only in PLA. Furthermore, localization of mTOR to the lysosome (LAMP2) in myosin heavy chain (MHC) II fibers increased 3 h after exercise only in PLA. mTOR-LAMP2 colocalization in MHC I fibers was greater in PLA vs. APAP 1 h after exercise. Myostatin mRNA expression was reduced 1 h after exercise only in PLA. MYF6 mRNA expression was increased 1 h and 3 h after exercise only in APAP. APAP consumption appears to alter the early adaptive cellular response of skeletal muscle to RE. These findings further highlight the mechanisms through which COX-inhibiting drugs impact the adaptive response of skeletal muscle to exercise. NEW & NOTEWORTHY The extent to which the cellular reaction to acetaminophen impacts the mechanisms regulating the adaptive response of human skeletal muscle to resistance exercise is not well understood. Consumption of acetaminophen before

  20. Postoperative analgesia using diclofenac and acetaminophen in children.

    Science.gov (United States)

    Hannam, Jacqueline A; Anderson, Brian J; Mahadevan, Murali; Holford, Nick H G

    2014-09-01

    Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg(-1) is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown. Children (n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg·kg(-1) before surgery and 20 mg·kg(-1) rectally at the end of surgery with diclofenac suspension 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first-order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout. Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect (EMAX ) was 4.9. The concentration resulting in 50% of EMAX (C50 ) was 1.23 mg·l(-1) for diclofenac and 13.3 mg·l(-1) for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg·kg(-1) with acetaminophen 15 mg·kg(-1) achieves equivalent analgesia to acetaminophen 30 mg·kg(-1) . Combination therapy can be used to achieve similar analgesia with lower doses of both drugs. © 2014 John Wiley & Sons Ltd.

  1. Oral paracetamol (acetaminophen) for cancer pain.

    Science.gov (United States)

    Wiffen, Philip J; Derry, Sheena; Moore, R Andrew; McNicol, Ewan D; Bell, Rae F; Carr, Daniel B; McIntyre, Mairead; Wee, Bee

    2017-07-12

    Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence. To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries. We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and

  2. In vivo assessment of the hepatotoxicity of a new Nostoc isolate from the Nile River: Nostoc sp. strain NRI.

    Science.gov (United States)

    Abu-Serie, Marwa M; Nasser, Nermine; Abd El-Wahab, Abeer; Shehawy, Rehab; Pienaar, Harrison; Baddour, Nahed; Amer, Ranya

    2018-03-01

    Nostoc sp. is one of the most widely distributed cyanobacterial genera that produce potentially protein phosphatase (PP) inhibitor; microcystins (MCs). MCs have posed a worldwide concern due to predominant hepatotoxicity to human health. We have previously isolated a Nostoc strain (NR1) from the Nile River (the main water supply in Egypt) and this strain exerted production of rare and highly toxic MC; demethylated microcystin-LR. There is no data concerning risk factors of liver diseases for human and animal exposure to NR1-contaminated drinking water yet. It is thus important to evaluate acute (LD 50 dose), subacute (0.01% and 10% of LD 50 dose) and subchronic (0.01% and 10% of LD 50 dose) hepatotoxicity's NR1 extract using experimental mice. Mice groups, who orally received 0.01% LD 50 , represented a permissible concentration of the World Health Organization (WHO) for MC in drinking water. Several parameters were detected, including hepatotoxicity (i.e. PP activity, liver function, oxidative stress markers and DNA fragmentation), pro-inflammatory cytokine (TNF-α) and liver histopathology. Our results demonstrated LD 50 of NR1 extract was at 15,350 mg/kg body weight and caused hepatotoxicity that attributed to PP inhibition and a significant increase of hepatic damage biomarkers with lipid accumulation. Moreover, NR1 extract induced hepatic oxidative damage that may have led to DNA fragmentation and production of TNF-α. As demonstrated from the histopathological study, NR1 extract caused a severe collapse of cytoskeleton with subsequent focal degeneration of hepatocytes, necroinflammation and steatosis. The grade of hepatotoxicity in subacute (10% of LD 50 ) group was higher than that in the subchronic (10% of LD 50 and 0.01% of LD 50 , WHOch, respectively) groups. No significant hepatotoxicity was detectable for subacute (0.01% of LD 50 , WHOac) group. NR1 is therefore considered as one of the harmful and life-threatening cyanobacteria for Egyptian people

  3. Dental pain as a risk factor for accidental acetaminophen overdose: a case-control study.

    Science.gov (United States)

    Vogel, Jody; Heard, Kennon J; Carlson, Catherine; Lange, Chad; Mitchell, Garrett

    2011-11-01

    Patients frequent take acetaminophen to treat dental pain. One previous study found a high rate of overuse of nonprescription analgesics in an emergency dental clinic. The purpose of this study is to determine if patients with dental pain are more likely to be treated for accidental acetaminophen poisoning than patients with other types of pain. We conducted a case-control study at 2 urban hospitals. Cases were identified by chart review of patients who required treatment for accidental acetaminophen poisoning. Controls were self-reported acetaminophen users taking therapeutic doses identified during a survey of emergency department patients. For our primary analysis, the reason for taking acetaminophen was categorized as dental pain or not dental pain. Our primary outcome was the odds ratio of accidental overdose to therapeutic users after adjustment for age, sex, alcoholism, and use of combination products using logistic regression. We identified 73 cases of accidental acetaminophen poisoning and 201 therapeutic users. Fourteen accidental overdose patients and 4 therapeutic users reported using acetaminophen for dental pain. The adjusted odds ratio for accidental overdose due to dental pain compared with other reasons for use was 12.8 (95% confidence interval, 4.2-47.6). We found that patients with dental pain are at increased risk to accidentally overdose on acetaminophen compared with patients taking acetaminophen for other reasons. Emergency physicians should carefully question patients with dental pain about overuse of analgesics. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Interaction of Aldehyde dehydrogenase with acetaminophen as examined by spectroscopies and molecular docking

    Directory of Open Access Journals (Sweden)

    Ayodele O. Kolawole

    2017-07-01

    Full Text Available The interaction of acetaminophen, a non-substrate anionic ligand, with Aldehyde Dehydrogenase was studied by fluorescence, UV–Vis absorption, and circular dichroism spectroscopies under simulated physiological conditions. The fluorescence spectra and data generated showed that acetaminophen binding to ALDH is purely dynamic quenching mechanism. The acetaminophen-ALDH is kinetically rapid reversible interaction with a binding constant, Ka, of 4.91×103 L mol−1. There was an existence of second binding site of ALDH for acetaminophen at saturating acetaminophen concentration. The binding sites were non-cooperative. The thermodynamic parameters obtained suggest that Van der Waal force and hydrogen bonding played a major role in the binding of acetaminophen to ALDH. The interaction caused perturbation of the ALDH structures with an obvious reduction in the α-helix. The binding distance of 4.43 nm was obtained between Acetaminophen and ALDH. Using Ficoll 400 as macro-viscosogen and glycerol as micro-viscosogen, Stoke-Einstein empirical plot demonstrated that acetaminophen-ALDH binding was diffusion controlled. Molecular docking showed the participation of some amino acids in the complex formation with −5.3 kcal binding energy. With these, ALDH might not an excipient detoxifier of acetaminophen but could be involved in its pegylation/encapsulation.

  5. Determination of the Antiproliferative Activity of New Theobromine Derivatives and Evaluation of Their In Vitro Hepatotoxic Effects.

    Science.gov (United States)

    Georgieva, Maya; Kondeva-Burdina, Magdalena; Mitkov, Javor; Tzankova, Virginia; Momekov, Georgi; Zlatkov, Alexander

    2016-01-01

    A new series of N-substituted 1-benzyltheobromine-8-thioacetamides were designed and synthesized. Their anti-proliferative activity against human chronic myelocytic leukemia cell K562, human T-cell leukemia cell SKW-3 and human acute myeloid leukemia HL-60 was evaluated. For the tested compounds a concentrationdependent cytotoxic activity was observed, with 7g outlined as the most active compound within the series. The targed compounds were obtained in yields of 56 to 85% and their structures were elucidated by FTIR, (1)H NMR, (13)C NMR and microanalyses. The compounds purity was proven by elemental analysis and spectral data. In general, the compounds showed low hepatotoxicity on sub-cellular and cellular level. On isolated rat microsomes only 7d showed toxic effect while theobromine, 1-benzyl-theobromine-thioacetic acid (BTTA) and the other new theobromine derivatives were devoid of toxicity. In isolated rat hepatocytes, when compared to theobromine and BTTA, 7f showed lower cytotoxic effects, and 7d exerted higher cytotoxicity. The results indicate 7g as a promising structure for the design of future compounds with low hepatotoxicity and good antiproliferative activity.

  6. The combination of atorvastatin and ethanol is not more hepatotoxic to rats than the administration of each drug alone

    Directory of Open Access Journals (Sweden)

    D.T. Ito

    2007-03-01

    Full Text Available Animal studies and premarketing clinical trials have revealed hepatotoxicity of statins, primarily minor elevations in serum alanine aminotransferase levels. The combined chronic use of medicines and eventual ethanol abuse are common and may present a synergistic action regarding liver injury. Our objective was to study the effect of the chronic use of atorvastatin associated with acute ethanol administration on the liver in a rat model. One group of rats was treated daily for 5 days a week for 2 months with 0.8 mg/kg atorvastatin by gavage. At the end of the treatment the livers were perfused with 72 mM ethanol for 60 min. Control groups (at least 4 animals in each group consisted of a group of 2-month-old male Wistar EPM-1 rats exposed to 10% ethanol (v/v ad libitum replacing water for 2 months, followed by perfusion of the liver with 61 nM atorvastatin for 60 min, and a group of animals without chronic ethanol treatment whose livers were perfused with atorvastatin and/or ethanol. The combination of atorvastatin with ethanol did not increase the release of injury marker enzymes (alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase from the liver and no change in liver function markers (bromosulfophthalein clearance, and oxygen consumption was observed. Our results suggest that the combination of atorvastatin with ethanol is not more hepatotoxic than the separate use of each substance.

  7. Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis.

    Science.gov (United States)

    Luckert, Claudia; Hessel, Stefanie; Lenze, Dido; Lampen, Alfonso

    2015-10-01

    1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 μM of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a |fold change| of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NFκB and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPARα/γ/δ were predicted to be inhibited. In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Effect of anemia on hepatotoxicity of HAART in HIV patients in Benin ...

    African Journals Online (AJOL)

    Background: Hepatotoxicity is a relevant adverse effect of highly active antiretroviral Treatment owing to its frequency, and it can cause interruption of therapy, hepatitis, and death. There is dearth of information on hepatotoxicity arising from highly active antiretroviral therapy (HAART) in anemic patients. Anemia is the most ...

  9. Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

    Directory of Open Access Journals (Sweden)

    Tomishima Yoshiro

    2013-01-01

    Full Text Available Abstract Background Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2 synthase inhibitor, on liver injury induced by APAP overdose in mice. Methods Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg. The effects of ozagrel (200 mg/kg treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL on cytochrome P450 2E1 (CYP2E1 activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1–100 muM were evaluated by the WST-1 cell viability assay. Results Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos and C/EBP homologous protein (chop, but did not suppress B-cell lymphoma 2-like protein11 (bim expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. Conclusions We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest

  10. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-09-15

    Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5 mM, 10 mM or 20 mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24 h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3 h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12 h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3 h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24 h and 48 h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6 h after APAP and a partial protection when given at 15 h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic. - Highlights: • APAP reproducibly causes cell death in freshly isolated primary human hepatocytes. • APAP induces adduct formation, JNK activation and mitochondrial dysfunction in PHH. • Mitochondrial adducts and JNK translocation are delayed in PHH compared to

  11. Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice.

    Science.gov (United States)

    Bandeira, Ana Carla Balthar; da Silva, Talita Prato; de Araujo, Glaucy Rodrigues; Araujo, Carolina Morais; da Silva, Rafaella Cecília; Lima, Wanderson Geraldo; Bezerra, Frank Silva; Costa, Daniela Caldeira

    2017-02-01

    Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Post hemorrhoidectomy pain control: rectal Diclofenac versus Acetaminophen

    Directory of Open Access Journals (Sweden)

    Rahimi M

    2009-03-01

    Full Text Available "nBackground: Anal surgeries are prevalent, but they didn't perform as outpatient surgeries because of concerns about postoperative pain. The aim of the present study was to compare the effects of rectal acetaminophen and diclofenac on postoperative analgesia after anal surgeries in adult patients. "nMethods: In a randomized, double-blinded, placebo-controlled study 60 ASA class I or II scheduled for haemorrhoidectomy, anal fissure or fistula repair, were randomized (with block randomization method to receive either a single dose of 650 mg rectal acetaminophen (n=20, 100 mg rectal diclofenac (n=20 or placebo suppositories (n=20 after the operation. The severity of pain, time to first request of analgesic agent after administration of suppositories and complications were compared between three groups. Pain scores were evaluated in patients by Visual Analogue Scale (VAS in 0 (after complete consciousness in recovery, 2, 4, 12 and 24 hours after surgery. The period between administration of the suppositories and the patients' first request to receive analgesic was compared between groups. "nResults: Pain scores were lower significantly in rectal diclofenac than the other groups. The period between administration of the suppositories and the patients' first request to receive analgesic in diclofenac group was 219±73 minutes, was significantly longer compared with placebo (153±47 minutes and acetaminophen (178±64 minutes groups. No complications were reported. "nConclusions: Diclofenac suppository is more effective than acetaminophen suppository in post hemorrhoidectomy pain management.

