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Sample records for acetaminophen apap overdose

  1. Protective effect of hyperoside against acetaminophen (APAP) induced liver injury through enhancement of APAP clearance.

    PubMed

    Xie, Wenyan; Jiang, Zhihui; Wang, Jian; Zhang, Xiaoying; Melzig, Matthias F

    2016-02-25

    Acetaminphen (APAP) overdose leads to severe hepatotoxicity. Apocynum venetum L. (A. venetum) possess potent hepatoprotective effect. Hyperoside is one of the major compounds exist in Apocynum venetum L. and might be a potential agent to protect against APAP-induce liver injury. In this study, we investigated the effect of hyperoside on APAP hepatotoxicity in mice. Mice were treated intragastrically with hyperoside (10, 50 or 100 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused severe liver injury characterized by significantly increased serum aminotransferase levels, hepatic malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) formation, as well as liver superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) depletions. Hyperoside significantly attenuated APAP-induced liver damages in a dose dependent manner, and 100 mg/kg was the most effective dose. Further study confirmed that hyperoside was able to increase activities and mRNA expressions of uridine diphoshate glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), as well as to inhibit CYP2E1 activities, and thereby suppressed toxic intermediate formation and promoted APAP hepatic detoxification. Nrf-2 activation might be involved in hyperoside induced up-regulation of phase II enzymes. Collectively, our data provide evidence that hyperoside protected the liver against APAP induced injury mainly by accelerating APAP harmless metabolism, implying that hyperoside can be considered as a potential natural hepatoprotective agent.

  2. Protective effect of hyperoside against acetaminophen (APAP) induced liver injury through enhancement of APAP clearance.

    PubMed

    Xie, Wenyan; Jiang, Zhihui; Wang, Jian; Zhang, Xiaoying; Melzig, Matthias F

    2016-02-25

    Acetaminphen (APAP) overdose leads to severe hepatotoxicity. Apocynum venetum L. (A. venetum) possess potent hepatoprotective effect. Hyperoside is one of the major compounds exist in Apocynum venetum L. and might be a potential agent to protect against APAP-induce liver injury. In this study, we investigated the effect of hyperoside on APAP hepatotoxicity in mice. Mice were treated intragastrically with hyperoside (10, 50 or 100 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused severe liver injury characterized by significantly increased serum aminotransferase levels, hepatic malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) formation, as well as liver superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) depletions. Hyperoside significantly attenuated APAP-induced liver damages in a dose dependent manner, and 100 mg/kg was the most effective dose. Further study confirmed that hyperoside was able to increase activities and mRNA expressions of uridine diphoshate glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), as well as to inhibit CYP2E1 activities, and thereby suppressed toxic intermediate formation and promoted APAP hepatic detoxification. Nrf-2 activation might be involved in hyperoside induced up-regulation of phase II enzymes. Collectively, our data provide evidence that hyperoside protected the liver against APAP induced injury mainly by accelerating APAP harmless metabolism, implying that hyperoside can be considered as a potential natural hepatoprotective agent. PMID:26772156

  3. Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity

    SciTech Connect

    Brown, J. Michael; Ball, John G.; Hogsett, Amy; Williams, Tierra; Valentovic, Monica

    2010-08-15

    Acetaminophen (APAP) is the leading cause of drug induced liver failure in the United States. Previous studies in our laboratory have shown that S-adenosyl methionine (SAMe) is protective for APAP hepatic toxicity. SAMe is critical for glutathione synthesis and transmethylation of nucleic acids, proteins and phospholipids which would facilitate recovery from APAP toxicity. SAMe is synthesized in cells through the action of methionine adenosyltransferase (MAT). This study tested the hypothesis that total hepatic and subcellular SAMe levels are decreased by APAP toxicity. Studies further examined MAT expression and activity in response to APAP toxicity. Male C57BL/6 mice (16-22 g) were treated with vehicle (Veh; water 15 ml/kg ip injections), 250 mg/kg APAP (15 ml/kg, ip), SAMe (1.25 mmol/kg) or SAMe administered 1 h after APAP injection (SAMe and SAMe + APAP). Hepatic tissue was collected 2, 4, and 6 h after APAP administration. Levels of SAMe and its metabolite S-adenosylhomocysteine (SAH) were determined by HPLC analysis. MAT expression was examined by Western blot. MAT activity was determined by fluorescence assay. Total liver SAMe levels were depressed at 4 h by APAP overdose, but not at 2 or 6 h. APAP depressed mitochondrial SAMe levels at 4 and 6 h relative to the Veh group. In the nucleus, levels of SAMe were depressed below detectable limits 4 h following APAP administration. SAMe administration following APAP (SAMe + APAP) prevented APAP associated decline in mitochondrial and nuclear SAMe levels. In conclusion, the maintenance of SAMe may provide benefit in preventing damage associated with APAP toxicity.

  4. Detection of Acetaminophen-Protein Adducts in Decedents with Suspected Opioid-Acetaminophen Combination Product Overdose.

    PubMed

    Thomas, Karen C; Wilkins, Diana G; Curry, Steven C; Grey, Todd C; Andrenyak, David M; McGill, Lawrence D; Rollins, Douglas E

    2016-09-01

    Acetaminophen overdose is a leading cause of drug-induced liver failure in the United States. Acetaminophen-protein adducts have been suggested as a biomarker of hepatotoxicity. The purpose of this study was to determine whether protein-derived acetaminophen-protein adducts are quantifiable in postmortem samples. Heart blood, femoral blood, and liver tissue were collected at autopsy from 22 decedents suspected of opioid-acetaminophen overdose. Samples were assayed for protein-derived acetaminophen-protein adducts, acetaminophen, and selected opioids found in combination products containing acetaminophen. Protein-derived APAP-CYS was detected in 17 of 22 decedents and was measurable in blood that was not degraded or hemolyzed. Heart blood concentrations ranged from 11 ng/mL (0.1 μM) to 7817 ng/mL (28.9 μM). Protein-derived acetaminophen-protein adducts were detectable in liver tissue for 20 of 22 decedents. Liver histology was also performed for all decedents, and no evidence of centrilobular hepatic necrosis was observed. PMID:27479586

  5. Biochemical mechanism of Acetaminophen (APAP) induced toxicity in melanoma cell lines

    PubMed Central

    Vad, Nikhil M.; Yount, Garret; Moore, Dan; Weidanz, Jon; Moridani, Majid Y.

    2008-01-01

    In this work, we investigated the biochemical mechanism of acetaminophen (APAP) induced toxicity in SK-MEL-28 melanoma cells using tyrosinase enzyme as a molecular cancer therapeutic target. Our results showed that APAP was metabolized 87% by tyrosinase at 2h incubation. AA and NADH, quinone reducing agents, were significantly depleted during APAP oxidation by tyrosinase. The IC50 (48h) of APAP towards SK-MEL-28, MeWo, SK-MEL-5, B16-F0 and B16-F10 melanoma cells was 100μM whereas it showed no significant toxicity towards BJ, Saos-2, SW-620, and PC-3 non-melanoma cells, demonstrating selective toxicity towards melanoma cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, enhanced APAP toxicity towards SK-MEL-28 cells. AA and GSH were effective in preventing APAP induced melanoma cell toxicity. Trifluoperazine and cyclosporin A, inhibitors of permeability transition pore in mitochondria, significantly prevented APAP melanoma cell toxicity. APAP caused time and dose-dependent decline in intracellular GSH content in SK-MEL-28, which preceded cell toxicity. APAP led to ROS formation in SK-MEL-28 cells which was exacerbated by dicoumarol and 1-bromoheptane whereas cyslosporin A and trifluoperazine prevented it. Our investigation suggests that APAP is a tyrosinase substrate, and that intracellular GSH depletion, ROS formation and induced mitochondrial toxicity contributed towards APAP's selective toxicity in SK-MEL-28 cells. PMID:18759348

  6. Comparison of Prothrombin Time and Aspartate Aminotransferase in Predicting Hepatotoxicity After Acetaminophen Overdose.

    PubMed

    Levine, Michael; O'Connor, Ayrn D; Padilla-Jones, Angela; Gerkin, Richard D

    2016-03-01

    Despite decades of experience with acetaminophen (APAP) overdoses, it remains unclear whether elevated hepatic transaminases or coagulopathy develop first. Furthermore, comparison of the predictive value of these two variables in determining hepatic toxicity following APAP overdoses has been poorly elucidated. The primary objective of this study is to determine the test characteristics of the aspartate aminotransferase (AST) and the prothrombin time (PT) in patients with APAP toxicity. A retrospective chart review of APAP overdoses treated with IV N-acetylcysteine at a tertiary care referral center was performed. Of the 304 subjects included in the study, 246 with an initial AST less than 1000 were analyzed to determine predictors of hepatic injury, defined as an AST exceeding 1000 IU/L. The initial AST >50 was 79.5 % sensitive and 82.6 % specific for predicting hepatic injury. The corresponding negative and positive predictive values were 95.5 and 46.3 %, respectively. In contrast, an initial abnormal PT had a sensitivity of 82.1 % and a specificity of 63.6 %. The negative and positive predictive values for initial PT were 94.9 and 30.2 %, respectively. Although the two tests performed similarly for predicting a composite endpoint of death or liver transplant, neither was a useful predictor. Initial AST performed better than the initial PT for predicting hepatic injury in this series of patients with APAP overdose. PMID:26341088

  7. 3,4-Dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, attenuates acetaminophen (APAP)-induced liver injury through activation of Nrf-2.

    PubMed

    Xue, Huiting; Xie, Wenyan; Jiang, Zhihui; Wang, Meng; Wang, Jian; Zhao, Hongqiong; Zhang, Xiaoying

    2016-10-01

    1. Acetaminophen (APAP) overdose leads to severe hepatotoxicity. 3,4-dihydroxyphenylacetic acid (DOPAC) is a scarcely studied microbiota-derived metabolite of quercetin. The aim of this study was to determine the protective effect of DOPAC against APAP-induced liver injury. 2. Mice were treated intragastrically with DOPAC (10, 20 or 50 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused increase in serum aminotransferase levels and changes in hepatic histopathology. APAP also promoted oxidative stress by increasing lipid peroxidation and decreasing anti-oxidant enzyme activities. These events led to hepatocellular necrosis and reduced liver function. DOPAC increased nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation to the nucleus and enhanced the expression of phase II enzymes and anti-oxidant enzymes, and thereby reduced APAP hepatotoxicity and enhanced anti-oxidant ability. 3. Our data provide evidence that DOPAC protected the liver against APAP-induced injury, which is involved in Nrf-2 activation, implying that DOPAC can be considered as a potential natural hepatoprotective agent.

  8. Comparison of S-Adenosyl-L-methionine (SAMe) and N-Acetylcysteine (NAC) Protective Effects on Hepatic Damage when Administered After Acetaminophen Overdose

    PubMed Central

    Terneus, Marcus V.; Brown, J. Michael; Carpenter, A. Betts; Valentovic, Monica A.

    2008-01-01

    In the clinical setting, antidotes are generally administered after the occurrence of a drug overdose. Therefore, the most pertinent evaluation of any new agent should model human exposure. This study tested whether acetaminophen (APAP) hepatotoxicity was reversed when S-adenosyl-L-methionine (SAMe) was administered after APAP exposure, similar to what occurs in clinical situations. Comparisons were made for potency between SAMe and N-acetylcysteine (NAC), the current treatment for APAP toxicity. Male C57BL/6 mice were fasted overnight and divided into groups: control (VEH), SAMe treated (SAMe), APAP treated (APAP), N-acetylcysteine treated (NAC), SAMe or NAC administered 1 h after APAP (SAMe+APAP) and (NAC+APAP), respectively. Mice were injected Intraperitoneal (ip) with water (VEH) or 250 mg/kg APAP (15 ml/kg). One 1h later, mice were injected (ip) with 1.25 mmol/kg SAMe (SAMe+APAP) or NAC (NAC+APAP). Hepatotoxicity was evaluated 4 h after APAP or VEH treatment. APAP induced centrilobular necrosis, increased liver weight and alanine transaminase (ALT) levels, depressed total hepatic glutathione (GSH), increased protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins. Treatment with SAMe 1 hr after APAP overdose (SAMe+APAP) was hepatoprotective and was comparable to NAC+APAP. Treatment with SAMe or NAC 1 h after APAP was sufficient to return total hepatic glutathione (GSH) to levels comparable to the VEH group. Western blot showed reversal of APAP mediated effects in the SAMe+APAP and NAC+APAP groups. In summary, SAMe was protective when given 1 h after APAP and was comparable to NAC. PMID:18068290

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

    PubMed

    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 <10 μg/mL, and his liver 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.

  10. Adolescents' Misperceptions of the Dangerousness of Acetaminophen in Overdose.

    ERIC Educational Resources Information Center

    Harris, Hope Elaine; Myers, Wade C.

    1997-01-01

    Assesses the generality and strength of nonclinical youths' (N=569) perceptions of the harmfulness and lethality of acetaminophen in overdose. Findings indicate that adolescents have ready access to acetaminophen and use it in suicide attempts but underestimate its potential for toxicity, lacking knowledge regarding side effects of overdose. (RJM)

  11. Evaluation of biochemical alterations produced by acetaminophen overdose in Bubalus bubalis

    PubMed Central

    Daundkar, Prashant Sudamrao; Sharma, Suresh Kumar

    2015-01-01

    Aim: Evaluation of the effect of acetaminophen (APAP) overdose on biochemical parameters in buffalo calves. Materials and Methods: The experiment was conducted on six healthy male buffalo calves of 6-12 months age. The APAP was administered intramuscularly at the dose rate of 250 mg/kg body weight (B.W.) on day 0, followed by two subsequent doses at the dose rate of 50 mg/kg B.W. on day 2 and 4, respectively. Biochemical parameters including alanine aminotransferase (ALT), alkaline phosphatase (ALP), amylase, blood urea nitrogen (BUN), creatinine, and total acid phosphate were estimated in the plasma samples collected on 0, 1, 2, 3, 4, 5, and 6th day from the start of treatment. Results: Significant increase in the plasma levels of ALT (446.0%), ALP (137%), BUN (216.8%) and creatinine (149.2%) was recorded on day 3, 4, 3, and 4, respectively, after the start of APAP dosing. However, a significant decrease was observed in amylase activity with a maximum decline of 48.3% on 6th day after the start of treatment. No significant alteration was observed in ACP activity after APAP overdose. Conclusion: Administration of APAP in overdose produced hepatic dysfunction as evidenced by a significant increase in the activities of ALT and ALP, whereas reduced amylase may indicate acute pancreatitis in buffalo calves. In addition, repeated dosing also resulted in renal impairment in these animals as seen by a significant elevation in BUN and creatinine levels, whereas negligible effect on prostatic function. PMID:27047122

  12. Acute Liver Failure including Acetaminophen Overdose

    PubMed Central

    Fontana, Robert J.

    2008-01-01

    Synopsis Acute liver failure (ALF) is a dramatic and highly unpredictable clinical syndrome defined by the sudden onset of coagulopathy and encephalopathy. Although many disease processes can cause ALF, acetaminophen overdose is the leading cause in the United States, and has a 66% chance of recovery with early N-acetylcysteine treatment and supportive care. Cerebral edema and infectious complications are notoriously difficult to detect and treat in ALF patients and may lead to irreversible brain damage and multi-organ failure. Emergency liver transplantation is associated with a 70% 1-year patient survival but 20% of listed patients die, highlighting the importance of early referral of ALF patients with a poor prognosis to a liver transplant center. PMID:18570942

  13. Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice.

    PubMed

    Tsai, Ming-Shiun; Chien, Chia-Chih; Lin, Ting-Hui; Liu, Chia-Chi; Liu, Rosa Huang; Su, Hong-Lin; Chiu, Yung-Tsung; Wang, Sue-Hong

    2015-11-01

    Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model. PMID:26501381

  14. Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice.

    PubMed

    Tsai, Ming-Shiun; Chien, Chia-Chih; Lin, Ting-Hui; Liu, Chia-Chi; Liu, Rosa Huang; Su, Hong-Lin; Chiu, Yung-Tsung; Wang, Sue-Hong

    2015-11-01

    Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model.

  15. Acetaminophen overdose associated with double serum concentration peaks.

    PubMed

    Papazoglu, Cristian; Ang, Jonathan R; Mandel, Michael; Basak, Prasanta; Jesmajian, Stephen

    2015-01-01

    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. PMID:26653695

  16. Acetaminophen overdose associated with double serum concentration peaks

    PubMed Central

    Papazoglu, Cristian; Ang, Jonathan R.; Mandel, Michael; Basak, Prasanta; Jesmajian, Stephen

    2015-01-01

    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. PMID:26653695

  17. The role of skeletal muscle in liver glutathione metabolism during acetaminophen overdose.

    PubMed

    Bilinsky, L M; Reed, M C; Nijhout, H F

    2015-07-01

    Marked alterations in systemic glutamate-glutamine metabolism characterize the catabolic state, in which there is an increased breakdown and decreased synthesis of skeletal muscle protein. Among these alterations are a greatly increased net release of glutamine (Gln) from skeletal muscle into blood plasma and a dramatic depletion of intramuscular Gln. Understanding the catabolic state is important because a number of pathological conditions with very different etiologies are characterized by its presence; these include major surgery, sepsis, trauma, and some cancers. Acetaminophen (APAP) overdose is also accompanied by dramatic changes in systemic glutamate-glutamine metabolism including large drops in liver glutathione (for which glutamate is a precursor) and plasma Gln. We have constructed a mathematical model of glutamate and glutamine metabolism in rat which includes liver, blood plasma and skeletal muscle. We show that for the normal rat, the model solutions fit experimental data including the diurnal variation in liver glutathione (GSH). We show that for the rat chronically dosed with dexamethasone (an artificial glucocorticoid which induces a catabolic state) the model can be used to explain empirically observed facts such as the linear decline in intramuscular Gln and the drop in plasma glutamine. We show that for the Wistar rat undergoing APAP overdose the model reproduces the experimentally observed rebound of liver GSH to normal levels by the 24-h mark. We show that this rebound is achieved in part by the action of the cystine-glutamate antiporter, an amino acid transporter not normally expressed in liver but induced under conditions of oxidative stress. Finally, we explain why supplementation with Gln, a Glu precursor, assists in the preservation of liver GSH during APAP overdose despite the fact that under normal conditions only Cys is rate-limiting for GSH formation.

  18. Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

    PubMed Central

    2013-01-01

    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 that it is a

  19. Platelets mediate acetaminophen hepatotoxicity.

    PubMed

    Lam, Fong W; Rumbaut, Rolando E

    2015-10-01

    In this issue of Blood, Miyakawa et al show that platelets and protease-activated receptor (PAR)-4 contribute to acetaminophen (APAP)-induced liver damage. Using various strategies in a mouse model of APAP overdose, the authors demonstrate that platelets participate in the progression of liver damage, and that the direct thrombin inhibitor lepirudin and PAR-4 deficiency attenuate hepatotoxicity. These findings have the potential to help identify future therapeutic targets for APAP-induced hepatotoxicity. PMID:26450954

  20. Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity.

    PubMed

    Owumi, Solomon E; Andrus, James P; Herzenberg, Leonard A; Herzenberg, Leonore A

    2015-08-01

    Preclinical Research Although acetaminophen (APAP) is an effective analgesic and anti-pyretic, APAP overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity. Administration of N-acetyl cysteine (NAC) within 8 hours of APAP overdose effectively mitigates APAP-induced hepatotoxicity. Thus, preventing APAP toxicity before it occurs by formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP. From a public health perspective, these findings support the concept that a co-formulation of APAP plus NAC is a viable over-the-counter (OTC) alternative to the current practice of providing APAP OTC and treating APAP toxicity if/when it occurs. In essence, our findings indicate that replacing the current OTC APAP with a safe and functional APAP/NAC formulation could prevent the accidental and intentional APAP toxicity that occurs today. PMID:26250417

  1. Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity.

    PubMed

    Owumi, Solomon E; Andrus, James P; Herzenberg, Leonard A; Herzenberg, Leonore A

    2015-08-01

    Preclinical Research Although acetaminophen (APAP) is an effective analgesic and anti-pyretic, APAP overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity. Administration of N-acetyl cysteine (NAC) within 8 hours of APAP overdose effectively mitigates APAP-induced hepatotoxicity. Thus, preventing APAP toxicity before it occurs by formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP. From a public health perspective, these findings support the concept that a co-formulation of APAP plus NAC is a viable over-the-counter (OTC) alternative to the current practice of providing APAP OTC and treating APAP toxicity if/when it occurs. In essence, our findings indicate that replacing the current OTC APAP with a safe and functional APAP/NAC formulation could prevent the accidental and intentional APAP toxicity that occurs today.

  2. 5-oxoproline-induced anion gap metabolic acidosis after an acute acetaminophen overdose.

    PubMed

    Lawrence, David T; Bechtel, Laura K; Charlton, Nathan P; Holstege, Christopher P

    2010-09-01

    Metabolic acidosis after acute acetaminophen overdose is typically attributed to either transient lactic acidosis without evidence of hepatic injury or hepatic failure. High levels of the organic acid 5-oxoprolinuria are usually reported in patients with predisposing conditions, such as sepsis, who are treated in a subacute or chronic fashion with acetaminophen. The authors report a case of a 40-year-old woman who developed anion gap metabolic acidosis and somnolence after an acute acetaminophen overdose. Substantial hepatic damage did not occur, which ruled out acetaminophen-induced hepatic insufficiency as a cause of the patient's acidosis or altered mental status. Urinalysis revealed elevated levels of 5-oxoproline, suggesting that the patient's acute acetaminophen overdose was associated with marked anion gap metabolic acidosis due solely to 5-oxoproline without hepatic complications. The acidosis fully resolved with N-acetylcysteine treatment and supportive care including hydration.

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

    SciTech Connect

    Williams, C. David; Bajt, Mary Lynn; Sharpe, Matthew R.; McGill, Mitchell R.; Farhood, Anwar; Jaeschke, Hartmut

    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

  4. An Analysis of Viral Testing in non-Acetaminophen (non-APAP) Pediatric Acute Liver Failure (PALF)

    PubMed Central

    Schwarz, Kathleen B.; Olio, Dominic Dell; Lobritto, Steven J.; Lopez, M James; Rodriguez-Baez, Norberto; Yazigi, Nada A.; Belle, Steven H.; Zhang, Song; Squires, Robert H.

    2014-01-01

    Objective Viral infections are often suspected to cause pediatric acute liver failure (PALF) but large-scale studies have not been performed. We analyzed results of viral testing among non-acetaminophen (non APAP) PALF study participants. Methods Participants were enrolled in the PALF registry. Diagnostic evaluation and final diagnosis were determined by the site investigator and methods for viral testing by local standard of care. Viruses were classified as either Causative Viruses (CV) or Associated Viruses (AV). Supplemental testing for CV was performed if not done clinically and serum was available. Final diagnoses included “Viral”, “Indeterminate” and “Other”. Results Of 860 participants, 820 had at least one test result for a CV or AV. A positive viral test was found in 166/820 (20.2%) participants and distributed among “Viral” [66/80 (82.5%)], “Indeterminate” [52/420 (12.4%)] and “Other” [48/320 (15.0%)] diagnoses. CV accounted for 81/166 (48.8%) positive tests. Herpes Simplex Virus (HSV) was positive in 39/335 (11.6%) who were tested: 26/103 (25.2%) and 13/232 (5.6%) among infants 0 - 6 months and over 6 months, respectively. HSV was not tested in 61.0% and 53% of the over-all cohort and those 0 - 6 months, respectively. Supplemental testing yielded 17 positive, including 5 HSV. Conclusions Viral testing in PALF occurs frequently but is often incomplete. Evidence for acute viral infection was found in 20.2% of those tested for viruses. HSV is an important viral cause for PALF in all age groups. The etiopathogenic role of CV and AV in PALF requires further investigation. PMID:25079486

  5. [A Case of Acetaminophen Poisoning Associated with Tramcet Overdose].

    PubMed

    Urabe, Shigehiko; Terao, Yoshiaki; Tuji, Tikako; Egashira, Takashi; Goto, Shino; Fukusaki, Makoto

    2016-06-01

    Tramcet is a mixture of tramadol and acetaminophen. Acetaminophen poisoning may be caused by excessive intake of Tramcet. A 17-year-old female took excessive quantity of Tramcet before noon. She reported it herself in the emergency room. Her main complaint was nausea and dizziness. Acetaminophen may cause liver damage with dose-dependent manner. Because there was a possibility of acetaminophen poisoning, we started oral acetylcysteine. She was discharged from hospital 5 days later without side effects of acetylecysteine and liver damage. PMID:27483669

  6. [A Case of Acetaminophen Poisoning Associated with Tramcet Overdose].