  13. Acetaminophen modulates the transcriptional response to recombinant interferon-beta.

    Directory of Open Access Journals (Sweden)

    Aaron Farnsworth

    Full Text Available BACKGROUND: Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-beta treatment. CD-1 mice were administered acetaminophen (APAP, interferon-beta (IFN-beta or a combination of IFN-beta+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-beta. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IkappaBK/NF-kappaB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. CONCLUSIONS/SIGNIFICANCE: A significant change in the transcriptional response was observed following co-administration of IFN-beta+APAP relative to IFN-beta treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-beta treatment.

  14. Acetaminophen and acetone sensing capabilities of nickel ferrite nanostructures

    Science.gov (United States)

    Mondal, Shrabani; Kumari, Manisha; Madhuri, Rashmi; Sharma, Prashant K.

    2017-07-01

    Present work elucidates the gas sensing and electrochemical sensing capabilities of sol-gel-derived nickel ferrite (NF) nanostructures based on the electrical and electrochemical properties. In current work, the choices of target species (acetone and acetaminophen) are strictly governed by their practical utility and concerning the safety measures. Acetone, the target analyte for gas sensing measurement is a common chemical used in varieties of application as well as provides an indirect way to monitor diabetes. The gas sensing experiments were performed within a homemade sensing chamber designed by our group. Acetone gas sensor (NF pellet sensor) response was monitored by tracking the change in resistance both in the presence and absence of acetone. At optimum operating temperature 300 °C, NF pellet sensor exhibits selective response for acetone in the presence of other common interfering gases like ethanol, benzene, and toluene. The electrochemical sensor fabricated to determine acetaminophen is prepared by coating NF onto the surface of pre-treated/cleaned pencil graphite electrode (NF-PGE). The common name of target analyte acetaminophen is paracetamol (PC), which is widespread worldwide as a well-known pain killer. Overdose of PC can cause renal failure even fatal diseases in children and demand accurate monitoring. Under optimal conditions NF-PGE shows a detection limit as low as 0.106 μM with selective detection ability towards acetaminophen in the presence of ascorbic acid (AA), which co-exists in our body. Use of cheap and abundant PGE instead of other electrodes (gold/Pt/glassy carbon electrode) can effectively reduce the cost barrier of such sensors. The obtained results elucidate an ample appeal of NF-sensors in real analytical applications viz. in environmental monitoring, pharmaceutical industry, drug detection, and health monitoring.

  15. Herbal hepatotoxicity: suspected cases assessed for alternative causes.

    Science.gov (United States)

    Teschke, Rolf; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel; Frenzel, Christian

    2013-09-01

    Alternative explanations are common in suspected drug-induced liver injury (DILI) and account for up to 47.1% of analyzed cases. This raised the question of whether a similar frequency may prevail in cases of assumed herb-induced liver injury (HILI). We searched the Medline database for the following terms: herbs, herbal drugs, herbal dietary supplements, hepatotoxic herbs, herbal hepatotoxicity, and herb-induced liver injury. Additional terms specifically addressed single herbs and herbal products: black cohosh, Greater Celandine, green tea, Herbalife products, Hydroxycut, kava, and Pelargonium sidoides. We retrieved 23 published case series and regulatory assessments related to hepatotoxicity by herbs and herbal dietary supplements with alternative causes. The 23 publications comprised 573 cases of initially suspected HILI; alternative causes were evident in 278/573 cases (48.5%). Among them were hepatitis by various viruses (9.7%), autoimmune diseases (10.4%), nonalcoholic and alcoholic liver diseases (5.4%), liver injury by comedication (DILI and other HILI) (43.9%), and liver involvement in infectious diseases (4.7%). Biliary and pancreatic diseases were frequent alternative diagnoses (11.5%), raising therapeutic problems if specific treatment is withheld; pre-existing liver diseases including cirrhosis (9.7%) were additional confounding variables. Other diagnoses were rare, but possibly relevant for the individual patient. In 573 cases of initially assumed HILI, 48.5% showed alternative causes unrelated to the initially incriminated herb, herbal drug, or herbal dietary supplement, calling for thorough clinical evaluations and appropriate causality assessments in future cases of suspected HILI.

  16. Potential protective effect of honey against paracetamol-induced hepatotoxicity.

    Science.gov (United States)

    Galal, Reem M; Zaki, Hala F; Seif El-Nasr, Mona M; Agha, Azza M

    2012-11-01

    Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates.  We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1β) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1β. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1β and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage.

  17. Incidence and risk of regorafenib-induced hepatotoxicity.

    Science.gov (United States)

    Zhao, Bin; Zhao, Hong

    2017-10-13

    Regorafenib, an oral multi-kinase inhibitor, has been approved for the treatments of several malignancies. Unlike traditional cytotoxic chemotherapeutic agents, regorafenib therapy often induces a distinct profile of adverse events (AEs) including hepatotoxicity. Here we conducted an up-to-date meta-analysis to assess the incidence and risk of regorafenib related hepatic toxicities. PubMed and Embase database were reviewed from inception to June 2017 for relevant trials. Eligible studies include subjects with solid tumors treated with 160 mg of regorafenib daily during the first three week of each four-week cycle, and adequate safety data reporting the elevation of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin. Statistical analyses were conducted to calculate the summary incidence and relative risk (RR). A total of 2,213 subjects from 14 trials were included. The incidences of regorafenib-associated all-grade and high-grade hepatotoxicity were: bilirubin elevation: 23% and 5%; AST elevation: 32% and 6%; ALT elevation: 27% and 5%; ALP elevation: 31% and 2%. Regorafenib-treated subjects had a significant increased risk of all-grade (RR = 3.10; 95% CI, 2.22-4.34) and high-grade (RR = 1.74; 95% CI, 1.09-2.80) bilirubin elevation; all-grade (RR = 1.51; 95% CI, 1.13-2.00) and high-grade (RR = 1.79; 95% CI, 1.00-3.22) AST elevation; all-grade (RR = 1.82; 95% CI, 1.25-2.64) and high-grade (RR = 3.07; 95% CI, 1.30-7.22) ALT elevation; and all-grade (RR = 2.11; 95% CI, 1.01-4.40) ALP elevation. Our results suggest that regorafenib is associated with an increased risk of hepatic toxicities. Hepatotoxicity examination at regular intervals should be advised to clinicians.

  18. Antioxidant modulation of nevirapine induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Awodele Olufunsho

    2015-03-01

    Full Text Available HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART. However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day, vitamin C (8 mg/kg/day, vitamin E (5 mg/kg/day and/or NVP (6 mg/kg/day for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (p<0.05 elevation in MDA level observed in the NVP group as compared with control. The results further showed non-significant decreases in the levels of MDA in the NVP plus antioxidant groups, except vitamin C, when compared with the NVP alone group. Vitamin E and Vitamin E plus C treated groups showed significantly (p<0.05 higher levels of SOD, CAT and GSH. The results also showed statistically significantly (p<0.05 lower levels of ALT and AST in the antioxidant treated groups There was an observed significantly (p<0.05 higher level of TP and urea in the antioxidant treated rats. A significantly (p<0.05 higher white blood cell count was observed in the antioxidant groups. Histopathological assessment of the liver extracted from the rats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART.

  19. Hepato-toxic effect of diuron in albino rats.

    Science.gov (United States)

    Agrawal, R C; Kumar, S

    1999-05-01

    Tumour initiating/promoting effect of diuron, a widely used substituted urea herbicide, was studied in rats using liver tumour model. Chronic exposure to diuron at a dose of 250 mg/kg body wt resulted in high mortality and weight loss in treated animals. The animals which received diuron + HCH treatment showed an increase in size and weight of liver as compared to controls. Liver tumours were not observed in any of the treated group whereas some significant histological changes were seen in diuron treated rat liver. Diuron thus has been found to be hepatotoxic albeit neither tumour initiating nor promoting in rat liver tumorigenesis assay system.

  20. Curcumin Attenuates Hepatotoxicity Induced by Zinc Oxide Nanoparticles in Rats

    Directory of Open Access Journals (Sweden)

    Layasadat Khorsandi

    2016-06-01

    Full Text Available Background: Zinc oxide nanoparticles (NZnO are increasingly used in modern life. Most metal nanoparticles have adverse effects on the liver. Aims: To explore the protective action of curcumin (Cur against hepatotoxicity induced by NZnO in rats. Study Design: Animal experimentation. Methods: Control group animals received normal saline, while the Cur group animals were treated with 200 mg/kg of Cur orally for 21 days. NZnO-intoxicated rats received 50 mg/kg of NZnO for 14 days by gavage method. In the NZnO+Cur group, rats were pretreated with Cur for 7 days before NZnO administration. Plasma activities of Alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP were measured as biomarkers of hepatotoxicity. Hepatic levels of malondialdehyde (MDA and superoxide dismutase (SOD and glutathione peroxidase (GPx activities were measured for detection of oxidative stress in liver tissue. Histological changes and apoptosis in liver tissue were studied by using Hematoxylin-eosin staining and the transferase dUTP nick end labeling (TUNEL method. Results: NZnO induced a significant increase in plasma AST (2.8-fold, ALT (2.7-fold and ALP (1.97-fold activity in comparison to the control group (p<0.01. NZnO increased MDA content and reduced SOD and GPx activities. NZnO caused liver damage including centrilobular necrosis and microvesicular steatosis. The percentage of apoptosis in hepatocytes was increased in NZnO-treated rats (p<0.01. Pre-treatment of Cur significantly reduced lipid peroxidation (39%, increased SOD (156% and GPx (26% activities, and attenuated ALT (47%, AST (41% and ALP (30% activities. Pre-treatment with Cur also decreased the histology changes and apoptotic index of hepatocytes (p<0.05. Conclusion: These findings indicate that Cur effectively protects against NZnO-induced hepatotoxicity in rats. However, future studies are required to propose Cur as a potential protective agent against hepatotoxicity

  1. Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial.

    Science.gov (United States)

    Janz, David R; Bastarache, Julie A; Rice, Todd W; Bernard, Gordon R; Warren, Melissa A; Wickersham, Nancy; Sills, Gillian; Oates, John A; Roberts, L Jackson; Ware, Lorraine B

    2015-03-01

    This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin. Single-center, randomized, double-blind, placebo-controlled phase II trial. Medical ICU in a tertiary, academic medical center. Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin. Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration. F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24-41) and placebo (36 pg/mL; interquartile range, 25-80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19-36) when compared with placebo (36 pg/mL; interquartile range, 23-55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6-1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83-2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599). In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.

  2. Fetal programming of mental health by acetaminophen? Response to the SMFM statement: prenatal acetaminophen use and ADHD.

    Science.gov (United States)

    Olsen, Jørn; Liew, Zeyan

    2017-12-01

    A number of studies indicate that acetaminophen taken during pregnancy may have a programming effect on the fetal brain development. The potential adverse consequences may only surface to clinical detection years later. Should we act on these findings now or do we wait for additional evidence? Areas covered: We argue for action inspired by these well analyzed studies that are based on five prospective cohorts data collected from different countries. Several analytical options have been employed especially to address confounding, and all analyses have consistently suggested that confounding alone is an unlikely explanation for this disturbing observation. Expert opinion: Acetaminophen is often used for minor symptom or discomfort where the treatment has no strong indication and carries little, if any risk for the pregnant women. The harm of doing nothing may well exceed the harm for taking precautionary actions considering the consequences at stake.

  3. Bisphenol A Induces Hepatotoxicity through Oxidative Stress in Rat Model

    Directory of Open Access Journals (Sweden)

    Zeinab K. Hassan

    2012-01-01

    Full Text Available Reactive oxygen species (ROS are cytotoxic agents that lead to significant oxidative damage. Bisphenol A (BPA is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to limited information concerning the effect of BPA on liver, this study investigates whether BPA causes hepatotoxicity by induction of oxidative stress in liver. Rats were divided into five groups: The first four groups, BPA (0.1, 1, 10, 50 mg/kg/day were administrated orally to rats for four weeks. The fifth group was taken water with vehicle. The final body weights in the 0.1 mg group showed a significant decrease compared to control group. Significant decreased levels of reduced glutathione, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase activity were found in the 50 mg BPA group compared to control groups. High dose of BPA (50 mg/kg significantly increased the biochemical levels of ALT, ALP and total bilirubin. BPA effect on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control. Data from this study demonstrate that BPA generate ROS and reduce the antioxidant gene expression that causes hepatotoxicity.

  4. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice.

    Science.gov (United States)

    Pan, Qiong; Sun, Yiming; Jin, Qili; Li, Qixiang; Wang, Qing; Liu, Hao; Zhao, Surong

    2016-11-01

    To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

  5. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J

    2016-04-09

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  6. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    Directory of Open Access Journals (Sweden)

    Miren García-Cortés

    2016-04-01

    Full Text Available Dietary supplements (DS are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™ while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang. Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  7. Engineered andrographolide nanosystems for smart recovery in hepatotoxic conditions

    Directory of Open Access Journals (Sweden)

    Roy P

    2014-10-01

    Full Text Available Partha Roy,1,2 Suvadra Das,1 Runa Ghosh Auddy,1,3 Arup Mukherjee1,3 1Division of Pharmaceutical and Fine Chemicals Technology, Department of Chemical Technology, University of Calcutta, Kolkata, India; 2Faculty of Technology (Pharmaceutical, Universiti Malaysia, Pahang, Malaysia; 3Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India Abstract: Andrographolide (AG is one of the most potent labdane diterpenoid-type free radical scavengers available from plant sources. The compound is the principal bioactive component in Andrographis paniculata leaf extracts, and is responsible for anti-inflammatory, anticancer, and immunomodulatory activity. The application of AG in therapeutics, however, is severely constrained, due to its low aqueous solubility, short biological half-life, and poor cellular permeability. Engineered nanoparticles in biodegradable polymer systems were therefore conceived as one solution to aid in further drug-like applications of AG. In this study, a cationic modified poly(lactic-co-glycolic acid nanosystem was applied for evaluation against experimental mouse hepatotoxic conditions. Biopolymeric nanoparticles of hydrodynamic size of 229.7±17.17 nm and ζ-potential +34.4±1.87 mV facilitated marked restoration in liver functions and oxidative stress markers. Superior dissolution for bioactive AG, hepatic residence, and favorable cytokine regulation in the liver tissues are some of the factors responsible for the newer nanosystem-assisted rapid recovery. Keywords: andrographolide, engineered nanosystems, poly(lactic-co-glycolic acid, cytokine regulation, hepatotoxicity

  8. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus.