    PubMed

    Urabe, Shigehiko; Terao, Yoshiaki; Tuji, Tikako; Egashira, Takashi; Goto, Shino; Fukusaki, Makoto

    2016-06-01

    Tramcet is a mixture of tramadol and acetaminophen. Acetaminophen poisoning may be caused by excessive intake of Tramcet. A 17-year-old female took excessive quantity of Tramcet before noon. She reported it herself in the emergency room. Her main complaint was nausea and dizziness. Acetaminophen may cause liver damage with dose-dependent manner. Because there was a possibility of acetaminophen poisoning, we started oral acetylcysteine. She was discharged from hospital 5 days later without side effects of acetylecysteine and liver damage.

  7. Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose.

    PubMed

    Curry, Steven C; Padilla-Jones, Angela; O'Connor, Ayrn D; Ruha, Anne-Michelle; Bikin, Dale S; Wilkins, Diana G; Rollins, Douglas E; Slawson, Matthew H; Gerkin, Richard D

    2015-06-01

    Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p < 0.001). CVVHDF failed to remove detectable amounts of APAP-CYS in any of the nine subjects studied. Sixty-eight percent of 557 urine samples from 168 subjects contained no detectable APAP-CYS, despite levels in serum up to 16.99 μM. Terminal elimination half-life of serum APAP-CYS was prolonged in patients with renal failure for reasons unrelated to renal urinary adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back-extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP-CYS, suggesting approximate APAP-protein adduct molecular weights ≥ 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal

  8. Efficacy of charcoal cathartic versus ipecac in reducing serum acetaminophen in a simulated overdose.

    PubMed

    McNamara, R M; Aaron, C K; Gemborys, M; Davidheiser, S

    1989-09-01

    The traditional role of gastric emptying as the initial step in the management of the poisoned patient has recently been questioned; immediate activated charcoal administration has been recommended by some. In the setting of acetaminophen overdose, ipecac-induced emesis may interfere with subsequent oral antidotal therapy. Therefore, we conducted a study to compare the efficacy of initial therapy with ipecac with therapy with activated charcoal-cathartic in a simulated acetaminophen overdosage. Ten healthy volunteers participated in a randomized, crossover trial. Subjects ingested 3.0 g acetaminophen, followed by either no intervention, 30 mL syrup of ipecac, or 50 g activated charcoal-sorbitol solution at one hour. Serial acetaminophen levels were determined at intervals over eight hours. Both interventions significantly reduced the area under the curve compared with control (P less than .05). When comparing ipecac with activated charcoal-cathartic, no significant difference was noted among these groups. PMID:2569851

  9. Liver transplant for intentional acetaminophen overdose and hepatic encephalopathy: a conflict between beneficence and justice.

    PubMed

    Willey, Joshua Z; Tolchin, Benjamin David

    2014-06-01

    In cases of severe acetaminophen-induced acute liver failure and hepatic encephalopathy, liver transplant can be the only real hope for neurologic recovery and indeed survival. In such cases, the bioethical principles of beneficence and justice often come into conflict. This article examines a case in which a neurologist managing an acetaminophen-overdose patient in the neurologic intensive care unit is faced with a conflict between her patient's need for a liver transplant and the needs of other patients on the transplant list.

  10. Bactrian ("double hump") acetaminophen pharmacokinetics: a case series and review of the literature.

    PubMed

    Hendrickson, Robert G; McKeown, Nathanael J; West, Patrick L; Burke, Christopher R

    2010-09-01

    After acute ingestion, acetaminophen (APAP) is generally absorbed within 4 h and the APAP concentration ([APAP]) slowly decreases with a predictable half-life. Alterations in these pharmacokinetic principles have been rarely reported. We report here three cases of an unusual double hump, or Bactrian, pattern of [APAP]. We review the literature to describe the case characteristics of these rare cases. A 38-year-old woman ingested 2 g hydrocodone/65 g acetaminophen. Her [APAP] peaked at 289 mcg/mL (8 h), decreased to 167 mcg/mL (31 h), then increased to 240 mcg/mL (39 h). She developed liver injury (peak AST 1603 IU/L; INR1.6). A 25-year-old man ingested 2 g diphenhydramine/26 g APAP. His [APAP] peaked at 211 mcg/mL (15 h), decreased to 185 mcg/mL (20 h), and increased again to 313 mcg/mL (37 h). He developed liver injury (peak AST 1153; INR 2.1). A 16-year-old boy ingested 5 g diphenhydramine and 100 g APAP. His [APAP] peaked at 470 mcg/mL (25 h), decreased to 313 mcg/mL (36 h), then increased to 354 mcg/mL (42 h). He developed liver injury (peak AST 8,686 IU/L; peak INR 5.9). We report three cases of Bactrian ("double hump") pharmacokinetics after massive APAP overdoses. Cases with double hump pharmacokinetics may be associated with large ingestions (26-100 g APAP) and are often coingested with antimuscarinics or opioids. Several factors may contribute to these altered kinetics including the insolubility of acetaminophen, APAP-induced delays in gastric emptying, opioid or antimuscarinic effects, or enterohepatic circulation. Patients with double hump APAP concentrations may be at risk for liver injury, with AST elevations and peaks occurring later than what is typical for acute APAP overdoses. PMID:20446076

  11. New problems arising from old drugs: second-generation effects of acetaminophen.

    PubMed

    Tiegs, Gisa; Karimi, Khalil; Brune, Kay; Arck, Petra

    2014-09-01

    Acetaminophen (APAP)/paracetamol is one of the most commonly used over-the-counter drugs taken worldwide for treatment of pain and fever. Although considered as safe when taken in recommended doses not higher than 4 g/day, APAP overdose is currently the most important cause of acute liver failure (ALF). ALF may require liver transplantation and can be fatal. The reasons for APAP-related ALF are mostly intentional (suicidal) or unintentional overdose. However, results from large scale epidemiological studies provide increasing evidence for second generation effects of APAP, even when taken in pharmacological doses. Most strikingly, APAP medication during pregnancy has been associated with health problems including neurodevelopmental and behavioral disorders such as attention deficit hyperactivity disorder and increase in the risk of wheezing and incidence of asthma among offspring. This article reviews the epidemiological findings and aims to shed light into the molecular and cellular mechanisms responsible for APAP-mediated prenatal risk for asthma. PMID:25075430

  12. Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity.

    PubMed

    Ghanem, Carolina I; Pérez, María J; Manautou, José E; Mottino, Aldo D

    2016-07-01

    Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe when administered within its therapeutic range, but in cases of acute intoxication, hepatotoxicity can occur. APAP overdose is the leading cause of acute liver failure in the northern hemisphere. Historically, studies on APAP toxicity have been focused on liver, with alterations in brain function attributed to secondary effects of acute liver failure. However, in the last decade the pharmacological mechanism of APAP as a cannabinoid system modulator has been documented and some articles have reported "in situ" toxicity by APAP in brain tissue at high doses. Paradoxically, low doses of APAP have been reported to produce the opposite, neuroprotective effects. In this paper we present a comprehensive, up-to-date overview of hepatic toxicity as well as a thorough review of both toxic and beneficial effects of APAP in brain. PMID:26921661

  13. Novel Protective Mechanisms for S-Adenosyl-L-methionine against Acetaminophen Hepatotoxicity: Improvement of Key Antioxidant Enzymatic Function

    PubMed Central

    Brown, J. Michael; Ball, John G.; Wright, Michael Scott; Van Meter, Stephanie; Valentovic, Monica A.

    2012-01-01

    Acetaminophen (APAP) overdose leads to severe hepatotoxicity, increased oxidative stress and mitochondrial dysfunction. S-adenosyl-L-methionine (SAMe) protects against APAP toxicity at a mmol/kg equivalent dose to N-acetylcysteine (NAC). SAMe acts as a principle biological methyl donor and participates in polyamine synthesis which increase cell growth and has a role in mitochondrial protection. The purpose of the current study tested the hypothesis that SAMe protects against APAP toxicity by maintaining critical antioxidant enzymes and markers of oxidative stress. Male C57Bl/6 mice were treated with vehicle (Veh; water 15 ml/kg, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg, ip), and SAMe + APAP (SAMe given 1 h following APAP). Liver was collected 2 and 4 h following APAP administration; mitochondrial swelling as well as hepatic catalase, glutathione peroxidase (GPx), glutathione reductase, and both Mn- and Cu/Zn-superoxide dismutase (SOD) enzyme activity were evaluated. Mitochondrial protein carbonyl, 3-nitrotyrosine cytochrome c leakage were analyzed by Western blot. SAMe significantly increased SOD, GPx, and glutathione reductase activity at 4 h following APAP overdose. SAMe greatly reduced markers of oxidative stress and cytochrome C leakage following APAP overdose. Our studies also demonstrate that a 1.25 mmol/kg dose of SAMe does not inhibit CYP 2E1 enzyme activity. The current study identifies a plausible mechanism for the decreased oxidative stress observed when SAMe is given following APAP. PMID:22683606

  14. Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Lu, Yihong; Sun, Jinchun; Petrova, Katya; Yang, Xi; Greenhaw, James; Salminen, William F; Beger, Richard D; Schnackenberg, Laura K

    2013-12-01

    Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Mice were orally administered GTE, APAP or GTE and APAP under three scenarios. APAP alone caused a high degree of hepatocyte necrosis associated with increases in serum transaminases and alterations in multiple metabolic pathways. The time of GTE oral administration relative to APAP either protected against or potentiated the APAP-induced hepatotoxicity. Dose dependent decreases in histopathology scores and serum transaminases were noted when GTE was administered prior to APAP; whereas, the opposite occurred when GTE was administered after APAP. Similarly, metabolites altered by APAP alone were less changed when GTE was given prior to APAP. Significantly altered pathways included fatty acid metabolism, glycerophospholipid metabolism, glutathione metabolism, and energy pathways. These studies demonstrate the complex interaction between GTE and APAP and the need to employ novel analytical strategies to understand the effects of dietary supplements on pharmaceutical compounds.

  15. Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy

    PubMed Central

    Baulies, Anna; Ribas, Vicent; Núñez, Susana; Torres, Sandra; Alarcón-Vila, Cristina; Martínez, Laura; Suda, Jo; Ybanez, Maria D.; Kaplowitz, Neil; García-Ruiz, Carmen; Fernández-Checa, Jose C.

    2015-01-01

    The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase)−/− mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase+/+ littermates. ASMase−/− hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase+/+ hepatocytes caused by U18666A reproduces the susceptibility of ASMase−/− hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase−/− mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury. PMID:26657973

  16. Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy.

    PubMed

    Baulies, Anna; Ribas, Vicent; Núñez, Susana; Torres, Sandra; Alarcón-Vila, Cristina; Martínez, Laura; Suda, Jo; Ybanez, Maria D; Kaplowitz, Neil; García-Ruiz, Carmen; Fernández-Checa, Jose C

    2015-12-11

    The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase)(-/-) mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase(+/+) littermates. ASMase(-/-) hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase(+/+) hepatocytes caused by U18666A reproduces the susceptibility of ASMase(-/-) hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase(-/-) mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury.

  17. Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection

    PubMed Central

    Gum, Sang Il

    2013-01-01

    Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection. PMID:24386516

  18. Comparison of inhibitory effects between acetaminophen-glutathione conjugate and reduced glutathione in human glutathione reductase.

    PubMed

    Nýdlová, Erika; Vrbová, Martina; Cesla, Petr; Jankovičová, Barbora; Ventura, Karel; Roušar, Tomáš

    2014-09-01

    Acetaminophen overdose is the most frequent cause of acute liver injury. The main mechanism of acetaminophen toxicity has been attributed to oxidation of acetaminophen. The oxidation product is very reactive and reacts with glutathione generating acetaminophen-glutathione conjugate (APAP-SG). Although this conjugate has been recognized to be generally nontoxic, we have found recently that APAP-SG could produce a toxic effect. Therefore, the aim of our study was to estimate the toxicity of purified APAP-SG by characterizing the inhibitory effect in human glutathione reductase (GR) and comparing that to the inhibitory effect of the natural inhibitor reduced glutathione. We used two types of human GR: recombinant and freshly purified from red blood cells. Our results show that GR was significantly inhibited in the presence of both APAP-SG and reduced glutathione. For example, the enzyme activity of recombinant and purified GR was reduced in the presence of 4 mm APAP-SG (with 0.5 mm glutathione disulfide) by 28% and 22%, respectively. The type of enzyme inhibition was observed to be competitive in the cases of both APAP-SG and glutathione. As glutathione inhibits GR activity in cells under physiological conditions, the rate of enzyme inhibition ought to be weaker in the case of glutathione depletion that is typical of acetaminophen overdose. Notably, however, enzyme activity likely remains inhibited due to the presence of APAP-SG, which might enhance the pro-oxidative status in the cell. We conclude that our finding could reflect some other pathological mechanism that may contribute to the toxicity of acetaminophen.