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system.

  9. Bee sting therapy-induced hepatotoxicity: A case report.

    Science.gov (United States)

    Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

    2011-10-27

    The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo.

  10. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J.

    2016-01-01

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. PMID:27070596

  11. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Results: Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. Conclusion: The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system. PMID:26862277

  12. Fulminate Hepatic Failure in a 5 Year Old Female after Inappropriate Acetaminophen Treatment

    Directory of Open Access Journals (Sweden)

    Irena Kasmi

    2015-09-01

    CONCLUSION: Healthcare providers should considered probable acetaminophen toxicity in any child who has received the drug and presented with liver failure. When there is a high index of suspicion of acetaminophen toxicity NAC should be initiated and continued until there are no signs of hepatic dysfunction.

  13. Aerial Application of Acetaminophen treated Baits for Control of Brown Treesnakes

    Science.gov (United States)

    2016-01-22

    This procedure followed NWRC Analytical Method 96B -Determination of Acetaminophen in Tablets. Brown tree snake and non-target animal carcasses ...274 viii ACRONYM LIST APHIS Animal and Plant Health Inspection Service ATOC Aviation and Training Operations Center...native rodent abundance, and impacts to non-target animals . TECHNOLOGY DESCRIPTION Thawed DNM were treated by inserting an 80 mg acetaminophen

  14. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    NARCIS (Netherlands)

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of

  15. Bees’ Honey Attenuation of Metanil-Yellow-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Abdulrahman L. Al-Malki

    2013-01-01

    Full Text Available The present study aims to investigate the protective effect of bees’ honey against metanil-yellow-induced hepatotoxicity in rats. Rats were divided into 7 groups: control group; three groups treated with 50, 100, and 200 mg/kg metanil yellow, and three groups treated with metanil yellow plus 2.5 mg·kg-1·day-1 bees’ honey for 8 weeks. The obtained data showed that the antioxidant/anti-inflammatory activity of bees’ honey reduced the oxidative stress in the liver tissue and downregulated the inflammatory markers. In addition, the elevated levels of AGE and the activated NF-κB in the metanil-yellow-treated animals were significantly attenuated. Moreover, the levels of TNF-α and IL-1β were significantly attenuated as a result of bees’ honey administration. Furthermore, the histopathological examination of the liver showed that bees’ honey reduced fatty degeneration, cytoplasmic vacuolization, and necrosis in metanil-yellow-treated rats. In conclusion, the obtained data suggest that bees’ honey has hepatoprotective effect on acute liver injuries induced by metanil-yellow in vivo, and the results suggested that the effect of bees’ honey against metanil yellow-induced liver damage is related to its antioxidant/anti-inflammatory properties which attenuate the activation of NF-κB and its controlled genes like TNF-α and IL-1β.

  16. Oral metformin-ascorbic acid co-administration ameliorates alcohol-induced hepatotoxicity in rats.

    Science.gov (United States)

    Adeneye, A A; Benebo, A S

    2007-01-01

    Alcoholic liver disease remains a major cause of liver failure worldwide with no available curative or prophylactic therapy as at present. High dose metformin is reported to ameliorate liver injuries in both human and animal models of acute and chronic alcoholic liver injuries. The aim of the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure. In the present study, ameliorating effect of 200 mg/ kg/day of ascorbic acid (Asc), 500 mg/kg/day of metformin (Met) and their co-administration (Met-Asc) were investigated in 5 groups of 50% ethanol-treated male Wistar rats for 2 weeks of the experiment. The body weight of each rat was taken on days 1, 7, and 14 of the experiment, respectively. On day 15, fasted blood samples for plasma lipids and liver enzyme markers were collected via cardiac puncture from the rats under diethyl ether anaesthesia. Results showed that administration of graded oral doses of 50% ethanol for 14 days significantly (pcholesterol (PTC), high density lipoprotein (HDL-c), and low density lipoprotein (LDL-c). However, these elevations were significantly (pascorbic acid co-administration protected the liver against the deleterious effects of chronic high dose alcohol and the hepatoprotective effect of Met-Asc appeared to be due mainly to the metformin molecule of the drug combination. However, further studies would be required to evaluate the mechanisms underlying the observed effects.

  17. Association of prenatal exposure to acetaminophen and coffee with childhood asthma

    DEFF Research Database (Denmark)

    Liu, Xiaoqin; Liew, Zeyan; Olsen, Jørn

    2016-01-01

    PurposeSome studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma......, and whether such a potential association could be modified by maternal coffee consumption. MethodsWe included 63 652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire...... and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards...

  18. Conjugation of nitrated acetaminophen to Der p1 amplifies peripheral blood monocyte response to Der p1.

    Directory of Open Access Journals (Sweden)

    Ryan G Thomas

    Full Text Available An association of acetaminophen use and asthma was observed in the International Study of Asthma and Allergies in Childhood study. However there are no clear mechanisms to explain an association between acetaminophen use and immunologic pathology. In acidic conditions like those in the stomach and inflamed airway, tyrosine residues are nitrated by nitrous and peroxynitrous acids. The resulting nitrotyrosine is structurally similar to 2,4-dinitrophenol and 2,4-dinitrochlorobenzene, known haptens that enhance immune responses by covalently binding proteins. Nitrated acetaminophen shares similar molecular structure.We hypothesized the acetaminophen phenol ring undergoes nitration under acidic conditions, producing 3-nitro-acetaminophen which augments allergic responses by acting as a hapten for environmental allergens.3-nitro-acetaminophen was formed from acetaminophen in the presence of acidified nitrite, purified by high performance liquid chromatography, and assayed by gas-chromatography mass spectrometry. Purified 3-nitro-acetaminophen was reacted with Dermatophagoides pteronyssinus (Der p1 and analyzed by mass spectrometry to identify the modification site. Human peripheral blood mononuclear cells proliferation response was measured in response to 3-nitro-acetaminophen and to 3-nitro-acetaminophen-modified Der p1.Acetaminophen was modified by nitrous acid forming 3-nitro-acetaminophen over a range of different acidic conditions consistent with airway inflammation and stomach acidity. The Der p1 protein-hapten adduct creation was confirmed by liquid chromatography-mass spectrometry proteomics modifying cysteine 132. Peripheral blood mononuclear cells exposed to 3-nitro-acetaminophen-modified Der p1 had increased proliferation and cytokine production compared to acetaminophen and Der p1 alone (n = 7; p < 0.05.These data suggests 3-nitro-acetaminophen formation and reaction with Der p1 provides a mechanism by which stomach acid or infection

  19. Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    Pajaree Sriuttha

    2018-01-01

    Full Text Available Background. Nonsteroidal anti-inflammatory drugs (NSAIDs are the most widely used medication in several countries, including Thailand. NSAIDs have been associated with hepatic side effects; however, the frequency of these side effects is uncertain. Aim of the Review. To systematically review published literature on randomized, controlled trials that assessed the risk of clinically significant hepatotoxicity associated with NSAIDs. Methods. Searches of bibliographic databases EMBASE, PubMed, and the Cochrane Library were conducted up to July 30, 2016, to identify randomized controlled trials of ibuprofen, naproxen, diclofenac, piroxicam, meloxicam, mefenamic acid, indomethacin, celecoxib, and etoricoxib in adults with any disease that provide information on hepatotoxicity outcomes. Results. Among the 698 studies, 18 studies met the selection criteria. However, only 8 studies regarding three NSAIDs (celecoxib, etoricoxib, and diclofenac demonstrated clinically significant hepatotoxic evidence based on hepatotoxicity justification criteria. Of all the hepatotoxicity events found from the above-mentioned three NSAIDs, diclofenac had the highest proportion, which ranged from 0.015 to 4.3 (×10−2, followed by celecoxib, which ranged from 0.13 to 0.38 (×10−2, and etoricoxib, which ranged from 0.005 to 0.930 (×10−2. Conclusion. Diclofenac had higher rates of hepatotoxic evidence compared to other NSAIDs. Hepatotoxic evidence is mostly demonstrated as aminotransferase elevation, while liver-related hospitalization or discontinuation was very low.

  20. Hepatotoxicity associated with microcystin/ Hepatotoxicidade associada à microcistina

    Directory of Open Access Journals (Sweden)

    Ana Paula Frederico Rodrigues Loureiro Bracarense

    2008-08-01

    Full Text Available Urban and industrial discharges, intense agricultural exploitation and fisheries have been causing the eutrophication in both drinking and recreational waters. A frequent consequence of eutrophication in waters is the massive development of cyanobacteria. The occurrence of these blooms induces a severe problem, as Microcystis aeruginosa, the most widespread distributed cyanobacteria, can produce microcystins (MC. Toxic effects of MC have been described in liver, lungs, stomach, and intestine. Deaths in wildlife, livestock and human beings were also associated with MC exposition. MC exposition can occurs directly by ingestion, inhalation, contact, intravenous inoculation of contaminated water (hemodialysis or indirectly, by the consumption of animals, as fish and mollusks, the majors ingestors of cyanobacteria and its toxins. The most toxic MC, an also the most common is microcystin-LR (MC-LR, that has the liver as the main target organ. Microcystin is taken up specifically into the liver by bile acid transporters and, after entering the cytoplasm, inhibit protein phosphatases 1 and 2A, which leads to the increase in protein phosphorylation. This effect has two main consequences: the destruction of cytoskeleton directly causing cytotoxic effects, and deregulation of cell division, leading to tumor-promoting activity. Acute exposition to MC induces severe intrahepatic hemorrhage, necrosis and apoptosis, while chronic exposure can cause hepatic or intestinal neoplasia. It has been documented that MC hepatotoxicity is closely associated with intracellular reactive oxygen species formation. Natural degradation of microcystins depends on the solar radiation and bacteria. If degradation is insufficient, MC will persist in the freshwater food chain. Microcystin contamination of waters is therefore a hazard to human and animal health, so efforts to avoid eutrophication of waters sources are essential, in order to minimize the risks to public health

  1. Hepatoprotective effect of fermented ginseng and its major constituent compound K in a rat model of paracetamol (acetaminophen)-induced liver injury.

    Science.gov (United States)

    Igami, Kentaro; Shimojo, Yosuke; Ito, Hisatomi; Miyazaki, Toshitsugu; Kashiwada, Yoshiki

    2015-04-01

    This work aimed at evaluating the effect of fermented ginseng (FG) and fermented red ginseng (FRG) against rat liver injury caused by paracetamol (acetaminophen (APAP)). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and histopathological changes in the liver were analysed to determine the degree of liver injury. Deoxyribonucleic acid (DNA) microarray analysis was performed to compare gene expression levels altered in the rat livers. Phosphorylated Jun-N-terminal kinase (JNK) in human hepatocellular carcinoma (HepG2) cells were detected using western blot analysis to investigate the anti-inflammatory activity of compound K. Pretreatment with FG, containing compound K at high concentration, attenuated AST as well as ALT levels in rats, while no obvious effect was observed in the group that received FRG, whose content of compound K was lower than that of FG. In addition, the results of our histopathological analysis were consistent with changes in the serum biochemical analysis. DNA microarray analysis indicated that JNK- and glutathione S-transferase (GST)-related genes were involved in the hepatotoxicity. Notably, compound K, a major ginsenoside in FG, inhibited the phosphorylation of JNK in HepG2 cells. FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver. © 2014 Royal Pharmaceutical Society.

  2. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

    Directory of Open Access Journals (Sweden)

    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

  3. Acute liver failure and self-medication.

    Science.gov (United States)

    de Oliveira, André Vitorio Câmara; Rocha, Frederico Theobaldo Ramos; Abreu, Sílvio Romero de Oliveira

    2014-01-01

    Not responsible self-medication refers to drug use in high doses without rational indication and often associated with alcohol abuse. It can lead to liver damage and drug interactions, and may cause liver failure. To warn about how the practice of self-medication can be responsible for acute liver failure. Were used the Medline via PubMed, Cochrane Library, SciELO and Lilacs, and additional information on institutional sites of interest crossing the headings acute liver failure [tiab] AND acetaminophen [tiab]; self-medication [tiab] AND acetaminophen [tiab]; acute liver failure [tiab] AND dietary supplements [tiab]; self-medication [tiab] AND liver failure [tiab] and self-medication [tiab] AND green tea [tiab]. In Lilacs and SciELO used the descriptor self medication in Portuguese and Spanish. From total surveyed were selected 27 articles and five sites specifically related to the purpose of this review. Legislation and supervision disabled and information inaccessible to people, favors the emergence of cases of liver failure drug in many countries. In the list of released drugs that deserve more attention and care, are some herbal medicines used for the purpose of weight loss, and acetaminophen. It is recommended that institutes of health intensify supervision and better orient their populations on drug seemingly harmless, limiting the sale of products or requiring a prescription for release them.

  4. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats

    International Nuclear Information System (INIS)

    Kalender, Yusuf; Yel, Mustafa; Kalender, Suna

    2005-01-01

    Doxorubicin (DXR) is an anthracycline antibiotic, broady used in tumor therapy. In the present study we investigated whether vitamin E and catechin can reduce the toxic effects of doxorubicin. Vitamin E (200 IU/kg/week), catechin (200 mg/kg/week), doxorubicin (5 mg/kg/week), doxorubicin + vitamin E (200 IU/kg/week), doxorubicin + catechin (200 mg/kg/week) combinations were given to rats weighing 210-230 g (n = 6/group). Changes in major enzymes participating in free radical metabolism superoxide dismutase (Cu,Zn-SOD), glutathione peroxidase (GSHPx), catalase (CAT) and malondialdehyde (MDA) were evaluated in the livers of all animals. Superoxide dismutase and catalase activity increased in the doxorubicin-treated group compared to control (P 0.05). Electron microscopic studies supported biochemical findings. We conclude that vitamin E and catechin significantly reduce doxorubicin-induced hepatotoxicity in rats

  5. Possible hepatotoxic consequence of nevirapine use in juvenile albino rats

    Directory of Open Access Journals (Sweden)

    Elias Adikwu

    2017-08-01

    Full Text Available Context: Nevirapine (NVP is used in human immunodeficiency virus exposed neonates. This could present safety concern due to decreased liver metabolizing enzymes activity and renal clearance in neonates. Aims: To determine the hepatotoxic effect of NVP in juvenile albino rats. Methods: Juvenile albino rats were weighed, divided into groups and treated orally with 4-32 mg/kg/day of NVP for 14 days including a recovery group. The control groups were treated with water (placebo and normal saline (solvent. At the end of NVP treatment, rats were weighed and sacrificed, blood was collected and serum extracted. Serum was analyzed for alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, total bilirubin (TB and conjugated bilirubin (CB. The liver was harvested via dissection, weighed and evaluated for AST, ALT, ALP, superoxide dismutase (SOD, catalase (CAT, glutathione (GSH, malondialdehyde (MDA levels and histological damage. Results: The body, absolute and relative liver weights of rats in NVP treated groups were not significantly different (p>0.05 when compared to placebo. However, serum levels of AST, ALT, ALP, TB and CB were significantly increased (p<0.05 in a dose-dependent manner in NVP-treated groups. Furthermore, liver levels of ALT, ALP, AST and MDA were significantly increased (p<0.05 while SOD, CAT, and GSH were decreased in a dose dependent manner in NVP-treated groups. NVP-treated rats were characterized by varying degrees of hepatic morphological alterations. However, in the recovery group, the effects of NVP were reversed. Conclusions: This study observed dose-dependent and reversible hepatotoxicity in nevirapine- treated juvenile albino rats.

  6. Hepatotoxicity and genotoxicity of gasoline fumes in albino rats

    Directory of Open Access Journals (Sweden)

    Folarin O. Owagboriaye

    2017-09-01

    Full Text Available Toxic effects of gasoline fumes have been reported, but evidence of its hepatotoxicity and genotoxicity are rare. Therefore, this study assesses hepatotoxicity and genotoxicity of gasoline fumes on forty Albino rats randomly assigned to five experimental treatments (T with eight rats per treatment (T1, T2, T3, T4 and T5. T1(Control was housed in a section of experimental animal house free from gasoline fumes while T2, T3, T4 and T5 were exposed to gasoline fumes in exposure chambers for one, three, five and nine hours daily respectively for twelve weeks. Serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP and histopathological examination of the liver tissues were used as diagnostic markers to assess liver dysfunction. Genotoxicity test was conducted on the lung tissues using randomly amplified polymorphic DNA fingerprinting polymerase chain reaction (RAPD PCR technique. Significant increase (p < 0.05 in the level of ALT, AST and ALP for T2, T3, T4 and T5 compared to T1 were recorded. Photomicrograph examination of the liver sections of T1 showed hepatic tissue with normal liver cell architecture while that of T2, T3, T4 and T5 revealed degenerative changes in the ultrastructural integrity of the hepatic cells. Genotoxicity test revealed DNA bands at a reducing intensity from T1 to T5. Dendrogram showed DNA damage in the lungs of T3, T4 and T5 were closely similar and the genotoxic impact was more in T3. Frequent exposure to gasoline fumes was observed to induce hepatoxicity and genotoxicity, hence impairing the normal liver function and gene structure.

  7. The effect of acetaminophen nanoparticles on liver toxicity in a rat model

    Directory of Open Access Journals (Sweden)

    Esmaeil Biazar

    2010-03-01

    Full Text Available Esmaeil Biazar1, S Mahdi Rezayat2, Naser Montazeri1, Khalil Pourshamsian1, Reza Zeinali3, Azadeh Asefnejad3, Mehdi Rahimi3, Mohammadmajid Zadehzare3, Mehran Mahmoudi3, Rohollah Mazinani3, Mehdi Ziaei31Department of Chemistry, Islamic Azad University, Tonekabon Branch, Mazandaran, Iran; 2Department of Pharmacology, School of Medicine, Tehran University of Medical Science, Tehran, Iran; 3Biomedical Engineering, Islamic Azad University, Research and Science Branch, Tehran, IranAbstract: Acetaminophen, a pain-reliever, is one of the most widely used medications in the world. Acetaminophen with normal dosage is considered a nontoxic drug for therapeutic applications, but when taken at overdose levels it produces liver damage in human and various animal species. By a high energy mechanically activated method, we produced acetaminophen in a nanometer crystalline size (24 nm. Forty-eight hours after injection of crystalline particles with normal and reduced size of our drug, the effect of liver toxicity was compared by determination of liver transferase enzymes such as alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase (ALT. These enzymes were examined by routine colorimetric methods using commercial kits and pathologic investigations. Statistical analysis and pathological figures indicated that ALT delivery and toxicity in reduced size acetaminophen was significantly reduced when compared with normal size acetaminophen. Pathology figures exhibited reduced necrosis effects, especially the confluent necrosis, in the central part of the lobule in the reduced size acetaminophen samples when compared with the normal samples.Keywords: acetaminophen, size reduction, pathological and enzymatic investigations, toxicity

  8. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years.

    Directory of Open Access Journals (Sweden)

    John M D Thompson

    Full Text Available OBJECTIVE: Our aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children. METHODS: Participants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress. RESULTS: Acetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11 if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners' Parent Rating Scale-Revised. CONCLUSIONS: These findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen.

  9. Associations between Acetaminophen Use during Pregnancy and ADHD Symptoms Measured at Ages 7 and 11 Years

    Science.gov (United States)

    Thompson, John M. D.; Waldie, Karen E.; Wall, Clare R.; Murphy, Rinky; Mitchell, Edwin A.

    2014-01-01

    Objective Our aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children. Methods Participants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics) were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress. Results Acetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11) if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners’ Parent Rating Scale-Revised). Conclusions These findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen. PMID:25251831

  10. Leflunomide for the treatment of rheumatoid arthritis in clinical practice: Incidence and severity of hepatotoxicity

    NARCIS (Netherlands)

    Van Roon, Eric N.; Jansen, Tim L.Th.A.; Houtman, Nella M.; Spoelstra, Piet; Brouwers, Jacobus R.B.J.

    2004-01-01

    Objective: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of

  11. Role and mechanisms of autophagy in acetaminophen-induced liver injury.

    Science.gov (United States)

    Chao, Xiaojuan; Wang, Hua; Jaeschke, Hartmut; Ding, Wen-Xing

    2018-04-23

    Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Acetaminophen/paracetamol: A history of errors, failures and false decisions.

    Science.gov (United States)

    Brune, K; Renner, B; Tiegs, G

    2015-08-01

    Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side-effect 'epidemy' (phenacetin nephropathy, drug-induced interstitial nephritis) and ends with the discovery of second-generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound. © 2014 European Pain Federation - EFIC®

  13. Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring.

    Science.gov (United States)

    Andrade, Chittaranjan

    2016-02-01

    Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%-65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention-deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring. © Copyright 2016 Physicians Postgraduate Press, Inc.

  14. Predicting Hepatotoxicity of Drug Metabolites Via an Ensemble Approach Based on Support Vector Machine

    Science.gov (United States)

    Lu, Yin; Liu, Lili; Lu, Dong; Cai, Yudong; Zheng, Mingyue; Luo, Xiaomin; Jiang, Hualiang; Chen, Kaixian

    2017-11-20

    Drug-induced liver injury (DILI) is a major cause of drug withdrawal. The chemical properties of the drug, especially drug metabolites, play key roles in DILI. Our goal is to construct a QSAR model to predict drug hepatotoxicity based on drug metabolites. 64 hepatotoxic drug metabolites and 3,339 non-hepatotoxic drug metabolites were gathered from MDL Metabolite Database. Considering the imbalance of the dataset, we randomly split the negative samples and combined each portion with all the positive samples to construct individually balanced datasets for constructing independent classifiers. Then, we adopted an ensemble approach to make prediction based on the results of all individual classifiers and applied the minimum Redundancy Maximum Relevance (mRMR) feature selection method to select the molecular descriptors. Eventually, for the drugs in the external test set, a Bayesian inference method was used to predict the hepatotoxicity of a drug based on its metabolites. The model showed the average balanced accuracy=78.47%, sensitivity =74.17%, and specificity=82.77%. Five molecular descriptors characterizing molecular polarity, intramolecular bonding strength, and molecular frontier orbital energy were obtained. When predicting the hepatotoxicity of a drug based on all its metabolites, the sensitivity, specificity and balanced accuracy were 60.38%, 70.00%, and 65.19%, respectively, indicating that this method is useful for identifying the hepatotoxicity of drugs. We developed an in silico model to predict hepatotoxicity of drug metabolites. Moreover, Bayesian inference was applied to predict the hepatotoxicity of a drug based on its metabolites which brought out valuable high sensitivity and specificity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms.

    Science.gov (United States)

    Chen, Yan; Guo, Jeff J; Healy, Daniel P; Lin, Xiaodong; Patel, Nick C

    2008-12-01

    With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin. To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs). Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin. A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS. A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.

  16. Paracetamol/acetaminophen (single administration) for perineal pain in the early postpartum period.

    Science.gov (United States)

    Chou, Doris; Abalos, Edgardo; Gyte, Gillian M L; Gülmezoglu, A Metin

    2013-01-31

    Perineal pain is a common but poorly studied adverse outcome following childbirth. Pain may result from perineal trauma due to bruising, spontaneous tears, surgical incisions (episiotomies), or in association with operative births (ventouse or forceps assisted births). To determine the efficacy of a single administration of paracetamol (acetaminophen) systemic drugs used in the relief of acute postpartum perineal pain We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 6 November 2012. Randomised controlled trials (RCTs) assessing paracetamol (acetaminophen) in a single dose compared with placebo for women with early postpartum perineal pain. We excluded quasi-RCTs and cross-over studies. Two review authors assessed each paper for inclusion and extracted data. One review author reviewed the decisions and confirmed calculations for pain relief scores. We did not identify any new trials from the updated search so the results remain unchanged as follows.We have included 10 studies describing two dosages of paracetamol. Of these, five studies (526 women) assessed 500 mg to 650 mg and six studies (841 women) assessed 1000 mg of paracetamol. We chose to use random-effects meta-analyses because of the heterogeneity in dosage used. Studies were from the 1970s to the early 1990s, and there was insufficient information to assess the risk of bias adequately, hence the findings need to be interpreted within this context.More women experienced pain relief with paracetamol compared with placebo (average risk ratio (RR) 2.14, 95% confidence interval (CI) 1.59 to 2.89, 10 studies, 1279 women). In addition, there were significantly fewer women having additional pain relief with paracetamol compared with placebo (RR 0.34, 95% CI 0.21 to 0.55, eight studies, 1132 women). Both the 500 mg to 650 mg and 1000 mg doses were effective in providing more pain relief than placebo.Maternal and neonatal potential adverse drug effects were not assessed in

  17. Hepatotoxicity evaluation of traditional Chinese medicines using a computational molecular model.

    Science.gov (United States)

    Zhao, Pan; Liu, Bin; Wang, Chunya

    2017-11-01

    Liver injury caused by traditional Chinese medicines (TCMs) is reported from many countries around the world. TCM hepatotoxicity has attracted worldwide concerns. This study aims to develop a more applicable and optimal tool to evaluate TCM hepatotoxicity. A quantitative structure-activity relationship (QSAR) analysis was performed based on published data and U.S. Food and Drug Administration's Liver Toxicity Knowledge Base (LTKB). Eleven herbal ingredients with proven liver toxicity in the literature were added into the dataset besides chemicals from LTKB. The finally generated QSAR model yielded a sensitivity of 83.8%, a specificity of 70.1%, and an accuracy of 80.2%. Among the externally tested 20 ingredients from TCMs, 14 hepatotoxic ingredients were all accurately identified by the QSAR model derived from the dataset containing natural hepatotoxins. Adding natural hepatotoxins into the dataset makes the QSAR model more applicable for TCM hepatotoxicity assessment, which provides a right direction in the methodology study for TCM safety evaluation. The generated QSAR model has the practical value to prioritize the hepatotoxicity risk of TCM compounds. Furthermore, an open-access international specialized database on TCM hepatotoxicity should be quickly established.

  18. Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

    Science.gov (United States)

    Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J

    2016-01-01

    MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.

  19. A novel transcriptomics based in vitro method to compare and predict hepatotoxicity based on mode of action

    International Nuclear Information System (INIS)

    De Abrew, K. Nadira; Overmann, Gary J.; Adams, Rachel L.; Tiesman, Jay P.; Dunavent, John; Shan, Yuqing K.; Carr, Gregory J.; Daston, George P.; Naciff, Jorge M.