  19. In vivo N-acetyl cysteine reduce hepatocyte death by induced acetaminophen

    NASA Astrophysics Data System (ADS)

    Lin, Chih-Ju; Li, Feng-Chieh; Wang, Sheng-Shun; Lee, Hsuan-Shu; Dong, Chen-Yuan

    2011-07-01

    Acetaminophen (APAP) is the famous drug in global, and taking overdose Acetaminophen will intake hepatic cell injure. Desptie substantial progress in our understanding of the mechanism of hepatocellular injury during the last 40 years, many aspects of the pathophysiology are still unknown or controversial.1 In this study, mice are injected APAP overdose to damage hepatocyte. APAP deplete glutathione and ATP of cell, N-Acetyl Cysteine (NAC) plays an important role to protect hepatocytes be injury. N-Acetyl Cysteine provides mitochondrial to produce glutathione to release drug effect hepatocyte. By 6-carboxyfluorescein diacetate (6-CFDA) metabolism in vivo, glutathione keep depleting to observe the hepatocyte morphology in time. Without NAC, cell necrosis increase to plasma membrane damage to release 6-CFDA, that's rupture. After 6-CFDA injection, fluorescence will be retained in hepatocyte. For cell retain with NAC and without NAC are almost the same. With NAC, the number of cell rupture decreases about 75%.

  20. Role of caspase-1 and interleukin-1{beta} in acetaminophen-induced hepatic inflammation and liver injury

    SciTech Connect

    Williams, C. David; Farhood, Anwar; Jaeschke, Hartmut

    2010-09-15

    Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1{beta} signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1{beta} formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1{beta} during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1{beta} gene transcription but prevented the increase in IL-1{beta} plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1{beta} to increase injury, mice were given pharmacological doses of IL-1{beta} after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1{beta} formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1{beta}, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.

  1. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning.

    PubMed

    Williams, C David; McGill, Mitchell R; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose.

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

    SciTech Connect

    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

    2013-06-15

    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

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

    SciTech Connect

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

    2012-11-01

    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

  4. Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury.

    PubMed

    Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

    2015-10-01

    The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose. PMID:26434492

  5. Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury.

    PubMed

    Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

    2015-10-01

    The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.

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

    PubMed

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

    2012-11-01

    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.

  7. Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury

    PubMed Central

    Hwang, Jung Hwan; Kim, Yong-Hoon; Noh, Jung-Ran; Choi, Dong-Hee; Kim, Kyoung-Shim; Lee, Chul-Ho

    2015-01-01

    The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose. PMID:26434492

  8. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    SciTech Connect

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson; Jaeschke, Hartmut

    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

  9. Potential of Extracellular MicroRNAs as Biomarkers of Acetaminophen Toxicity in Children

    PubMed Central

    Yang, Xi; Salminen, William F; Shi, Qiang; Greenhaw, James; Gill, Pritmohinder S; Bhattacharyya, Sudeepa; Beger, Richard D; Mendrick, Donna L; Mattes, William B.; James, Laura P

    2015-01-01

    Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n=10), 2) hospitalized children receiving therapeutic doses of APAP (n=10) and 3) children hospitalized for APAP overdose (n=8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, −375, −423-5p, −30d-5p, −125b-5p, −4732-5p, −204-5p, and −574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, −940, −9-3p and −302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetylpara-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R=0.94; p<0.01) followed by miR-375 (R=0.70; p=0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity. PMID:25708609

  10. Preparation of hydrophilic C60(OH)10/2-hydroxypropyl-β-cyclodextrin nanoparticles for the treatment of a liver injury induced by an overdose of acetaminophen.

    PubMed

    Umezaki, Yoshitaka; Iohara, Daisuke; Anraku, Makoto; Ishitsuka, Yoichi; Irie, Tetsumi; Uekama, Kaneto; Hirayama, Fumitoshi

    2015-03-01

    Stable hydrophilic C60(OH)10 nanoparticles were prepared from 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and applied to the treatment of an acetaminophen overdose induced liver Injury. C60(OH)10 nanoparticles were produced by cogrinding α-CD, β-CD, γ-CD and HP-β-CD and characterized in terms of solubility, mean particle diameter, ζ-potential and long term dispersibility in water. Hydrophilic C60(OH)10 nanoparticles with particle sizes less than 50 nm were effectively produced by cogrinding HP-β-CD with C60(OH)10 at a molar ratio of 1:3 (C60(OH)10:CD). The resulting C60(OH)10/HP-β-CD nanoparticles were stable in water and showed no aggregation over a 1 month period. The C60(OH)10/CDs nanoparticles scavenged not only free radicals (DPPH and ABTS radicals) but also reactive oxygen species (O2(•-) and •OH). When C60(OH)10/HP-β-CD nanoparticles were intraperitoneally administered to mice with a liver injury induced by an overdose of acetaminophen (APAP), the ALT and AST levels were markedly reduced to almost the same level as that for normal mice. Furthermore, the administration of the nanoparticles prolonged the survival rate of liver injured mice, while all of the mice that were treated with APAP died within 40 h. To reveal the mechanism responsible for liver protection by C60(OH)10 nanoparticles, GSH level, CYP2E1 expression and peroxynitrite formation in the liver were assessed. C60(OH)10/HP-β-CD nanoparticles had no effect on CYP2E1 expression and GSH depletion, but suppressed the generation of peroxynitrite in the liver. The findings indicate that the protective effect of C60(OH)10/HP-β-CD nanoparticles was due to the suppression of oxidative stress in mitochondria, as the result of scavenging ROS such as O2(•-), NO and peroxynitrite, which act as critical mediators in the liver injuries. PMID:25662501

  11. Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children

    SciTech Connect

    Yang, Xi; Salminen, William F.; Shi, Qiang; Greenhaw, James; Gill, Pritmohinder S.; Bhattacharyya, Sudeepa; Beger, Richard D.; Mendrick, Donna L.; Mattes, William B.; and others

    2015-04-15

    Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n = 10), 2) hospitalized children receiving therapeutic doses of APAP (n = 10) and 3) children hospitalized for APAP overdose (n = 8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, -940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R = 0.94; p < 0.01) followed by miR-375 (R = 0.70; p = 0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity. - Highlights: • Serum miR-122 and miR-375 levels were increased in children with APAP overdose. • Urine levels of miR-375 and miR-940 were increased in the APAP overdose group. • Peak serum miR-122 levels were correlated with peak serum APAP protein adducts.

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

    SciTech Connect

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

    2011-05-01

    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-1{beta} (IL-1{beta}), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1{beta} 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-1{beta} 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.

  13. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

    SciTech Connect

    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18 h or 1 h prior to an APAP overdose. Administration of allopurinol 18 h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6 h after APAP; however, 1 h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2 h) however late JNK activation (6 h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18 h or 1 h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18 h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. - Highlights: • 18 h allopurinol pretreatment protects against acetaminophen-induced liver injury. • 1 h allopurinol pretreatment does not protect from APAP

  14. Acetaminophen-induced acute liver injury in mice.

    PubMed

    Mossanen, J C; Tacke, F

    2015-04-01

    The induction of acute hepatic damage by acetaminophen (N-acetyl-p-aminophenol [APAP]), also termed paracetamol, is one of the most commonly used experimental models of acute liver injury in mice. The specific values of this model are the highly reproducible, dose-dependent hepatotoxicity of APAP and its outstanding translational importance, because acetaminophen overdose is one of the most frequent reasons for acute liver failure (ALF) in humans. However, preparation of concentrated APAP working solutions, application routes, fasting period and variability due to sex, genetic background or barrier environment represent important considerations to be taken into account before implementing this model. This standard operating procedure (SOP) provides a detailed protocol for APAP preparation and application in mice, aimed at facilitating comparability between research groups as well as minimizing animal numbers and distress. The mouse model of acetaminophen poisoning therefore helps to unravel the pathogenesis of APAP-induced toxicity or subsequent immune responses in order to explore new therapeutic interventions for improving the prognosis of ALF in patients.

  15. Benzyl alcohol protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes but causes mitochondrial dysfunction and cell death at higher doses.

    PubMed

    Du, Kuo; McGill, Mitchell R; Xie, Yuchao; Jaeschke, Hartmut

    2015-12-01

    Acetaminophen (APAP) hepatotoxicity is a serious public health problem in western countries. Current treatment options for APAP poisoning are limited and novel therapeutic intervention strategies are needed. A recent publication suggested that benzyl alcohol (BA) protects against APAP hepatotoxicity and could serve as a promising antidote for APAP poisoning. To assess the protective mechanisms of BA, C56Bl/6J mice were treated with 400 mg/kg APAP and/or 270 mg/kg BA. APAP alone caused extensive liver injury at 6 h and 24 h post-APAP. This injury was attenuated by BA co-treatment. Assessment of protein adduct formation demonstrated that BA inhibits APAP metabolic activation. In support of this, in vitro experiments also showed that BA dose-dependently inhibits cytochrome P450 activities. Correlating with the hepatoprotection of BA, APAP-induced oxidant stress and mitochondrial dysfunction were reduced. Similar results were obtained in primary mouse hepatocytes. Interestingly, BA alone caused mitochondrial membrane potential loss and cell toxicity at high doses, and its protective effect could not be reproduced in primary human hepatocytes (PHH). We conclude that BA protects against APAP hepatotoxicity mainly by inhibiting cytochrome P450 enzymes in mice. Considering its toxic effect and the loss of protection in PHH, BA is not a clinically useful treatment option for APAP overdose patient. PMID:26522885

  16. Protective Effect of Baccharis trimera Extract on Acute Hepatic Injury in a Model of Inflammation Induced by Acetaminophen

    PubMed Central

    Pádua, Bruno da Cruz; Rossoni Júnior, Joamyr Victor; de Brito Magalhães, Cíntia Lopes; Chaves, Míriam Martins; Silva, Marcelo Eustáquio; Pedrosa, Maria Lucia; de Souza, Gustavo Henrique Bianco; Brandão, Geraldo Célio; Rodrigues, Ivanildes Vasconcelos; Lima, Wanderson Geraldo; Costa, Daniela Caldeira

    2014-01-01

    Background. Acetaminophen (APAP) is a commonly used analgesic and antipyretic. When administered in high doses, APAP is a clinical problem in the US and Europe, often resulting in severe liver injury and potentially acute liver failure. Studies have demonstrated that antioxidants and anti-inflammatory agents effectively protect against the acute hepatotoxicity induced by APAP overdose. Methods. The present study attempted to investigate the protective effect of B. trimera against APAP-induced hepatic damage in rats. The liver-function markers ALT and AST, biomarkers of oxidative stress, antioxidant parameters, and histopathological changes were examined. Results. The pretreatment with B. trimera attenuated serum activities of ALT and AST that were enhanced by administration of APAP. Furthermore, pretreatment with the extract decreases the activity of the enzyme SOD and increases the activity of catalase and the concentration of total glutathione. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by APAP. Conclusions. The hepatoprotective action of B. trimera extract may rely on its effect on reducing the oxidative stress caused by APAP-induced hepatic damage in a rat model. General Significance. These results make the extract of B. trimera a potential candidate drug capable of protecting the liver against damage caused by APAP overdose. PMID:25435714

  17. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

    PubMed

    Carvalho, Nélson R; da Rosa, Edovando F; da Silva, Michele H; Tassi, Cintia C; Dalla Corte, Cristiane L; Carbajo-Pescador, Sara; Mauriz, Jose L; González-Gallego, Javier; Soares, Félix A