    2015-01-01

    High-content data have the potential to inform mechanism of action for toxicants. However, most data to support this notion have been generated in vivo. Because many cell lines and primary cells maintain a differentiated cell phenotype, it is possible that cells grown in culture may also be useful in predictive toxicology via high-content approaches such as whole-genome microarray. We evaluated global changes in gene expression in primary rat hepatocytes exposed to two concentrations of ten hepatotoxicants: acetaminophen (APAP), β-naphthoflavone (BNF), chlorpromazine (CPZ), clofibrate (CLO), bis(2-ethylhexyl)phthalate (DEHP), diisononyl phthalate (DINP), methapyrilene (MP), valproic acid (VPA), phenobarbital (PB) and WY14643 at two separate time points. These compounds were selected to cover a range of mechanisms of toxicity, with some overlap in expected mechanism to address the question of how predictive gene expression analysis is, for a given mode of action. Gene expression microarray analysis was performed on cells after 24 h and 48 h of exposure to each chemical using Affymetrix microarrays. Cluster analysis suggests that the primary hepatocyte model was capable of responding to these hepatotoxicants, with changes in gene expression that appear to be mode of action-specific. Among the different methods used for analysis of the data, a combination method that used pathways (MOAs) to filter total probesets provided the most robust analysis. The analysis resulted in the phthalates clustering closely together, with the two other peroxisome proliferators, CLO and WY14643, eliciting similar responses at the whole-genome and pathway levels. The Cyp inducers PB, MP, CPZ and BNF also clustered together. VPA and APAP had profiles that were unique. A similar analysis was performed on externally available (TG-GATES) in vivo data for 6 of the chemicals (APAP, CLO, CPZ, MP, MP and WY14643) and compared to the in vitro result. These results indicate that transcription

  20. Effect of Intravenous Acetaminophen on Postoperative Opioid Use in Bariatric Surgery Patients

    OpenAIRE

    Wang, Shan; Saha, Ronik; Shah, Neal; Hanna, Adel; DeMuro, Jonas; Calixte, Rose; Brathwaite, Collin

    2015-01-01

    Opioids are often used to relieve pain after surgery, but they are associated with serious adverse effects. In this retrospective chart-review analysis, the use of intravenous acetaminophen did not reduce opioid use following bariatric surgery.

  1. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

    DEFF Research Database (Denmark)

    van den Driesche, Sander; Macdonald, Joni; Anderson, Richard A

    2015-01-01

    Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons...

  2. Sleep Disruption and Proprioceptive Delirium due to Acetaminophen in a Pediatric Patient

    Directory of Open Access Journals (Sweden)

    Carla Carnovale

    2013-01-01

    Full Text Available We present the case of a 7-year-old boy, who received acetaminophen for the treatment of hyperpyrexia, due to an infection of the superior airways. 13 mg/kg (260 mg of acetaminophen was administered orally before bedtime, and together with the expected antipyretic effect, the boy experienced sleep disruption and proprioceptive delirium. The symptoms disappeared within one hour. In the following six months, acetaminophen was administered again twice, and the reaction reappeared with similar features. Potential alternative explanations were excluded, and analysis with the Naranjo algorithm indicated a “probable” relationship between acetaminophen and this adverse reaction. We discuss the potential mechanisms involved, comprising imbalances in prostaglandin levels, alterations of dopamine, and cannabinoid and serotonin signalings.

  3. Modulatory potentials of the aqueous stem bark extract of Mangifera indica on carbon tetrachloride-induced hepatotoxicity in rats

    Science.gov (United States)

    Adeneye, Adejuwon Adewale; Awodele, Olufunsho; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

    2015-01-01

    group, with more protection offered in the curative than the chemopreventive models of CCl4 hepatotoxicity. Thus, these results indicate that MIASE has a profound protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its free radicals scavenging effect, inhibition of lipid peroxidation, and its ability to increase antioxidant activity. PMID:26151020

  4. Modulatory potentials of the aqueous stem bark extract of Mangifera indica on carbon tetrachloride-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Adejuwon Adewale Adeneye

    2015-04-01

    group, with more protection offered in the curative than the chemopreventive models of CCl4 hepatotoxicity. Thus, these results indicate that MIASE has a profound protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its free radicals scavenging effect, inhibition of lipid peroxidation, and its ability to increase antioxidant activity.

  5. Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats

    International Nuclear Information System (INIS)

    Xu, Ming-Yuan; Wang, Pan; Sun, Ying-Jian; Wu, Yi-Jun

    2017-01-01

    Pesticides and heavy metals are widespread environmental pollutants. Although the acute toxicity of organophosphorus pesticide chlorpyrifos (CPF) and toxic heavy metal cadmium (Cd) is well characterized, the combined toxicity of CPF and Cd, especially the hepatotoxicity of the two chemicals with long-term exposure at a low dose, remained unclear. In this study, we investigated the toxicity in the liver of rats upon subchronic exposure to CPF and Cd at environmentally relevant doses. Rats were given three different doses (1/135 LD 50 , 1/45 LD 50 and 1/15 LD 50 ) of CPF and Cd as well as their mixtures by oral gavage for 90 days. After treatment, the liver tissues were subjected to histopathological examination and biochemical analysis. Gas chromatography-mass spectrometry (GC–MS) was used to analyze the metabolomic changes in the rat liver upon CPF, Cd and their mixtures treatment. The results showed that CPF and Cd-induced oxidative damage and disrupted energy, amino acid, and fatty acid metabolism in the liver. Eleven biomarkers in liver were identified for CPF-, Cd-, and their mixture-treated rats. Three metabolites, i.e., butanedioic acid, myo-inositol, and urea, were identified as unique biomarkers for the mixture-treated rats. Moreover, we found that Cd could accelerate the metabolism of CPF in the liver when given together to the rats, which may lead to the potential antagonistic interaction between CPF and Cd. In conclusion, our results indicated that even at environmentally relevant doses, CPF and Cd could disrupt the liver metabolism. In addition, the accelerated metabolism of CPF by Cd may lead to their potential antagonistic interaction.

  6. Ipomoea aquatica Extract Shows Protective Action Against Thioacetamide-Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    A. Hamid A. Hadi

    2012-05-01

    Full Text Available In the Indian system of traditional medicine (Ayurveda it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD rats were orally fed with I. aquatica (250 and 500 mg/kg for two months along with administration of TAA (i.p injection 200 mg/kg three times a week for two months. The results showed that the treatment of I. aquatica significantly lowered the TAA-induced serum levels of hepatic enzyme markers (ALP, ALT, AST, protein, albumin, bilirubin and prothrombin time. The hepatic content of activities and expressions SOD and CAT that were reduced by TAA were brought back to control levels by the plant extract supplement. Meanwhile, the rise in MDA level in the TAA receiving groups also were significantly reduced by I. aquatica treatment. Histopathology of hepatic tissues by H&E and Masson trichrome stains displayed that I. aquatica has reduced the incidence of liver lesions, including hepatic cells cloudy swelling, infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by TAA in rats. Therefore, the results of this study show that the protective effect of I. aquatica in TAA-induced liver damage might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects. Moreover, it confirms a scientific basis for the traditional use of I. aquatica for the treatment of liver disorders.

  7. Association Between Prenatal Acetaminophen Exposure and Future Risk of Attention Deficit/Hyperactivity Disorder in Children.

    Science.gov (United States)

    Hoover, Rebecca M; Hayes, V Autumn Gombert; Erramouspe, John

    2015-12-01

    To evaluate the effect of prenatal acetaminophen exposure on the future development of attention deficit/hyperactivity disorder (ADHD) in children. Literature searches of MEDLINE (1975 to June 2015), International Pharmaceutical Abstracts (1975 to June 2015), and Cochrane Database (publications through June 2015) for prospective clinical trials assessing the relationship of prenatal acetaminophen exposure and the development of attention deficit disorders or hyperactivity. Studies comparing self-reported maternal acetaminophen use during pregnancy to development of ADHD or ADHD-like behaviors in offspring between the ages of 3 and 12 years. Four studies examining the effects of prenatal acetaminophen exposure on subsequent ADHD behaviors were identified. Of these, one early study found no link to ADHD behaviors while the other studies found statistically significant correlations with the most prominent being a study finding a higher risk for using ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44) or having ADHD-like behaviors at age 7 years as determined by the Strengths and Difficulties Questionnaire (risk ratio = 1.13; 95% CI, 1.01-1.27) in children whose mothers used acetaminophen during pregnancy. While there does appear to be a mild correlation between prenatal acetaminophen use and the development of ADHD symptoms in children, current data do not provide sufficient evidence that prenatal acetaminophen exposure leads to development of ADHD symptoms late in life. Acetaminophen is a preferred option for pain management during pregnancy when compared with other medications such as nonsteroidal anti-inflammatory drugs or opioids for pyretic or pain relief. © The Author(s) 2015.

  8. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism

    DEFF Research Database (Denmark)

    Jensen, Morten Søndergaard; Rebordosa, Cristina; Thulstrup, Ane Marie

    2010-01-01

    Cyclooxygenase (COX) inhibitors-acetaminophen, ibuprofen and acetylsalicylic acid-have endocrine-disruptive properties in the rainbow trout. In humans, aspirin blocks the androgen response to human chorionic gonadotropin (hCG), and, because hCG-stimulated androgen production in utero is crucial...... for normal testicular descent, exposure to COX inhibitors at vulnerable times during gestation may impair testicular descent. We examined whether prenatal exposure to acetaminophen, ibuprofen, and acetylsalicylic acid was associated with increased occurrence of cryptorchidism....

  9. Can mixtures of cyanotoxins represent a risk to the zooplankton? The case study of Daphnia magna Straus exposed to hepatotoxic and neurotoxic cyanobacterial extracts.

    Science.gov (United States)

    Freitas, Emanuela Cristina; Pinheiro, Carlos; Rocha, Odete; Loureiro, Susana

    2014-01-01

    Worldwide, cyanobacterial blooms have been increasing in intensity and frequency, with toxic cyanobacteria sometimes dominant throughout the year in many freshwater bodies. Since the coexistence of more than one type of cyanotoxins in freshwater environments is a common phenomenon, studies on the joint effects of these toxins would be very useful. In this study, the single and combined effects of two cyanotoxins with different modes of action (hepatotoxic and neurotoxic) on the survival (lethal exposure) and feeding (sublethal exposure) of the cladoceran Daphnia magna were investigated. With the single exposures, it was observed that both the survival and feeding activity of the daphnids were impaired by the hepatotoxic and neurotoxic extracts at environmentally relevant concentrations. In the combined exposures, both survival and feeding rate endpoints showed a good fit to the independent action model. For the acute assay and 24h exposure period in the feeding inhibition test, there was no interaction between components of the hepatotoxic and neurotoxic extracts, although a slight tendency to a synergistic deviation could be seen in the feeding rates. On the other hand, for the 4h post-exposure period, a synergistic deviation was found in feeding rates at all mixture concentrations tested. Hence, the combined exposure of hepatotoxins and neurotoxins should also be taken into account in risk assessments of freshwater bodies, since the mixture of these toxins can result in more severe post-exposure effects on the feeding of daphnids than the sum of those expected for single exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. LC-MS/MS method development for quantitative analysis of acetaminophen uptake by the aquatic fungus Mucor hiemalis.

    Science.gov (United States)

    Esterhuizen-Londt, Maranda; Schwartz, Katrin; Balsano, Evelyn; Kühn, Sandra; Pflugmacher, Stephan

    2016-06-01

    Acetaminophen is a pharmaceutical, frequently found in surface water as a contaminant. Bioremediation, in particular, mycoremediation of acetaminophen is a method to remove this compound from waters. Owing to the lack of quantitative analytical method for acetaminophen in aquatic organisms, the present study aimed to develop a method for the determination of acetaminophen using LC-MS/MS in the aquatic fungus Mucor hiemalis. The method was then applied to evaluate the uptake of acetaminophen by M. hiemalis, cultured in pellet morphology. The method was robust, sensitive and reproducible with a lower limit of quantification of 5 pg acetaminophen on column. It was found that M. hiemalis internalize the pharmaceutical, and bioaccumulate it with time. Therefore, M. hiemalis was deemed a suitable candidate for further studies to elucidate its pharmaceutical tolerance and the longevity in mycoremediation applications. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. High-performance liquid chromatographic assay for acetaminophen and phenacetin in the presence of their metabolites in biological fluids

    International Nuclear Information System (INIS)

    Pang, K.S.; Taburet, A.M.; Hinson, J.A.; Gillette, J.R.

    1979-01-01

    The authors propose a method in which tracer amounts of a radiolabeled compound are used as the internal standard for the same unlabeled compound in high-performance liquid chromatography. The approach is valuable when a response from the internal standard becomes undesirable due to the presence of interference by the metabolites. The authors tested their approach with phenacetin and its metabolites, 2-hydroxyphenacetin, N-hydroxyphenacetin, phenetidine, acetaminophen sulfate conjugate and acetaminophen glucuronide conjugate in biological fluids with the use of [ 14 C] phenacetin and [ 3 H] acetaminophen as the internal standards, and were able to quantitate both phenacetin and acetaminophen simultaneously. They also tested the alternative approach in which the unlabeled drug was used as internal standard for tracer amounts of the same radiolabeled compound, with phenacetin and acetaminophen as the internal standards for tracer amounts of [ 14 C] phenacetin and [ 3 H] acetaminophen. Again, they were able to quantiate the two tracer radiolabeled compounds simultaneously. (Auth.)