    2013-01-01

    The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced. PMID:24349162

  18. N-acetylcysteine amide, a promising antidote for acetaminophen toxicity.

    PubMed

    Khayyat, Ahdab; Tobwala, Shakila; Hart, Marcia; Ercal, Nuran

    2016-01-22

    Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over the counter antipyretic and analgesic medications. It is safe at therapeutic doses, but its overdose can result in severe hepatotoxicity, a leading cause of drug-induced acute liver failure in the USA. Depletion of glutathione (GSH) is one of the initiating steps in APAP-induced hepatotoxicity; therefore, one strategy for restricting organ damage is to restore GSH levels by using GSH prodrugs. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an acetaminophen overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and I.V. administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteine amide (NACA), a novel antioxidant with higher bioavailability, and compared it with NAC in APAP-induced hepatotoxicity in C57BL/6 mice. Our results showed that NACA is better than NAC at a low dose (106mg/kg) in preventing oxidative stress and protecting against APAP-induced damage. NACA significantly increased GSH levels and the GSH/GSSG ratio in the liver to 66.5% and 60.5% of the control, respectively; and it reduced the level of ALT by 30%. However, at the dose used, NAC was not effective in combating the oxidative stress induced by APAP. Thus, NACA appears to be better than NAC in reducing the oxidative stress induced by APAP. It would be of great value in the health care field to develop drugs like NACA as more effective and safer options for the prevention and therapeutic intervention in APAP-induced toxicity. PMID:26602168

  19. N-acetylcysteine amide, a promising antidote for acetaminophen toxicity.

    PubMed

    Khayyat, Ahdab; Tobwala, Shakila; Hart, Marcia; Ercal, Nuran

    2016-01-22

    Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over the counter antipyretic and analgesic medications. It is safe at therapeutic doses, but its overdose can result in severe hepatotoxicity, a leading cause of drug-induced acute liver failure in the USA. Depletion of glutathione (GSH) is one of the initiating steps in APAP-induced hepatotoxicity; therefore, one strategy for restricting organ damage is to restore GSH levels by using GSH prodrugs. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an acetaminophen overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and I.V. administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteine amide (NACA), a novel antioxidant with higher bioavailability, and compared it with NAC in APAP-induced hepatotoxicity in C57BL/6 mice. Our results showed that NACA is better than NAC at a low dose (106mg/kg) in preventing oxidative stress and protecting against APAP-induced damage. NACA significantly increased GSH levels and the GSH/GSSG ratio in the liver to 66.5% and 60.5% of the control, respectively; and it reduced the level of ALT by 30%. However, at the dose used, NAC was not effective in combating the oxidative stress induced by APAP. Thus, NACA appears to be better than NAC in reducing the oxidative stress induced by APAP. It would be of great value in the health care field to develop drugs like NACA as more effective and safer options for the prevention and therapeutic intervention in APAP-induced toxicity.

  20. Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse.

    PubMed

    Tai, Minghui; Zhang, Jingyao; Song, Sidong; Miao, RunChen; Liu, Sushun; Pang, Qing; Wu, Qifei; Liu, Chang

    2015-07-01

    Acetaminophen (APAP) is widely used as a safety analgesic and antipyretic agent. Although considered safe at therapeutic doses, overdose of APAP can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. Luteolin is a naturally occurring flavonoid which is abundant in plants. The objective of this study was to investigate corresponding anti-oxidative and anti-inflammatory activities of luteolin, using acetaminophen-treated mice as a model system. Male C57BL/C mice were randomly divided into three groups (n=6 each). The control group was given phosphate buffered saline (PBS) orally. The APAP group was given APAP by intraperitoneal injection (i.p) at 300 mg/kg suspended in PBS. The luteolin-treated group was given APAP and luteolin (0-100 mg/kg/day, 1 or 3 days before APAP administration) suspended in PBS orally. 16 h after APAP administration, the liver and serum were collected to determine the liver injury. Luteolin administration significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) levels, as well as glutathione (GSH) depletion and decrease of superoxide dismutase (SOD). Luteolin restored SOD, GSH and GSH-px activities and depressed the expression of pro-inflammatory factors, such as inducible nitric oxide synthase (i-NOS), TNF-α, nuclear factor kappa B (NF-κB), and IL-6, respectively. Moreover, luteolin down-regulated acetaminophen-induced nitrotyrosine (NT) formation and endoplasmic reticulum (ER) stress. These results suggest the presence of anti-oxidative, anti-inflammatory and anti-ER stress properties of luteolin in response to acetaminophen-induced liver injury in mice.

  1. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update.

    PubMed

    Yoon, Eric; Babar, Arooj; Choudhary, Moaz; Kutner, Matthew; Pyrsopoulos, Nikolaos

    2016-06-28

    Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways. PMID:27350943

  2. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update

    PubMed Central

    Yoon, Eric; Babar, Arooj; Choudhary, Moaz; Kutner, Matthew; Pyrsopoulos, Nikolaos

    2016-01-01

    Abstract Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways. PMID:27350943

  3. Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice.

    PubMed

    Miyakawa, Kazuhisa; Joshi, Nikita; Sullivan, Bradley P; Albee, Ryan; Brandenberger, Christina; Jaeschke, Hartmut; McGill, Mitchell R; Scott, Michael A; Ganey, Patricia E; Luyendyk, James P; Roth, Robert A

    2015-10-01

    Acetaminophen (APAP)-induced liver injury in humans is associated with robust coagulation cascade activation and thrombocytopenia. However, it is not known whether coagulation-driven platelet activation participates in APAP hepatotoxicity. Here, we found that APAP overdose in mice caused liver damage accompanied by significant thrombocytopenia and accumulation of platelets in the liver. These changes were attenuated by administration of the direct thrombin inhibitor lepirudin. Platelet depletion with an anti-CD41 antibody also significantly reduced APAP-mediated liver injury and thrombin generation, indicated by the concentration of thrombin-antithrombin (TAT) complexes in plasma. Compared with APAP-treated wild-type mice, biomarkers of hepatocellular and endothelial damage, plasma TAT concentration, and hepatic platelet accumulation were reduced in mice lacking protease-activated receptor (PAR)-4, which mediates thrombin signaling in mouse platelets. However, selective hematopoietic cell PAR-4 deficiency did not affect APAP-induced liver injury or plasma TAT levels. These results suggest that interconnections between coagulation and hepatic platelet accumulation promote APAP-induced liver injury, independent of platelet PAR-4 signaling. Moreover, the results highlight a potential contribution of nonhematopoietic cell PAR-4 signaling to APAP hepatotoxicity. PMID:26179083

  4. BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils.

    PubMed

    Kojo, Ken; Ito, Yoshiya; Eshima, Koji; Nishizawa, Nobuyuki; Ohkubo, Hirotoki; Yokomizo, Takehiko; Shimizu, Takao; Watanabe, Masahiko; Majima, Masataka

    2016-01-01

    Leukotriene B4 (LTB4) is a potent chemoattractant for neutrophils. Signalling of LTB4 receptor type 1 (BLT1) has pro-inflammatory functions through neutrophil recruitment. In this study, we investigated whether BLT1 signalling plays a role in acetaminophen (APAP)-induced liver injury by affecting inflammatory responses including the accumulation of hepatic neutrophils. BLT1-knockout (BLT1(-/-)) mice and their wild-type (WT) counterparts were subjected to a single APAP overdose (300 mg/kg), and various parameters compared within 24 h after treatment. Compared with WT mice, BLT1(-/-) mice exhibited exacerbation of APAP-induced liver injury as evidenced by enhancement of alanine aminotransferase level, necrotic area, hepatic neutrophil accumulation, and expression of cytokines and chemokines. WT mice co-treated with APAP and ONO-0457, a specific antagonist for BLT1, displayed amplification of the injury, and similar results to those observed in BLT1(-/-) mice. Hepatic neutrophils in BLT1(-/-) mice during APAP hepatotoxicity showed increases in the production of reactive oxygen species and matrix metalloproteinase-9. Administration of isolated BLT1-deficient neutrophils into WT mice aggravated the liver injury elicited by APAP. These results demonstrate that BLT1 signalling dampens the progression of APAP hepatotoxicity through inhibiting an excessive accumulation of activated neutrophils. The development of a specific agonist for BLT1 could be useful for the prevention of APAP hepatotoxicity. PMID:27404729

  5. BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils

    PubMed Central

    Kojo, Ken; Ito, Yoshiya; Eshima, Koji; Nishizawa, Nobuyuki; Ohkubo, Hirotoki; Yokomizo, Takehiko; Shimizu, Takao; Watanabe, Masahiko; Majima, Masataka

    2016-01-01

    Leukotriene B4 (LTB4) is a potent chemoattractant for neutrophils. Signalling of LTB4 receptor type 1 (BLT1) has pro-inflammatory functions through neutrophil recruitment. In this study, we investigated whether BLT1 signalling plays a role in acetaminophen (APAP)-induced liver injury by affecting inflammatory responses including the accumulation of hepatic neutrophils. BLT1-knockout (BLT1−/−) mice and their wild-type (WT) counterparts were subjected to a single APAP overdose (300 mg/kg), and various parameters compared within 24 h after treatment. Compared with WT mice, BLT1−/− mice exhibited exacerbation of APAP-induced liver injury as evidenced by enhancement of alanine aminotransferase level, necrotic area, hepatic neutrophil accumulation, and expression of cytokines and chemokines. WT mice co-treated with APAP and ONO-0457, a specific antagonist for BLT1, displayed amplification of the injury, and similar results to those observed in BLT1−/− mice. Hepatic neutrophils in BLT1−/− mice during APAP hepatotoxicity showed increases in the production of reactive oxygen species and matrix metalloproteinase-9. Administration of isolated BLT1-deficient neutrophils into WT mice aggravated the liver injury elicited by APAP. These results demonstrate that BLT1 signalling dampens the progression of APAP hepatotoxicity through inhibiting an excessive accumulation of activated neutrophils. The development of a specific agonist for BLT1 could be useful for the prevention of APAP hepatotoxicity. PMID:27404729

  6. Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity.

    PubMed

    Cheng, Jie; Ma, Xiaochao; Krausz, Kristopher W; Idle, Jeffrey R; Gonzalez, Frank J

    2009-08-01

    Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAP-induced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands.

  7. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    PubMed

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  8. Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Ishii, Isao; Kamata, Shotaro; Hagiya, Yoshifumi; Abiko, Yumi; Kasahara, Tadashi; Kumagai, Yoshito

    2015-12-01

    The key mechanism for hepatotoxicity resulting from acetaminophen (APAP) overdose is cytochrome P450-dependent formation of N-acetyl-p-benzoquinone imine (NAPQI), a potent electrophilic metabolite that forms protein adducts. The fundamental roles of glutathione in the effective conjugation/clearance of NAPQI have been established, giving a molecular basis for the clinical use of N-acetylcysteine as a sole antidote. Recent evidence from in vitro experiments suggested that sulfide anions (S(2-)) to yield hydrogen sulfide anions (HS(-)) under physiological pH could effectively react with NAPQI. This study evaluated the protective roles of HS(-) against APAP-induced hepatotoxicity in mice. We utilized cystathionine γ-lyase-deficient (Cth(-/-)) mice that are highly sensitive to acetaminophen toxicity. Intraperitoneal injection of acetaminophen (150 mg/kg) into Cth(-/-) mice resulted in highly elevated levels of serum alanine/aspartate aminotransferases and lactate dehydrogenase associated with marked increases in oncotic hepatocytes; all of which were significantly inhibited by intraperitoneal preadministration of sodium hydrosulfide (NaHS). NaHS preadministration significantly suppressed APAP-induced serum malondialdehyde level increases without abrogating APAP-induced rapid depletion of hepatic glutathione. These results suggest that exogenous HS(-) protects hepatocytes by directly scavenging reactive NAPQI rather than by increasing cystine uptake and thereby elevating intracellular glutathione levels, which provides a novel therapeutic approach against acute APAP poisoning. PMID:26558465

  9. Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Ishii, Isao; Kamata, Shotaro; Hagiya, Yoshifumi; Abiko, Yumi; Kasahara, Tadashi; Kumagai, Yoshito

    2015-12-01

    The key mechanism for hepatotoxicity resulting from acetaminophen (APAP) overdose is cytochrome P450-dependent formation of N-acetyl-p-benzoquinone imine (NAPQI), a potent electrophilic metabolite that forms protein adducts. The fundamental roles of glutathione in the effective conjugation/clearance of NAPQI have been established, giving a molecular basis for the clinical use of N-acetylcysteine as a sole antidote. Recent evidence from in vitro experiments suggested that sulfide anions (S(2-)) to yield hydrogen sulfide anions (HS(-)) under physiological pH could effectively react with NAPQI. This study evaluated the protective roles of HS(-) against APAP-induced hepatotoxicity in mice. We utilized cystathionine γ-lyase-deficient (Cth(-/-)) mice that are highly sensitive to acetaminophen toxicity. Intraperitoneal injection of acetaminophen (150 mg/kg) into Cth(-/-) mice resulted in highly elevated levels of serum alanine/aspartate aminotransferases and lactate dehydrogenase associated with marked increases in oncotic hepatocytes; all of which were significantly inhibited by intraperitoneal preadministration of sodium hydrosulfide (NaHS). NaHS preadministration significantly suppressed APAP-induced serum malondialdehyde level increases without abrogating APAP-induced rapid depletion of hepatic glutathione. These results suggest that exogenous HS(-) protects hepatocytes by directly scavenging reactive NAPQI rather than by increasing cystine uptake and thereby elevating intracellular glutathione levels, which provides a novel therapeutic approach against acute APAP poisoning.

  10. Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Barman, P K; Mukherjee, R; Prusty, B K; Suklabaidya, S; Senapati, S; Ravindran, B

    2016-01-01

    Acetaminophen (N-acetyl-para-aminophenol (APAP)) toxicity causes acute liver failure by inducing centrilobular hepatic damage as a consequence of mitochondrial oxidative stress. Sterile inflammation, triggered by hepatic damage, facilitates gut bacterial translocation leading to systemic inflammation; TLR4-mediated activation by LPS has been shown to have a critical role in APAP-mediated hepatotoxicity. In this study, we demonstrate significant protection mediated by chitohexaose (Chtx) in mice challenged with a lethal dose of APAP (400 mg/kg b.w.). Decreased mortality by Chtx was associated with reduced hepatic damage, increased peritoneal migration of neutrophils, decreased mRNA expression of IL-1β as well as inhibition of inflammasome activation in liver. Further, an alternate mouse model of co-administration of a sublethal doses of APAP (200 mg/kg b.w.) and LPS (5 mg/kg b.w.) operating synergistically and mediating complete mortality was developed. Overwhelming inflammation, characterized by increased inflammatory cytokines (TNF-α, IL-1β and so on) in liver as well as in circulation and mortality was demonstrable in this model. Also, Chtx administration mediated significant reversal of mortality in APAP+LPS co-administered mice, which was associated with reduced IL-1β in liver and plasma cytokines in this model. In conclusion, Chtx being a small molecular weight linear carbohydrate offers promise for clinical management of liver failure associated with APAP overdose. PMID:27171266

  11. Differential Cytotoxicity of Acetaminophen in Mouse Macrophage J774.2 and Human Hepatoma HepG2 Cells: Protection by Diallyl Sulfide.

    PubMed

    Raza, Haider; John, Annie

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs), including acetaminophen (APAP), have been reported to induce cytotoxicity in cancer and non-cancerous cells. Overdose of acetaminophen (APAP) causes liver injury in humans and animals. Hepatic glutathione (GSH) depletion followed by oxidative stress and mitochondrial dysfunction are believed to be the main causes of APAP toxicity. The precise molecular mechanism of APAP toxicity in different cellular systems is, however, not clearly understood. Our previous studies on mouse macrophage J774.2 cells treated with APAP strongly suggest induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. In the present study, using human hepatoma HepG2 cells, we have further demonstrated that macrophages are a more sensitive target for APAP-induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis and DNA fragmentation were seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of drug metabolism by the different cytochrome P450s and detoxification by glutathione S-transferase enzyme systems. Our results demonstrate a marked increase in the activity and expression of glutathione transferase (GST) and multidrug resistance (MDR1) proteins in APAP-treated HepG2 cells compared to macrophages. This may explain the apparent resistance of HepG2 cells to APAP toxicity. However, treatment of these cells with diallyl sulfide (DAS, 200 μM), a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 μmol/ml for 18h) exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems. PMID:26714183

  12. Differential Cytotoxicity of Acetaminophen in Mouse Macrophage J774.2 and Human Hepatoma HepG2 Cells: Protection by Diallyl Sulfide.

    PubMed

    Raza, Haider; John, Annie

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs), including acetaminophen (APAP), have been reported to induce cytotoxicity in cancer and non-cancerous cells. Overdose of acetaminophen (APAP) causes liver injury in humans and animals. Hepatic glutathione (GSH) depletion followed by oxidative stress and mitochondrial dysfunction are believed to be the main causes of APAP toxicity. The precise molecular mechanism of APAP toxicity in different cellular systems is, however, not clearly understood. Our previous studies on mouse macrophage J774.2 cells treated with APAP strongly suggest induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. In the present study, using human hepatoma HepG2 cells, we have further demonstrated that macrophages are a more sensitive target for APAP-induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis and DNA fragmentation were seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of drug metabolism by the different cytochrome P450s and detoxification by glutathione S-transferase enzyme systems. Our results demonstrate a marked increase in the activity and expression of glutathione transferase (GST) and multidrug resistance (MDR1) proteins in APAP-treated HepG2 cells compared to macrophages. This may explain the apparent resistance of HepG2 cells to APAP toxicity. However, treatment of these cells with diallyl sulfide (DAS, 200 μM), a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 μmol/ml for 18h) exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems.

  13. Patient perception and knowledge of acetaminophen in a large family medicine service.

    PubMed

    Herndon, Christopher M; Dankenbring, Dawn M

    2014-06-01

    The use of acetaminophen is currently under increased scrutiny by the US Food and Drug Administration (FDA) due to the risk of intentional and more concerning, unintentional overdose-related hepatotoxicity. Acetaminophen is responsible for an estimated 48% of all acute liver failure diagnoses. The purpose of this study is to evaluate patient perception and knowledge of the safe use and potential toxicity of acetaminophen-containing products. The authors conducted a descriptive, 2-week study using a convenience sample from a large family medicine clinic waiting room. Survey questions assessed ability to identify acetaminophen, knowledge of the current recommended maximum daily dose, respondent acetaminophen use patterns, common adverse effects associated with acetaminophen, and respondent self-reported alcohol consumption. Acetaminophen safety information was provided to all persons regardless of participation in the study. Of the 102 patients who chose to participate, 79% recognized acetaminophen as a synonym of Tylenol, whereas only 9% identified APAP as a frequently used abbreviation. One third of respondents thought acetaminophen was synonymous with ibuprofen and naproxen. Approximately one fourth of patients correctly identified the then maximum recommended daily acetaminophen dose of 4 g. Seventy-eight percent of patients correctly identified hepatotoxicity as the most common serious adverse effect. We conclude that patient deficiencies in knowledge of acetaminophen recognition, dosing, and toxicity warrant public education by health professionals at all levels of interaction. Current initiatives are promising; however, further efforts are required.

  14. Metabolic phenotyping applied to pre-clinical and clinical studies of acetaminophen metabolism and hepatotoxicity.

    PubMed

    Coen, Muireann

    2015-02-01

    Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high-resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF.

  15. Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells

    PubMed Central

    Tobwala, Shakila; Khayyat, Ahdab; Fan, Weili

    2015-01-01

    Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over-the-counter antipyretic analgesic medications. Despite being safe at therapeutic doses, an accidental or intentional overdose can result in severe hepatotoxicity; a leading cause of drug-induced liver failure in the U.S. Depletion of glutathione (GSH) is implicated as an initiating event in APAP-induced toxicity. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an APAP overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and intravenous administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteineamide (NACA), a novel antioxidant, with higher bioavailability and compared it with NAC in APAP-induced hepatotoxicity in a human-relevant in vitro system, HepaRG. Our results indicated that exposure of HepaRG cells to APAP resulted in GSH depletion, reactive oxygen species (ROS) formation, increased lipid peroxidation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase release. Both NAC and NACA protected against APAP-induced hepatotoxicity by restoring GSH levels, scavenging ROS, inhibiting lipid peroxidation, and preserving mitochondrial membrane potential. However, NACA was better than NAC at combating oxidative stress and protecting against APAP-induced damage. The higher efficiency of NACA in protecting cells against APAP-induced toxicity suggests that NACA can be developed into a promising therapeutic option for treatment of an APAP overdose. PMID:25245075

  16. Immune mechanisms in acetaminophen-induced acute liver failure.

    PubMed

    Krenkel, Oliver; Mossanen, Jana C; Tacke, Frank

    2014-12-01

    An overdose of acetaminophen (N-acetyl-p-aminophenol, APAP), also termed paracetamol, can cause severe liver damage, ultimately leading to acute liver failure (ALF) with the need of liver transplantation. APAP is rapidly taken up from the intestine and metabolized in hepatocytes. A small fraction of the metabolized APAP forms cytotoxic mitochondrial protein adducts, leading to hepatocyte necrosis. The course of disease is not only critically influenced by dose of APAP and the initial hepatocyte damage, but also by the inflammatory response following acetaminophen-induced liver injury (AILI). As revealed by mouse models of AILI and corresponding translational studies in ALF patients, necrotic hepatocytes release danger-associated-molecular patterns (DAMPs), which are recognized by resident hepatic macrophages, Kupffer cell (KC), and neutrophils, leading to the activation of these cells. Activated hepatic macrophages release various proinflammatory cytokines, such as TNF-α or IL-1β, as well as chemokines (e.g., CCL2) thereby further enhancing inflammation and increasing the influx of immune cells, like bone-marrow derived monocytes and neutrophils. Monocytes are mainly recruited via their receptor CCR2 and aggravate inflammation. Infiltrating monocytes, however, can mature into monocyte-derived macrophages (MoMF), which are, in cooperation with neutrophils, also involved in the resolution of inflammation. Besides macrophages and neutrophils, distinct lymphocyte populations, especially γδ T cells, are also linked to the inflammatory response following an APAP overdose. Natural killer (NK), natural killer T (NKT) and T cells possibly further perpetuate inflammation in AILI. Understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression is essential to identify novel therapeutic targets for human disease. PMID:25568858

  17. Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity

    PubMed Central

    2013-01-01

    Background Adenosine triphosphate (ATP) is secreted from hepatocytes under physiological conditions and plays an important role in liver biology through the activation of P2 receptors. Conversely, higher extracellular ATP concentrations, as observed during necrosis, trigger inflammatory responses that contribute to the progression of liver injury. Impaired calcium (Ca2+) homeostasis is a hallmark of acetaminophen (APAP)-induced hepatotoxicity, and since ATP induces mobilization of the intracellular Ca2+ stocks, we evaluated if the release of ATP during APAP-induced necrosis could directly contribute to hepatocyte death. Results APAP overdose resulted in liver necrosis, massive neutrophil infiltration and large non-perfused areas, as well as remote lung inflammation. In the liver, these effects were significantly abrogated after ATP metabolism by apyrase or P2X receptors blockage, but none of the treatments prevented remote lung inflammation, suggesting a confined local contribution of purinergic signaling into liver environment. In vitro, APAP administration to primary mouse hepatocytes and also HepG2 cells caused cell death in a dose-dependent manner. Interestingly, exposure of HepG2 cells to APAP elicited significant release of ATP to the supernatant in levels that were high enough to promote direct cytotoxicity to healthy primary hepatocytes or HepG2 cells. In agreement to our in vivo results, apyrase treatment or blockage of P2 receptors reduced APAP cytotoxicity. Likewise, ATP exposure caused significant higher intracellular Ca2+ signal in APAP-treated primary hepatocytes, which was reproduced in HepG2 cells. Quantitative real time PCR showed that APAP-challenged HepG2 cells expressed higher levels of several purinergic receptors, which may explain the hypersensitivity to extracellular ATP. This phenotype was confirmed in humans analyzing liver biopsies from patients diagnosed with acute hepatic failure. Conclusion We suggest that under pathological conditions

  18. Acetaminophen

    MedlinePlus

    ... headaches, muscle aches, menstrual periods, colds and sore throats, toothaches, backaches, and reactions to vaccinations (shots), and ... acetaminophen to a child who has a sore throat that is severe or does not go away, ...