  12. "Nifedipine in the treatment of liver toxicity induced by Acetaminophen overdose in mice "

    Directory of Open Access Journals (Sweden)

    Kalantari H

    2000-11-01

    Full Text Available Acetaminophen is an analgesic and antipyretic drug, which is widely used by public and poisoning with this drug, is common. One of the most important adverse effects of acetaminophen poisoning is centrilobullar necrosis in hepatic cells, which depends on activity of microsomal cytochrome P-450 (CYP enzymes. The aim of this investigation was to find out the protective effect of nifedipine against liver toxicity caused by acetaminophen overdose (700 mg/kg as calcium channel blocker. In this study doses of 5, 50, 100, 250, 500 mg/kg of nifedipine were administered to mice orally one hour before acetaminophen administration. The negative control group receive normal saline. The positive control group was administered with acetaminophen at a dose of 700 mg/kg one hour after nifedipine administration. After 24 hours, enzyme activity (ALT, AST, histopathological examination and liver weight were compared with the control groups. The results revealed that nifedipine at dose of 500 mg/kg was the most effective and protected damage from acetaminophen toxicity.

  13. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

    Science.gov (United States)

    Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

    2000-01-01

    The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

  14. [Efficacy of tramadol/acetaminophen medication for central post-stroke pain].

    Science.gov (United States)

    Tanei, Takafumi; Kajita, Yasukazu; Noda, Hiroshi; Takebayashi, Shigenori; Hirano, Masaki; Nakahara, Norimoto; Wakabayashi, Toshihiko

    2013-08-01

    Central post-stroke pain(CPSP)is the most difficult type of central neuropathic pain to control with medical treatment. Opioids are commonly used for chronic neuropathic pain, but their efficacy in treating central neuropathic pain, particularly CPSP, is not clear. Tramadol is an opioid analgesic that, in combination with acetaminophen, has been approved since 2011 for the treatment of non-cancer pain in Japan. In this study we evaluated the efficacy of tramadol/acetaminophen medication for CPSP. We retrospectively reviewed nine cases of CPSP that received oral tramadol/acetaminophen medication. All cases received tramadol/acetaminophen medication after first taking pregabalin then antidepressant medication. Pain levels were assessed before tramadol/acetaminophen medication began and one month after a maintenance dose was reached, using a visual analogue scale(VAS)and the McGill pain questionnaire(MPQ). The mean dose of tramadol was 121±61.6 mg/day. Tramadol/acetaminophen medication was effective in reducing pain in seven of nine cases(77.8%). The VAS improved 32.9±13.8% from pre-to post-medication, and the MPQ improved from 15.4±9.1 pre-medication to 8.1±4.7 post-medication(ppain levels in patients with CPSP, and is a medication option for the treatment of CPSP.

  15. From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain.

    Science.gov (United States)

    Mischkowski, Dominik; Crocker, Jennifer; Way, Baldwin M

    2016-09-01

    Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  16. Engineered andrographolide nanosystems for smart recovery in hepatotoxic conditions

    Science.gov (United States)

    Roy, Partha; Das, Suvadra; Auddy, Runa Ghosh; Mukherjee, Arup

    2014-01-01

    Andrographolide (AG) is one of the most potent labdane diterpenoid-type free radical scavengers available from plant sources. The compound is the principal bioactive component in Andrographis paniculata leaf extracts, and is responsible for anti-inflammatory, anticancer, and immunomodulatory activity. The application of AG in therapeutics, however, is severely constrained, due to its low aqueous solubility, short biological half-life, and poor cellular permeability. Engineered nanoparticles in biodegradable polymer systems were therefore conceived as one solution to aid in further drug-like applications of AG. In this study, a cationic modified poly(lactic-co-glycolic) acid nanosystem was applied for evaluation against experimental mouse hepatotoxic conditions. Biopolymeric nanoparticles of hydrodynamic size of 229.7±17.17 nm and ζ-potential +34.4±1.87 mV facilitated marked restoration in liver functions and oxidative stress markers. Superior dissolution for bioactive AG, hepatic residence, and favorable cytokine regulation in the liver tissues are some of the factors responsible for the newer nanosystem-assisted rapid recovery. PMID:25336950

  17. Hepatotoxicity Evaluation of Aqueous Extract from Scutia buxifolia

    Directory of Open Access Journals (Sweden)

    Margareth Linde Athayde

    2013-06-01

    Full Text Available Nowadays there is an increase in the number of people taking herbals worldwide. Scutia buxifolia is used for the treatment of hypertension, but little is known about its action on liver. Thirty-two Wistar rats were divided into four groups: control and groups treated during 30 days with 100, 200 and 400 mg of lyophilized aqueous extract of S. buxifolia (SBSB/kg of body weight. This study was planned to explore hepatotoxic effect of SBSB, which was assessed by serum transaminases (ALT and AST. Thiobarbituric acid reactive substances (TBARS levels were determined in liver, along with thiols content (NPSH, catalase (CAT activity and, superoxide dismutase (SOD enzymes. Histopathological studies of liver tissue were performed. Flavonoids and phenolics were quantified in SBSB by high performance liquid chromatography with diode array detection (HPLC/DAD. We did not observe alterations on redox status (TBARS, NPSH, CAT and, SOD in the control and experimental groups. An increase on AST activity was only observed at 200 mg of SBSB, whereas ALT score was not affected by SBSB. Moreover, no morphological alterations were observed on the hepatocytes, matching the analysed biochemical parameters. This way, we conclude that SBSB was not toxic.

  18. [Determination of serum acetaminophen based on the diazo reaction and its application in the evaluation of gastric emptying].

    Science.gov (United States)

    Li, Cai-na; Sun, Su-juan; Shen, Zhu-fang

    2015-05-01

    This study aims to establish a method to determine the serum acetaminophen concentration based on diazo reaction, and apply it in the gastric emptying evaluation. Theoretically, acetaminophen could take hydrolysis reaction in hydrochloric acid solution to produce p-aminophenol, which could then take diazo reaction resulting in a product with special absorption peak at 312 nm. Then the serum acetaminophen concentration and recovery rate were calculated according to the standard curve drawn with absorbance at 312 nm. ICR mice were given a dose of acetaminophen (500 mg x kg(-1)) by gavage and the serum acetaminophen was dynamically measured through the diazo reaction. Besides, ICR mice were subcutaneously injected with the long-acting GLP-1 analog GW002 before the gavage of acetaminophen, and serum acetaminophen concentration was measured as above to study how GW002 could influence the gastric emptying. The data showed acetaminophen ranging from 0 to 160 μg x mL(-1) could take diazo reaction with excellent linear relationship, and the regression equation was y = 0.0181 x +0.0104, R2 = 0.9997. The serum acetaminophen was also measured with good linear relationship (y = 0.0045 x + 0.0462, R = 0.9982) and the recovery rate was 97.4%-116.7%. The serum concentration of acetaminophen reached peak at about 0.5 h after gavage, and then gradually decreased. GW002 could significantly lower the serum acetaminophen concentration and make the area under the concentration-time curve (AUC) decrease by 28.4%. In conclusion, a method for the determination of serum acetaminophen based on the diazo reaction was established with good accuracy and could be used in the evaluation of gastric emptying.

  19. Bioavailability of suppository acetaminophen in healthy and hospitalized ill dogs.

    Science.gov (United States)

    Sikina, E R; Bach, J F; Lin, Z; Gehring, R; KuKanich, B

    2018-05-13

    To determine the plasma pharmacokinetics of suppository acetaminophen (APAP) in healthy dogs and clinically ill dogs. This prospective study used six healthy client-owned and 20 clinically ill hospitalized dogs. The healthy dogs were randomized by coin flip to receive APAP orally or as a suppository in crossover study design. Blood samples were collected up to 10 hr after APAP dosing. The hospitalized dogs were administered APAP as a suppository, and blood collected at 2 and 6 hr after dosing. Plasma samples were analyzed by ultra-performance liquid chromatography with triple quadrupole mass spectrometry. In healthy dogs, oral APAP maximal concentration (C MAX =2.69 μg/ml) was reached quickly (T MAX =1.04 hr) and eliminated rapidly (T1/2 = 1.81 hr). Suppository APAP was rapidly, but variably absorbed (C MAX =0.52 μg/ml T MAX =0.67 hr) and eliminated (T 1/2  = 3.21 hr). The relative (to oral) fraction of the suppository dose absorbed was 30% (range <1%-67%). In hospitalized ill dogs, the suppository APAP mean plasma concentration at 2 hr and 6 hr was 1.317 μg/ml and 0.283 μg/ml. Nonlinear mixed-effects modeling did not identify significant covariates affecting variability and was similar to noncompartmental results. Results supported that oral and suppository acetaminophen in healthy and clinical dogs did not reach or sustain concentrations associated with efficacy. Further studies performed on different doses are needed. © 2018 John Wiley & Sons Ltd.

  20. Application of toxicogenomics in hepatic systems toxicology for risk assessment: Acetaminophen as a case study

    NARCIS (Netherlands)

    Kienhuis, A.S.; Bessems, J.G.M.; Pennings, J.L.A.; Driessen, M.; Luijten, M.; Delft, van J.H.M.; Ven, van der L.T.M.

    2011-01-01

    Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have

  1. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China.

    Science.gov (United States)

    Yang, Jun; Li, Lin-Fa; Xu, Qin; Zhang, Jun; Weng, Wan-Wen; Zhu, Yang-Jun; Dong, Meng-Jie

    2015-03-01

    Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31). Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

  2. Association of Variants of Arginine Vasopressin and Arginine Vasopressin Receptor 1A With Severe Acetaminophen Liver InjurySummary

    Directory of Open Access Journals (Sweden)

    Matthew Randesi

    2017-05-01

    Full Text Available Background & Aims: Acetaminophen-related acute liver injury and liver failure (ALF result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder. Methods: We examined a series of 21 single nucleotide polymorphisms (SNPs in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls. Results: The mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain. There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64 and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89, both of which have been previously linked to a drug use disorder diagnosis. Conclusions: Patients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders. Keywords: Impulsivity, Stress Responsivity, Pituitary-Adrenal Axis, Overdose

  3. Enduring large use of acetaminophen suppositories for fever management in children: a national survey of French parents and healthcare professionals' practices.

    Science.gov (United States)

    Bertille, Nathalie; Fournier-Charrière, Elisabeth; Pons, Gérard; Khoshnood, Babak; Chalumeau, Martin

    2016-07-01

    The pharmacological specificities of the rectal formulation of acetaminophen led to a debate on its appropriateness for managing fever in children, but few data are available on the formulation's current use and determinants of use. In a national cross-sectional study between 2007 and 2008, healthcare professionals were asked to include five consecutive patients with acute fever. Among the 6255 children (mean age 4.0 years ± 2.8 SD) who received acetaminophen given by parents or prescribed/recommended by healthcare professionals, determinants of suppository use were studied by multilevel models. A suppository was given by 27 % of parents and prescribed/recommended by 19 % of healthcare professionals, by 24 and 16 %, respectively, for children 2 to 5 years old, and by 13 and 8 %, respectively, for those 6 to 12 years old. Among children who received suppositories from parents and healthcare professionals, 83 and 84 %, respectively, did not vomit. Suppository use was independently associated with several patient- and healthcare professional-level characteristics: young age of children, presence of vomiting, or lack of diarrhea. We report an enduring large use of suppositories in France for the symptomatic management of fever in children, including in non-vomiting and/or older children. The rational for such use should be questioned. • The pharmacological specificities of the rectal formulation of acetaminophen have led to a debate on its appropriateness for managing fever in children. Few data are available on the formulation's current use and determinants of the use. What is New: • In a national cross-sectional study, we observed a large use of suppositories in France for symptomatic management of fever in children. Suppositories were frequently used for the youngest children but also for older and/or non-vomiting children.

  4. Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing.

    Science.gov (United States)

    Heard, Kennon; Green, Jody L; Anderson, Victoria; Bucher-Bartelson, Becki; Dart, Richard C

    2016-03-01

    Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 μmol l(-1) have been suggested as a marker of paracetamol-induced hepatotoxicity. However, there is little information on the range of concentrations observed during prolonged therapeutic dosing. The aim of the present study was to describe the concentration of PPA in the serum of subjects taking therapeutic doses of paracetamol for at least 16 days. Preplanned secondary aim of a prospective randomized controlled (placebo vs. 4g day(-1) paracetamol) trial. We measured subjects' serum PPA concentrations every 3 days for a minimum of 16 days. We also measured concentrations on study days 1-3 and 16-25 in subsets of patients. PPA were quantified as APAP-CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry. Ninety per cent of subjects had detectable PPA after five doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 μmol l(-1) on day 7, where they remained. The highest concentration measured was 1.1 μmol l(-1) and two subjects never had detectable PPA levels. PPA were detected in the serum of 78% of subjects 9 days after their final dose. PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 μmol l(-1) in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped. © 2015 The British Pharmacological Society.

  5. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

    Science.gov (United States)

    Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Formulation and Characterization of Acetaminophen Nanoparticles in Orally Disintegrating Films

    Science.gov (United States)

    AI-Nemrawi, Nusaiba K.

    The purpose of this study is to prepare acetaminophen loaded nanoparticles to be cast directly, while still in the emulsion form, into Orally Disintegrating Films (ODF). By casting the nanoparticles in the films, we expected to keep the particles in a stable form where the nanoparticles would be away from each other to prevent their aggregation. Once the films are applied on the buccal mucosa, they are supposed to dissolve within seconds, releasing the nanoparticles. Then the nanoparticles could be directly absorbed through the mucosa to the blood stream and deliver acetaminophen there. The oral cavity mucosa is one of the most attractive sites for systemic drug delivery due to its high permeability and blood supply. Furthermore, it is robust and shows short recovery times after stress or damage, and the drug bypasses first pass effect and avoids presystemic elimination in the GI tract. Nanoencapsulation increases drug efficacy, specificity, tolerability and therapeutic index. These Nanocapsules have several advantages in the protection of premature degradation and interaction with the biological environment, enhancement of absorption into a selected tissue, bioavailability, retention time and improvement of intracellular penetration. The most important characteristics of nanoparticles are their size, encapsulation efficiency (EE), zeta potential (surface charge), and the drug release profiles. Unfortunately, nanoparticles tend to precipitate or aggregate into larger particles within a short time after preparation or during storage. Some solutions for this problem were mentioned in literature including lyophilization and spray drying. These methods are usually expensive and give partial solutions that might have secondary problems; such as low re-dispersion efficacy of the lyophilized NPs. Furthermore, most of the formulations of NPs are invasive or topical. Few formulas are available to be given orally. Fast disintegrating films (ODFs) are rapidly gaining interest

  7. The hepatotoxicity of multi-walled carbon nanotubes in mice

    Science.gov (United States)

    Ji, Zongfei; Zhang, Danying; Li, Ling; Shen, Xizhong; Deng, Xiaoyong; Dong, Ling; Wu, Minhong; Liu, Yuanfang

    2009-11-01

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg-1 by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- α, NF-κB signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  8. Acute bile nephropathy secondary to anabolic steroids.

    Science.gov (United States)

    Alkhunaizi, Ahmed M; ElTigani, Mohamed A; Rabah, Rola S; Nasr, Samih H

    2016-02-01

    Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis.

  9. Preemptive Analgesia with Ibuprofen and Acetaminophen in Pediatric Lower Abdominal Surgery

    Directory of Open Access Journals (Sweden)

    P Kashefi

    2005-07-01

    Full Text Available Background: Postoperative pain is a significant problem in pediatrics. Preemptive administration of analgesics has recently emerged as a method to enhance pain management associated with surgery. The objective of this study was to compare the analgesic efficacy of a single-dose of preoperative oral ibuprofen versus acetaminophen in preventing pain after lower abdominal surgery in pediatrics. Methods: In this randomized, double-blind study, following lower abdominal surgery, 75 children, aging 3 to 12 years, were assigned to receive either ibuprofen 20 mg /kg (n=25 or acetaminophen 35 mg/kg (n=25 or placebo (n=25 2 hours before surgery. Agitation in recovery was measured and postoperative pain was quantified 3 and 24 hours after surgery by Oucher’s scale. The amount of postoperative analgesic needed in the ward was also assessed. Results: It was found that preoperative administration of ibuprofen and acetaminophen can reduce agitation in recovery but there was no difference in the agitation score between ibuprofen and acetaminophen groups (P=0.145. Agitation score was significantly lower in ibuprofen group compared to placebo (P>0.005. Similarly, patients in the acetaminophen group were considerably less agitated than those in the placebo group (P=0.002. No significant difference was observed in pain intensity 3 and 24 hours after operation between the three groups [(P=0.495 and (P=0.582 respectively]. The amount of postoperative analgesic needed during ward hospitalization was not significantly different among the three groups (P>0.005. Conclusion: These results provide evidence that preemptive acetaminophen and ibuprofen may reduce agitation during recovery but they neither improve the postoperative pain nor reduce analgesics consumption in ward Key words: Postoperative analgesia, Acetaminophen, Ibuprofen, Preemptive analgesia

  10. Eucalyptus globulus extract protects upon acetaminophen-induced kidney damages in male rat

    Science.gov (United States)

    Dhibi, Sabah; Mbarki, Sakhria; Elfeki, Abdelfettah; Hfaiedh, Najla

    2014-01-01

    Plants have historically been used in treating many diseases. Eucalyptus globules, a rich source of bioactive compounds, and have been shown to possess antioxidative properties. The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of Eucalyptus globulus extract upon acetaminophen-induced damages in kidney. Our study is realized in the Department of Biology, Faculty of Sciences of Sfax (Tunisia). 32 Wistar male rats; were divided into 4 batches: a control group (n=8), a group of rats treated with acetaminophen (goomg/kg) by intraperitoneal injection during 4 days (n=8), a group receiving Eucalyptus globulus extract (130 mg of dry leaves/kg/day) in drinking water during 42 days after 2 hours of acetaminophen administration (during 4 days) (n=8) and group received only Eucalyptus (n=8) during 42 days. After 6 weeks, animals from each group were rapidly sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, acetaminophen poisoning resulted in an oxidative stress evidenced by statistically significant losses in the activities of catalase (CAT), superoxide-dismutase (SOD), glutathione-peroxidase (GPX) activities and an increase in lipids peroxidation level in renal tissue of acetaminophen-treated group compared with the control group. Acetaminophen also caused kidney damage as evident by statistically significant (p<0.05) increase in levels of creatinine and urea and decreased levels of uric acid and proteins in blood. Histological analysis demonstrated alteration of proximal tubules, atrophy of the glomerule and dilatation of urinary space. Previous administration of plant extract is found to alleviate this acetaminophen-induced damage. PMID:24856382

  11. TRPV1 in brain is involved in acetaminophen-induced antinociception.

    Directory of Open Access Journals (Sweden)

    Christophe Mallet

    2010-09-01

    Full Text Available Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404 by fatty acid amide hydrolase (FAAH in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV(1 in vitro. Pharmacological activation of TRPV(1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV(1 in the brain contributes to the analgesic effect of acetaminophen.Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV(1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E(2 (PGE(2 and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV(1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV(1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test.This study shows that TRPV(1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV(1 in the brain.

  12. Acetaminophen degradation by electro-Fenton and photoelectro-Fenton using a double cathode electrochemical cell

    Energy Technology Data Exchange (ETDEWEB)

    Luna, Mark Daniel G. de [Department of Chemical Engineering, University of the Philippines, 1011 Diliman, Quezon City (Philippines); Environmental Engineering Graduate Program, University of the Philippines, 1011 Diliman, Quezon City (Philippines); Veciana, Mersabel L. [Environmental Engineering Graduate Program, University of the Philippines, 1011 Diliman, Quezon City (Philippines); Su, Chia-Chi [Department of Environmental Resources Management, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China); Lu, Ming-Chun, E-mail: mmclu@mail.chan.edu.tw [Department of Environmental Resources Management, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China)

    2012-05-30

    Highlights: Black-Right-Pointing-Pointer The electro-Fenton reactor using a double cathode electrochemical cell was applied. Black-Right-Pointing-Pointer The initial Fe{sup 2+} concentration was the most significant parameter for the acetaminophen degradation. Black-Right-Pointing-Pointer Thirteen intermediates were identified and a degradation pathway was proposed. - Abstract: Acetaminophen is a widely used drug worldwide and is one of the most frequently detected in bodies of water making it a high priority trace pollutant. This study investigated the applicability of the electro-Fenton and photoelectro-Fenton processes using a double cathode electrochemical cell in the treatment of acetaminophen containing wastewater. The Box-Behnken design was used to determine the effects of initial Fe{sup 2+} and H{sub 2}O{sub 2} concentrations and applied current density. Results showed that all parameters positively affected the degradation efficiency of acetaminophen with the initial Fe{sup 2+} concentration being the most significant parameter for both processes. The acetaminophen removal efficiency for electro-Fenton was 98% and chemical oxygen demand (COD) removal of 43% while a 97% acetaminophen removal and 42% COD removal were observed for the photoelectro-Fenton method operated at optimum conditions. The electro-Fenton process was only able to obtain 19% total organic carbon (TOC) removal while the photoelectro-Fenton process obtained 20%. Due to negligible difference between the treatment efficiencies of the two processes, the electro-Fenton method was proven to be more economically advantageous. The models obtained from the study were applicable to a wide range of acetaminophen concentrations and can be used in scale-ups. Thirteen different types of intermediates were identified and a degradation pathway was proposed.

  13. Acetaminophen degradation by electro-Fenton and photoelectro-Fenton using a double cathode electrochemical cell

    International Nuclear Information System (INIS)

    Luna, Mark Daniel G. de; Veciana, Mersabel L.; Su, Chia-Chi; Lu, Ming-Chun

    2012-01-01

    Highlights: ► The electro-Fenton reactor using a double cathode electrochemical cell was applied. ► The initial Fe 2+ concentration was the most significant parameter for the acetaminophen degradation. ► Thirteen intermediates were identified and a degradation pathway was proposed. - Abstract: Acetaminophen is a widely used drug worldwide and is one of the most frequently detected in bodies of water making it a high priority trace pollutant. This study investigated the applicability of the electro-Fenton and photoelectro-Fenton processes using a double cathode electrochemical cell in the treatment of acetaminophen containing wastewater. The Box–Behnken design was used to determine the effects of initial Fe 2+ and H 2 O 2 concentrations and applied current density. Results showed that all parameters positively affected the degradation efficiency of acetaminophen with the initial Fe 2+ concentration being the most significant parameter for both processes. The acetaminophen removal efficiency for electro-Fenton was 98% and chemical oxygen demand (COD) removal of 43% while a 97% acetaminophen removal and 42% COD removal were observed for the photoelectro-Fenton method operated at optimum conditions. The electro-Fenton process was only able to obtain 19% total organic carbon (TOC) removal while the photoelectro-Fenton process obtained 20%. Due to negligible difference between the treatment efficiencies of the two processes, the electro-Fenton method was proven to be more economically advantageous. The models obtained from the study were applicable to a wide range of acetaminophen concentrations and can be used in scale-ups. Thirteen different types of intermediates were identified and a degradation pathway was proposed.

  14. Assessment of protein modifications in liver of rats under chronic treatment with paracetamol (acetaminophen) using two complementary mass spectrometry-based metabolomic approaches.

    Science.gov (United States)

    Mast, Carole; Lyan, Bernard; Joly, Charlotte; Centeno, Delphine; Giacomoni, Franck; Martin, Jean-François; Mosoni, Laurent; Dardevet, Dominique; Pujos-Guillot, Estelle; Papet, Isabelle

    2015-04-29

    Liver protein can be altered under paracetamol (APAP) treatment. APAP-protein adducts and other protein modifications (oxidation/nitration, expression) play a role in hepatotoxicity induced by acute overdoses, but it is unknown whether liver protein modifications occur during long-term treatment with non-toxic doses of APAP. We quantified APAP-protein adducts and assessed other protein modifications in the liver from rats under chronic (17 days) treatment with two APAP doses (0.5% or 1% of APAP in the diet w/w). A targeted metabolomic method was validated and used to quantify APAP-protein adducts as APAP-cysteine adducts following proteolytic hydrolysis. The limit of detection was found to be 7ng APAP-cysteine/mL hydrolysate i.e. an APAP-Cys to tyrosine ratio of 0.016‰. Other protein modifications were assessed on the same protein hydrolysate by untargeted metabolomics including a new strategy to process the data and identify discriminant molecules. These two complementary mass spectrometry (MS)-based metabolic approaches enabled the assessment of a wide range of protein modifications induced by chronic treatment with APAP. APAP-protein adducts were detected even in the absence of glutathione depletion and hepatotoxicity, i.e. in the 0.5% APAP group, and increased by 218% in the 1% APAP group compared to the 0.5% APAP group. At the same time, the untargeted metabolomic method revealed a decrease in the binding of cysteine, cysteinyl-glycine and GSH to thiol groups of protein cysteine residues, an increase in the oxidation of tryptophan and proline residues and a modification in protein expression. This wide range of modifications in liver proteins occurred in rats under chronic treatment with APAP that did not induce hepatotoxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Metabolite kinetics: formation of acetaminophen from deuterated and nondeuterated phenacetin and acetanilide on acetaminophen sulfation kinetics in the perfused rat liver preparation

    International Nuclear Information System (INIS)

    Pang, K.S.; Waller, L.; Horning, M.G.; Chan, K.K.

    1982-01-01

    The role of hepatic intrinsic clearance for metabolite formation from various precursors on subsequent metabolite elimination was was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors: [ 14 C] phenacetin-d5 and [ 3 H] phenacetin-do, [ 14 C] acetanilide and [ 3 H] phenacetin were delivered by constant flow (10 ml/min/liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The data showed that the higher the hepatocellular activity (intrinsic clearance) for acetaminophen formation, the greater the extent of subsequent acetaminophen sulfation. The findings were explained on the basis of blood transit time and metabolite duration time. Because of blood having only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite sulfation and the less will be the degree of subsequent sulfation. Conversely, when the drug forms the primary metabolite rapidly, a longer time will remain for the metabolite to be sulfated in liver to result in a greater degree of metabolite sulfation. Finally, the effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed

  16. NADH:ubiquinone reductase and succinate dehydrogenase activity in the liver of rats with acetaminophen-induced toxic hepatitis on the background of alimentary protein deficiency

    Directory of Open Access Journals (Sweden)

    G. P. Kopylchuk

    2015-02-01

    Full Text Available The ratio between the redox forms of the nicotinamide coenzymes and key enzymatic activity of the I and II respiratory chain complexes in the liver cells mitochondria of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein was studied. It was estimated, that under the conditions of acute acetaminophen-induced hepatitis of rats kept on a low-protein diet during 4 weeks a significant decrease of the NADH:ubiquinone reductase and succinate dehydrogenase activity with simultaneous increase of the ratio between redox forms of the nicotinamide coenzymes (NAD+/NADН is observed compared to the same indices in the liver cells of animals with experimental hepatitis kept on the ration balanced by all nutrients. Results of research may become basic ones for the biochemical rationale for the approaches directed to the correction and elimination of the consequences­ of energy exchange in the toxic hepatitis, induced on the background of protein deficiency.

  17. Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems

    DEFF Research Database (Denmark)

    Hurtado-Gonzalez, Pablo; Anderson, Richard A; Macdonald, Joni

    2018-01-01

    /ovaries using in vitro and xenograft approaches. METHODS: Gonocyte (TFAP2C+) number was reduced relative to controls in first-trimester human fetal testes exposed in vitro to acetaminophen (-28%) or ibuprofen (-22%) and also in ovaries exposed to acetaminophen (-43%) or ibuprofen (-49%). Acetaminophen exposure...