  19. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine

    SciTech Connect

    Stern, Stephan T.; Bruno, Mary K.; Hennig, Gayle E.; Horton, Robert A.; Roberts, Jeanette C.; Cohen, Steven D. . E-mail: scohen@mcp.edu

    2005-01-15

    Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Recent studies suggest a contributory role for glutathione (GSH)-derived conjugates of APAP in the development of nephrotoxicity. Inhibitors of either {gamma}-glutamyl transpeptidase ({gamma}-GT) or the probenecid-sensitive organic anion transporter ameliorate APAP-induced nephrotoxicity but not hepatotoxicity in mice and inhibition of {gamma}-GT similarly protected rats from APAP nephrotoxicity. Protection against APAP nephrotoxicity by disruption of these GSH conjugate transport and metabolism pathways suggests that GSH conjugates are involved. APAP-induced renal injury may involve the acetaminophen-glutathione (APAP-GSH) conjugate or a metabolite derived from APAP-GSH. Acetaminophen-cysteine (APAP-CYS) is a likely candidate for involvement in APAP nephrotoxicity because it is both a product of the {gamma}-GT pathway and a probable substrate for the organic anion transporter. The present experiments demonstrated that APAP-CYS treatment alone depleted renal but not hepatic glutathione (GSH) in a dose-responsive manner. This depletion of renal GSH may predispose the kidney to APAP nephrotoxicity by diminishing GSH-mediated detoxification mechanisms. Indeed, pretreatment of male CD-1 mice with APAP-CYS before challenge with a threshold toxic dose of APAP resulted in significant enhancement of APAP-induced nephrotoxicity. This was evidenced by histopathology and plasma blood urea nitrogen (BUN) levels at 24 h after APAP challenge. APAP alone was minimally nephrotoxic and APAP-CYS alone produced no detectable injury. By contrast, APAP-CYS pretreatment did not alter the liver injury induced by APAP challenge. These data are consistent with there being a selective, contributory role for APAP-GSH-derived metabolites in APAP-induced renal injury that may involve renal-selective GSH depletion.

  20. Differential Cytotoxicity of Acetaminophen in Mouse Macrophage J774.2 and Human Hepatoma HepG2 Cells: Protection by Diallyl Sulfide

    PubMed Central

    Raza, Haider; John, Annie

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs), including acetaminophen (APAP), have been reported to induce cytotoxicity in cancer and non-cancerous cells. Overdose of acetaminophen (APAP) causes liver injury in humans and animals. Hepatic glutathione (GSH) depletion followed by oxidative stress and mitochondrial dysfunction are believed to be the main causes of APAP toxicity. The precise molecular mechanism of APAP toxicity in different cellular systems is, however, not clearly understood. Our previous studies on mouse macrophage J774.2 cells treated with APAP strongly suggest induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. In the present study, using human hepatoma HepG2 cells, we have further demonstrated that macrophages are a more sensitive target for APAP—induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis and DNA fragmentation were seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of drug metabolism by the different cytochrome P450s and detoxification by glutathione S-transferase enzyme systems. Our results demonstrate a marked increase in the activity and expression of glutathione transferase (GST) and multidrug resistance (MDR1) proteins in APAP-treated HepG2 cells compared to macrophages. This may explain the apparent resistance of HepG2 cells to APAP toxicity. However, treatment of these cells with diallyl sulfide (DAS, 200 μM), a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 μmol/ml for 18h) exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems. PMID:26714183

  1. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

    PubMed

    Vliegenthart, A D B; Shaffer, J M; Clarke, J I; Peeters, L E J; Caporali, A; Bateman, D N; Wood, D M; Dargan, P I; Craig, D G; Moore, J K; Thompson, A I; Henderson, N C; Webb, D J; Sharkey, J; Antoine, D J; Park, B K; Bailey, M A; Lader, E; Simpson, K J; Dear, J W

    2015-01-01

    Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury. PMID:26489516

  2. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

    PubMed

    Vliegenthart, A D B; Shaffer, J M; Clarke, J I; Peeters, L E J; Caporali, A; Bateman, D N; Wood, D M; Dargan, P I; Craig, D G; Moore, J K; Thompson, A I; Henderson, N C; Webb, D J; Sharkey, J; Antoine, D J; Park, B K; Bailey, M A; Lader, E; Simpson, K J; Dear, J W

    2015-10-22

    Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

  3. Comparison of the protective actions of N-acetylcysteine, hypotaurine and taurine against acetaminophen-induced hepatotoxicity in the rat.

    PubMed

    Acharya, Miteshkumar; Lau-Cam, Cesar A

    2010-01-01

    When used in overdoses, acetaminophen (APAP) is a common cause of morbidity and mortality in humans. At present, N-acetylcysteine (NAC) is the antidote of choice for acetaminophen overdoses. Prompt administration of NAC can prevent the deleterious actions of APAP in the liver. In view of the similarities in antioxidant effects demonstrated by NAC, hypotaurine (HYTAU) and taurine (TAU) in this and other our laboratories, the present study was undertaken to compare these compounds for the ability to attenuate plasma and liver biochemical changes associated with a toxic dose of APAP. For this purpose, fasted male Sprague-Dawley rats, 225-250 g in weight, were intraperitoneally treated with APAP (800 mg/kg), NAC, HYTAU or TAU (2.4 mM/kg) followed 30 min later by APAP, or 50% PEG 400 (the vehicle for APAP). At 6 hr after APAP administration, all animals were sacrificed by decapitation and their blood and livers collected. The plasma fractions were analyzed for indices of liver damage (alanine transaminase, aspartate transaminase, lactate dehydrogenase), levels of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione, and activities of glutathione reductase (GR), glutathione S-transferase (GST) and gamma-glutamylcisteinyl synthetase (GCS). Suitable liver homogenates were analyzed for the same biochemical parameters as the plasma but indices of liver damage. By itself, APAP increased MDA formation and had a significant lowering influence on the levels of GSH and GSSG, the GSH/GSSH ratio, and the activities of GR, GST and GCS both in the plasma and liver. In addition, APAP promoted the leakage of transaminases and lactate dehydrogenase from the liver into the plasma. Without exceptions, a pretreatment with a sulfur-containing compound led to a significant attenuation of the liver injury and the biochemical changes induced by APAP. Within a narrow range of potency differences, HYTAU appeared to be the most protective and TAU the least. The present results

  4. Hepato-protective effects of six schisandra lignans on acetaminophen-induced liver injury are partially associated with the inhibition of CYP-mediated bioactivation.

    PubMed

    Jiang, Yiming; Fan, Xiaomei; Wang, Ying; Tan, Huasen; Chen, Pan; Zeng, Hang; Huang, Min; Bi, Huichang

    2015-04-25

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra fructus is widely-used traditional Chinese medicine which possesses hepato-protective potential. Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), and Schisantherin A (SthA) are the major bioactive lignans. Most recently, we found SolB exerts significant hepato-protection against APAP-induced liver injury. In this study, the protective effects of the other five schisandra lignans against APAP-induced acute hepatotoxicity in mice were investigated and compared with that of SolB. The results of morphological and biochemical assessment clearly demonstrated significant protective effects of SinA, SinB, SinC, SolA, SolB, and SthA against APAP-induced liver injury. Among these schisandra lignans, SinC and SolB exerted the strongest hepato-protective effects against APAP-induced hepatotoxicity. Six lignans pretreatment before APAP dosing could prevent the depletions of total liver glutathione (GSH) and mitochondrial GSH caused by APAP. Additionally, the lignans treatment inhibited the enzymatic activities of three CYP450 isoforms (CYP2E1, CYP1A2, and CYP3A11) related to APAP bioactivation, and further decreased the formation of APAP toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) in mouse microsomal incubation system. This study demonstrated that SinA, SinB, SinC, SolA, SolB and SthA exhibited significant protective actions toward APAP-induced liver injury, which was partially associated with the inhibition of CYP-mediated APAP bioactivation.

  5. Hydrocodone and acetaminophen overdose

    MedlinePlus

    ... Walls RM, et al, eds. Rosen's Emergency Medicine: Concepts and Clinical Practice . 8th ed. Philadelphia, PA: Elsevier ... Walls RM, et al, eds. Rosen's Emergency Medicine: Concepts and Clinical Practice . 8th ed. Philadelphia, PA: Elsevier ...

  6. Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose.

    PubMed

    Arai, Tomoya; Koyama, Ryo; Yuasa, Makoto; Kitamura, Daisuke; Mizuta, Ryushin

    2014-01-01

    Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.

  7. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α–Mediated Apoptosis

    PubMed Central

    Yan, Tingting; Wang, Hong; Zhao, Min; Yagai, Tomoki; Chai, Yingying; Krausz, Kristopher W.; Xie, Cen; Cheng, Xuefang; Zhang, Jun; Che, Yuan; Li, Feiyan; Wu, Yuzheng; Brocker, Chad N.; Gonzalez, Frank J.

    2016-01-01

    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics–pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factor α (TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics–pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL’s protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID:26965985

  8. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α-Mediated Apoptosis.

    PubMed

    Yan, Tingting; Wang, Hong; Zhao, Min; Yagai, Tomoki; Chai, Yingying; Krausz, Kristopher W; Xie, Cen; Cheng, Xuefang; Zhang, Jun; Che, Yuan; Li, Feiyan; Wu, Yuzheng; Brocker, Chad N; Gonzalez, Frank J; Wang, Guangji; Hao, Haiping

    2016-05-01

    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID:26965985

  9. Mechanism of protection by metallothionein against acetaminophen hepatotoxicity

    SciTech Connect

    Saito, Chieko; Yan, H.-M.; Artigues, Antonio; Villar, Maria T.; Farhood, Anwar; Jaeschke, Hartmut

    2010-01-15

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the US. Metallothionein (MT) expression attenuates APAP-induced liver injury. However, the mechanism of this protection remains incompletely understood. To address this issue, C57BL/6 mice were treated with 100 mumol/kg ZnCl{sub 2} for 3 days to induce MT. Twenty-four hours after the last dose of zinc, the animals received 300 mg/kg APAP. Liver injury (plasma ALT activities, area of necrosis), DNA fragmentation, peroxynitrite formation (nitrotyrosine staining), MT expression, hepatic glutathione (GSH), and glutathione disulfide (GSSG) levels were determined after 6 h. APAP alone caused severe liver injury with oxidant stress (increased GSSG levels), peroxynitrite formation, and DNA fragmentation, all of which were attenuated by zinc-induced MT expression. In contrast, MT knockout mice were not protected by zinc. Hydrogen peroxide-induced cell injury in primary hepatocytes was dependent only on the intracellular GSH levels but not on MT expression. Thus, the protective effect of MT in vivo was not due to the direct scavenging of reactive oxygen species. Zinc treatment had no effect on the early GSH depletion kinetics after APAP administration, which is an indicator of the metabolic activation of APAP to its reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). However, MT was able to effectively trap NAPQI by covalent binding. We conclude that MT scavenges some of the excess NAPQI after GSH depletion and prevents covalent binding to cellular proteins, which is the trigger for the propagation of the cell injury mechanisms through mitochondrial dysfunction and nuclear DNA damage.

  10. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury

    SciTech Connect

    Xie, Yuchao; Ramachandran, Anup; Breckenridge, David G.; Liles, John T.; Lebofsky, Margitta; Farhood, Anwar; Jaeschke, Hartmut

    2015-07-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24 h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5 h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1 inhibitor is

  11. Heroin overdose

    MedlinePlus

    Acetomorphine overdose; Diacetylmorphine overdose; Opiate overdose; Opioid overdose ... Saunders; 2015:chap 317. National Institute on Drug Abuse. Heroin. www.drugabuse.gov/drugs-abuse/heroin . Updated ...

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

    SciTech Connect

    Williams, C. David; Koerner, Michael R.; Lampe, Jed N.; Farhood, Anwar; Jaeschke, Hartmut

    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

  13. Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration.

    PubMed

    Jiang, Yiming; Fan, Xiaomei; Wang, Ying; Chen, Pan; Zeng, Hang; Tan, Huasen; Gonzalez, Frank J; Huang, Min; Bi, Huichang

    2015-01-01

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration. PMID:25319358

  14. Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration.

    PubMed

    Jiang, Yiming; Fan, Xiaomei; Wang, Ying; Chen, Pan; Zeng, Hang; Tan, Huasen; Gonzalez, Frank J; Huang, Min; Bi, Huichang

    2015-01-01

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration.

  15. Dextromethorphan overdose

    MedlinePlus

    DXM overdose; Robo overdose; Orange crush overdose; Red devils overdose; Triple C's overdose ... streets under the names: Orange crush Triple Cs Red Devils Skittles Dex Other products may also contain ...