  18. Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers.

    Science.gov (United States)

    Stangier, J; Su, C A; Fraunhofer, A; Tetzloff, W

    2000-12-01

    Two open-label, two-way, crossover studies were performed to assess any pharmacokinetic interaction of telmisartan with either acetaminophen or ibuprofen. Healthy male adult volunteers (n = 12) received a single oral dose of acetaminophen 1 g alone and with oral telmisartan 120 mg in one study. Oral ibuprofen 400 mg three times daily with and without oral once-daily telmisartan 120 mg was given for 7 days in the other study conducted in 6 males and 6 females. In both studies, there was a washout period of > or = 13 days between single and combination medication administration. The primary end points Cmax and AUC were compared between combination (acetaminophen or ibuprofen + telmisartan) and single-agent medication (acetaminophen or ibuprofen). Pharmacokinetic drug interaction was assessed by analysis of variance (ANOVA) and calculation of 90% confidence intervals (CI) for treatment ratios using log-transformed parameters. Bioequivalence (i.e., lack of interaction) was concluded if the 90% CI of the ratios for both Cmax and AUC were within the acceptance limit of 0.80 to 1.25. Geometric mean Cmax values for acetaminophen and R-(-)- and S-(+)-ibuprofen enantiomers were similar with and without telmisartan coadministration (12.6 micrograms/mL vs. 14.1 micrograms/mL; 17.3 micrograms/mL vs. 16.7 micrograms/mL; 19.4 micrograms/mL vs. 19.5 micrograms/mL, respectively), and values for R-(-)- as well as S-(+)-ibuprofen were bioequivalent. Geometric mean AUC values for acetaminophen and R-(-)- and S-(+)-ibuprofen were also bioequivalent with and without telmisartan. The distribution and elimination parameters of both acetaminophen and ibuprofen were comparable in the presence or absence of telmisartan. The concomitant and single-agent medications were all well tolerated. In conclusion, the long half-life and excellent safety profile of telmisartan were unaffected by concurrent acetaminophen or ibuprofen medication; thus, once-daily dosing of telmisartan can be maintained

  19. Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide.

    Science.gov (United States)

    Sabordo, L; Sallustio, B C; Evans, A M; Nation, R L

    2000-10-01

    Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-beta-D-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 microM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 microM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean +/- S. D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 +/- 1.4 ml/min, 94.1 +/- 17.9 ml/min, 0.346 +/- 0.046, and 30.9 +/- 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.

  20. Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation

    International Nuclear Information System (INIS)

    Hwang, Hye-Jung; Kwon, Mi-Jin; Nam, Taek-Jeong

    2007-01-01

    The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells

  1. Globular adiponectin protects rat hepatocytes against acetaminophen-induced cell death via modulation of the inflammasome activation and ER stress: Critical role of autophagy induction.

    Science.gov (United States)

    Kim, Eun Hye; Park, Pil-Hoon

    2018-05-24

    Acetaminophen (APAP) overdose treatment causes severe liver injury. Adiponectin, a hormone predominantly produced by adipose tissue, exhibits protective effects against APAP-induced hepatotoxicity. However, the underlying mechanisms are not clearly understood. In the present study, we examined the protective effect of globular adiponectin (gAcrp) on APAP-induced hepatocyte death and its underlying mechanisms. We found that APAP (2 mM)-induced hepatocyte death was prevented by inhibition of the inflammasome. In addition, treatment with gAcrp (0.5 and 1 μg/ml) inhibited APAP-induced activation of the inflammasome, judged by suppression of interleukin-1β maturation, caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation, suggesting that protective effects of gAcrp against APAP-induced hepatocyte death is mediated via modulation of the inflammasome. APAP also induced ER stress and treatment with tauroursodeoxycholic acid (TUDCA), an ER chaperone and inhibitor of ER stress, abolished APAP-induced inflammasomes activation, implying that ER stress acts as signaling event leading to the inflammasome activation in hepatocytes stimulated with APAP. Moreover, gAcrp significantly suppressed APAP-induced expression of ER stress marker genes. Finally, the modulatory effects of gAcrp on ER stress and inflammasomes activation were abrogated by treatment with autophagy inhibitors, while an autophagy inducer (rapamycin) suppressed APAP-elicited ER stress, demonstrating that autophagy induction plays a crucial role in the suppression of APAP-induced inflammasome activation and ER stress by gAcrp. Taken together, these results indicate that gAcrp protects hepatocytes against APAP-induced cell death by modulating ER stress and the inflammasome activation, at least in part, via autophagy induction. Copyright © 2018. Published by Elsevier Inc.

  2. A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine.

    Science.gov (United States)

    Zell-Kanter, Michele; Coleman, Patrick; Whiteley, Patrick M; Leikin, Jerrold B

    2013-01-01

    The objective of this report is to describe an acidemic patient with one of the largest recorded acetaminophen ingestions in a patient with acidemia who was treated with supportive care and intravenous (IV) N-acetylcysteine. A 59-year-old female with a history of depression was found comatose. In the Emergency Department, she was obtunded with agonal respirations and immediately intubated. Activated charcoal was given through a nasogastric tube. An initial acetaminophen serum level was 1141 mg/L. The patient was started on IV N-acetylcysteine. The acetaminophen level peaked 2 hours later at 1193 mg/L. She was continued on the IV N-acetylcysteine protocol. The next day her aspartate aminotransferase was 3150 U/L, alanine aminotransferase was 2780 U/L, and creatinine phosphokinase was 16,197 U/L. There was no elevation in bilirubin or international normalized ratio (INR). Transaminase levels decreased on day 3 and normalized by day 4 when she was transferred to a psychiatric unit. Few cases have been reported of strikingly elevated acetaminophen levels in poisoned patients who did not receive hemodialysis. These patients did have increased lactate levels, and some had normal liver function tests. All of these patients received N-acetylcysteine and survived the poisoning without sequelae. This patient in this report was unique in that she had the highest reported serum acetaminophen level with acidosis and was treated successfully with only IV N-acetylcysteine and supportive care.

  3. Use of intravenous acetaminophen (paracetamol) in a pediatric patient at the end of life: case report.

    Science.gov (United States)

    Marks, Adam D; Keefer, Patricia; Saul, D'Anna

    2013-12-01

    For the better part of 100 years, acetaminophen (or paracetamol as it is known outside of the United States) has been a common first-line analgesic in pediatrics and is typically well tolerated with minimal side effects. Its use as an anti-pyretic is also well-documented and thus it is used broadly for symptom control in the general pediatric population. In pediatric palliative care, acetaminophen is also used as an adjuvant to opioid therapy for pain as well as an anti-pyretic. For many pediatric patients near end-of-life, however, the ability to tolerate oral intake is diminished and rectal suppository administration can be distressing or contraindicated as in the setting of neutropenia, thus limiting use of acetaminophen by its usual routes. In Europe and Australia, an intravenous formulation of acetaminophen has been used for many years and has only recently become available in the United States. Here, we describe a case using intravenous acetaminophen in a pediatric patient at the end of life.

  4. Influence of organic amendment on fate of acetaminophen and sulfamethoxazole in soil

    International Nuclear Information System (INIS)

    Li, Juying; Ye, Qingfu; Gan, Jay

    2015-01-01

    Land application of biosolids or compost constitutes an important route of soil contamination by emerging contaminants such as acetaminophen and sulfamethoxazole. Using "1"4C labeling, we evaluated the influence of biosolids and compost on individual fate processes of acetaminophen and sulfamethoxazole in soil. The amendment of biosolids or compost consistently inhibited the mineralization of both compounds but simultaneously enhanced the dissipation of their extractable residues or parent form. Immediately after treatment, the majority of "1"4C-residue became non-extractable, reaching 80.3–92.3% of the applied amount at the end of 84-d incubation. Addition of biosolids or compost appreciably accelerated the formation of bound residue, likely due to the fact that the organic material provided additional sites for binding interactions or introduced exogenous microorganisms facilitating chemical transformations. This effect of biosolids or compost should be considered in risk assessment of these and other emerging contaminants. - Highlights: • "1"4C Labeling was used to understand the fate processes of acetaminophen and sulfamethoxazole in aerobic soil. • Majority of acetaminophen and sulfamethoxazole quickly became non-extractable or mineralized. • Biosolids or compost amendment inhibited mineralization. • Biosolids or compost appreciably enhanced the formation of bound residue. - Biosolids or compost amendment inhibited mineralization of acetaminophen and sulfamethoxazole and appreciably enhanced the formation of bound residue.

  5. STUDIES ON INDUCED HEPATOTOXICITY IN MALE ALBINO RATS (RATTUS NORVEGICUS)

    International Nuclear Information System (INIS)

    ABULYAZID, I.; ABBAS, O.A.; FAYEZ, V.

    2008-01-01

    Levanox, a hepato protective drug, and garlic powder have been considered as safe anti-oxidant agents. The present investigation refers to biochemical and molecular studies to evaluate the protective role of levanox and/or garlic powder toward CCl4-induced toxicity in adult male albino rats. CCl4 intoxication was attempted using a dose of 0.03 ml/kg of rat body weight.Pre-treatment with levanox (one capsule/ kg of rat body weight, each capsule contains 100 mg catechu, 7.5 mg dandelion, 75 mg termiric 2 % curcumin , 17.5 mg silymarin, 100 mg lecithin) was more effective than garlic powder (100mg/kg of rat body weight) in reducing CCl4-induced hepatotoxicity as revealed by its higher potency in reducing elevation of aspartate (AST) and alanine (ALT) aminotransferases in serum. Serum of control rats and those treated with levanox or garlic or CCl4 produced 13 types of proteins, differing in the molecular weight (MW) and densities, while those of levanox + garlic or garlic +CCl4 produced 14 bands differing in the MW and densities. The similarity index at the epigenetic level was also studied using the primers under study. The control sample produced one amplified DNA fragment with Rf of 0.73 and a molecular size (MS) of 67 base pair (bp) . Using the same primers, no amplified DNA fragment with the same MS was produced in the sample taken from levanox + garlic treated group.OPA-2 primer of sequence 5?- AGA TGC AGC C-3? produced one amplified DNA band with MS of 292 bp and Rf of 0.46 . However, the same primer produced one amplified DNA characteristic band with a molecular size of 363 bp and Rf of 0.43 in the sample of levanox + garlic group.In the control sample, OPA-4 primer of sequence 5? - ACG CAC AAC C-3? produced one amplified DNA band of MS of 299 bp and Rf of 0.43. The same primer produced one amplified characteristic DNA band with MS of 363 bp and Rf of 0.43 in the sample of levanox + garlic group.Dual treatment with levanox and garlic powder resulted in a

  6. Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Medine Cumhur Cüre

    2016-10-01

    Full Text Available Background: Cisplatin (Cis is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α. Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. Aims: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis. Study Design: Animal experimentation. Methods: Male Wistar albino rats were divided in three groups as follows: Cis group, infliximab + Cis (CIN group and the control group. Each group comprised 10 animals. Animals in the Cis group received an intraperitoneal single-dose injection of Cis (7 mg/kg. In the CIN group, a single dose of infliximab (7 mg/kg was administered 72 h prior to the Cis injection. After 72 h, a single dose of Cis (7 mg/kg was administered. All rats were sacrificed five days after Cis injection. Results: TNF-α levels in the Cis group were significantly higher (345.5±40.0 pg/mg protein than those of the control (278.7±62.1 pg/mg protein, p=0.003 and CIN groups (239.0±64.2 pg/mg protein, p=0.013. The Cis group was found to have high carbonic anhydrase (CA-II and low carbamoyl phosphate synthetase-1 (CPS-1 levels. Aspartate transaminase (AST and alanine transaminase (ALT levels were lower in the CIN group as compared to the Cis group. Total histological damage was greater in the Cis group as compared to the control and CIN groups. Conclusion: Cis may lead to liver damage by increasing cytokine levels. It may increase oxidative stress-induced tissue damage by increasing carbonic anhydrase II (CA-II enzyme levels and decreasing CPS-1 enzyme levels. Infliximab decreases Cis-induced hepatic damage by blocking TNF-α and it may also protect against liver damage by regulating CPS-1 and

  7. Solubility of Acetaminophen in Some Alcohol Free Solvent Systems

    Directory of Open Access Journals (Sweden)

    H. Barzegar-Jalali

    1990-07-01

    Full Text Available In an attempt to formulate an alcohol free acetaminophen solution for use in pediatrics, the effect of different concentra¬tions of polyethylene glycol 400 (PEG 400 and polysorbate 80 ( Iween 80 on the solubility of the drug in water .as well as in the vehicles composed of (propylene glycol 10?o V/V + glycerol 20% V/V in water and (propylene glycol 12?o V/V + glycerol 40?o V/V in water was investigated at 20 C. There was a linear relationship between the logarithm of the drug solubility and volume fraction of PEG 400 in the vehicles. Also, a linear relation was established between the solubility of the drug in water and the volume fraction of Tween 80. After the solubilization studies, the appropriate concentration of the cosolvents and Tween 80 were chosen for the tolerance test of the solutions at a low temperature (4 C against crystalization. These studies led us to propose two alcohol free drug solutions with suitable sweetening and flavoring agents. Properties of the products including a simple method of determination of drug concentration, density and viscosity measure¬ments have been also reported.

  8. What do we (not) know about how paracetamol (acetaminophen) works?

    Science.gov (United States)

    Toussaint, K; Yang, X C; Zielinski, M A; Reigle, K L; Sacavage, S D; Nagar, S; Raffa, R B

    2010-12-01

    Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

  9. <