  16. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the {gamma}-glutamyl cycle

    SciTech Connect

    Stern, Stephan T.; Bruno, Mary K.; Horton, Robert A.; Hill, Dennis W.; Roberts, Jeanette C.; Cohen, Steven D. . E-mail: scohen@mcp.edu

    2005-01-15

    Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Our recent investigations have focused on the possible involvement of glutathione-derived APAP metabolites in APAP nephrotoxicity and have demonstrated that administration of acetaminophen-cysteine (APAP-CYS) potentiated APAP-induced renal injury with no effects on APAP-induced liver injury. Additionally, APAP-CYS treatment alone resulted in a dose-responsive renal GSH depletion. This APAP-CYS-induced renal GSH depletion could interfere with intrarenal detoxification of APAP or its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) and may be the mechanism responsible for the potentiation of APAP nephrotoxicity. Renal-specific GSH depletion has been demonstrated in mice and rats following administration of amino acid {gamma}-glutamyl acceptor substrates for {gamma}-glutamyl transpeptidase ({gamma}-GT). The present study sought to determine if APAP-CYS-induced renal glutathione depletion is the result of disruption of the {gamma}-glutamyl cycle through interaction with {gamma}-GT. The results confirmed that APAP-CYS-induced renal GSH depletion was antagonized by the {gamma}-glutamyl transpeptidase ({gamma}-GT) inhibitor acivicin. In vitro analysis demonstrated that APAP-CYS is a {gamma}-glutamyl acceptor for both murine and bovine renal {gamma}-GT. Analysis of urine from mice pretreated with acivicin and then treated with APAP, APAP-CYS, or acetaminophen-glutathione identified a {gamma}-glutamyl-cysteinyl-acetaminophen metabolite. These findings are consistent with the hypothesis that APAP-CYS contributes to APAP nephrotoxicity by depletion of renal GSH stores through interaction with the {gamma}-glutamyl cycle.

  17. Role of food-derived antioxidant agents against acetaminophen-induced hepatotoxicity.

    PubMed

    Eugenio-Pérez, Dianelena; Montes de Oca-Solano, Héctor Adolfo; Pedraza-Chaverri, José

    2016-10-01

    Context Acetaminophen (APAP), also known as paracetamol and N-acetyl p-aminophenol, is one of the most frequently used drugs for analgesic and antipyretic purposes on a worldwide basis. It is safe and effective at recommended doses but has the potential for causing hepatotoxicity and acute liver failure (ALF) with overdose. To solve this problem, different strategies have been developed, including the use of compounds isolated from food, which have been studied to characterize their efficacy as natural dietary antioxidants. Objective The objective of this study is to show the beneficial effects of a variety of natural compounds and their use against acetaminophen-induced hepatotoxicity. Methods PubMed database was reviewed to compile data about natural compounds with hepatoprotective effects against APAP toxicity. Results and conclusion As a result, the health-promoting properties of 13 different food-derived compounds with protective effect against APAP-induced hepatotoxicity were described as well as the mechanisms involved in hepatoprotection. PMID:26955890

  18. Therapeutic and protective effects of Caesalpinia gilliesii and Cajanus cajan proteins against acetaminophen overdose-induced renal damage.

    PubMed

    Aly, Hanan F; Rizk, Maha Z; Abo-Elmatty, Dina M; Desoky, M M; Ibrahim, N A; Younis, Eman A

    2016-04-01

    The present work aims to evaluate the protective and ameliorative effects of two plant-derived proteins obtained from the seeds of Cajanus cajan and Caesalpinia gilliesii(Leguminosae) against the toxic effects of acetaminophen in kidney after chronic dose through determination of certain biochemical markers including total urea, creatinine, and kidney marker enzyme, that is, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In addition histopathological examination of intoxicated and treated kidney with both proteins was performed. The present results show a significant increase in serum total urea and creatinine, while significant decrease in GAPDH. Improvement in all biochemical parameters studied was demonstrated, which was documented by the amelioration signs in rats kidney architecture. Thus, both plant protein extracts can counteract the nephrotoxic process, minimize damage to the kidney, delay disease progression, and reduce its complications. PMID:24280655

  19. c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity

    SciTech Connect

    Saito, Chieko; Lemasters, John J.; Jaeschke, Hartmut

    2010-07-15

    Acetaminophen (APAP) overdose, which causes liver injury in animals and humans, activates c-jun N-terminal kinase (JNK). Although it was shown that the JNK inhibitor SP600125 effectively reduced APAP hepatotoxicity, the mechanisms of protection remain unclear. C57Bl/6 mice were treated with 10 mg/kg SP600125 or vehicle (8% dimethylsulfoxide) 1 h before 600 mg/kg APAP administration. APAP time-dependently induced JNK activation (detected by JNK phosphorylation). SP600125, but not the vehicle, reduced JNK activation, attenuated mitochondrial Bax translocation and prevented the mitochondrial release of apoptosis-inducing factor at 4-12 h. Nuclear DNA fragmentation, nitrotyrosine staining, tissue GSSG levels and liver injury (plasma ALT release and necrosis) were partially attenuated by the vehicle (- 65%) and completely eliminated by SP600125 (- 98%) at 6 and 12 h. Furthermore, SP600125 attenuated the increase of inducible nitric oxide synthase (iNOS) mRNA and protein. However, APAP did not enhance plasma nitrite + nitrate levels (NO formation); SP600125 had no effect on this parameter. The iNOS inhibitor L-NIL did not reduce NO formation or injury after APAP but prevented NO formation caused by endotoxin. Since SP600125 completely eliminated the increase in hepatic GSSG levels, an indicator of mitochondrial oxidant stress, it is concluded that the inhibition of peroxynitrite was mainly caused by reduced superoxide formation. Our data suggest that the JNK inhibitor SP600125 protects against APAP-induced liver injury in part by attenuation of mitochondrial Bax translocation but mainly by preventing mitochondrial oxidant stress and peroxynitrite formation and thereby preventing the mitochondrial permeability transition pore opening, a key event in APAP-induced cell necrosis.

  20. STAT3, a Key Parameter of Cytokine-Driven Tissue Protection during Sterile Inflammation – the Case of Experimental Acetaminophen (Paracetamol)-Induced Liver Damage

    PubMed Central

    Mühl, Heiko

    2016-01-01

    Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol) overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger-associated molecular patterns (DAMPs) from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT)-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL)-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients, standard therapy may fail and APAP intoxication can proceed toward a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions. PMID:27199988

  1. Is montelukast as effective as N-acetylcysteine in hepatic injury due to acetaminophen intoxication in rats?

    PubMed

    İçer, Mustafa; Zengin, Yilmaz; Gunduz, Ercan; Dursun, Recep; Durgun, Hasan Mansur; Turkcu, Gul; Yuksel, Hatice; Üstündağ, Mehmet; Guloglu, Cahfer

    2016-01-01

    This study aims to investigate the acute protective effect of montelukast sodium in hepatic injury secondary to acetaminophen (APAP) intoxication. This study used 60 rats. The rats were grouped into 6 groups. The control group was administered oral distilled water 10 ml/kg, the APAP group oral APAP 1 g/kg, the montelukast sodium (MK) group oral MK 30 mg/kg, the acetaminophen+N-acetylcysteine (APAP+NAC) group oral APAP 1 g/kg, followed by a single dose of intraperitoneal NAC 1.5 g/kg three hours later, the acetaminophen+montelukast sodium (APAP+MK) group oral APAP 1 g/kg, followed by oral MK 30 mg/kg 3 h later, the acetaminophen+N-acetylcysteine+montelukast sodium (APAP+NAC+MK) group oral APAP 1 g/kg, followed by a single intraperitoneal NAC 1.5 g/kg plus oral MK 30 mg/kg 3 h later. Blood and liver tissue samples were taken 24h after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were studied from the blood samples. Liver tissue samples were used for histopathological examination. Compared with the control group, serum AST and ALT activities were higher in the APAP and APAP+NAC groups. APAP+NAC, APAP+MK, and APAP+NAC+MK groups had reduced serum ALT and AST activities than the group administered APAP alone. APAP+MK and APAP+NAC+MK groups had a lower serum ALP activity than the control group. Histopathologically, there was a difference between the group administered APAP alone and the APAP+MK and APAP+NAC+MK groups. MK is as protective as NAC in liver tissue in APAP intoxication in rats.

  2. Is montelukast as effective as N-acetylcysteine in hepatic injury due to acetaminophen intoxication in rats?

    PubMed

    İçer, Mustafa; Zengin, Yilmaz; Gunduz, Ercan; Dursun, Recep; Durgun, Hasan Mansur; Turkcu, Gul; Yuksel, Hatice; Üstündağ, Mehmet; Guloglu, Cahfer

    2016-01-01

    This study aims to investigate the acute protective effect of montelukast sodium in hepatic injury secondary to acetaminophen (APAP) intoxication. This study used 60 rats. The rats were grouped into 6 groups. The control group was administered oral distilled water 10 ml/kg, the APAP group oral APAP 1 g/kg, the montelukast sodium (MK) group oral MK 30 mg/kg, the acetaminophen+N-acetylcysteine (APAP+NAC) group oral APAP 1 g/kg, followed by a single dose of intraperitoneal NAC 1.5 g/kg three hours later, the acetaminophen+montelukast sodium (APAP+MK) group oral APAP 1 g/kg, followed by oral MK 30 mg/kg 3 h later, the acetaminophen+N-acetylcysteine+montelukast sodium (APAP+NAC+MK) group oral APAP 1 g/kg, followed by a single intraperitoneal NAC 1.5 g/kg plus oral MK 30 mg/kg 3 h later. Blood and liver tissue samples were taken 24h after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were studied from the blood samples. Liver tissue samples were used for histopathological examination. Compared with the control group, serum AST and ALT activities were higher in the APAP and APAP+NAC groups. APAP+NAC, APAP+MK, and APAP+NAC+MK groups had reduced serum ALT and AST activities than the group administered APAP alone. APAP+MK and APAP+NAC+MK groups had a lower serum ALP activity than the control group. Histopathologically, there was a difference between the group administered APAP alone and the APAP+MK and APAP+NAC+MK groups. MK is as protective as NAC in liver tissue in APAP intoxication in rats. PMID:26462568

  3. Non-cytotoxic concentrations of acetaminophen induced mitochondrial biogenesis and antioxidant response in HepG2 cells.

    PubMed

    Zhang, Tingfen; Zhang, Qiang; Guo, Jiabin; Yuan, Haitao; Peng, Hui; Cui, Lan; Yin, Jian; Zhang, Li; Zhao, Jun; Li, Jin; White, Andrew; Carmichael, Paul L; Westmoreland, Carl; Peng, Shuangqing

    2016-09-01

    Mitochondrial dysfunction has been implicated in acute, severe liver injury caused by overdose of acetaminophen (APAP). However, whether mitochondrial biogenesis is involved is unclear. Here we demonstrated that mitochondrial biogenesis, as indicated by the amounts of mitochondrial DNA and proteins, increased significantly in HepG2 cells exposed to low, non-cytotoxic concentrations of APAP. This heightened response was accompanied by upregulated expression of PGC-1α, NRF-1 and TFAM, which are key transcriptional regulators of mitochondrial biogenesis. Additionally, antioxidants including glutathione, MnSOD, HO-1, NQO1, and Nrf2 were also significantly upregulated. In contrast, for HepG2 cells exposed to high, cytotoxic concentration of APAP, mitochondrial biogenesis was inhibited and the expression of its regulatory proteins and antioxidants were concentration-dependently downregulated. In summary, our study indicated that mitochondrial biogenesis, along with antioxidant induction, may be an important cellular adaptive mechanism counteracting APAP-induced toxicity and overwhelming this cytoprotective capacity could result in liver injury. PMID:27438896

  4. Acetaminophen metabolism, cytotoxicity, and genotoxicity in rat primary hepatocyte cultures

    SciTech Connect

    Milam, K.M.; Byard, J.L.

    1985-06-30

    Acetaminophen (APAP) metabolism, cytotoxicity, and genotoxicity were measured in primary cultures of rat hepatocytes. Although 3 mM APAP caused a slight increase in cellular release of lactate dehydrogenase into the culture medium, cellular glutathione concentration (an index of APAP metabolism) was reduced by 50%. APAP at 7 mM was significantly more toxic to these hepatocytes and had a similar but more marked effect on glutathione concentrations. In spite of its cytotoxicity, neither dose of APAP stimulated DNA repair synthesis when monitored by the rate of incorporation of (/sup 3/H)thymidine into DNA following exposure to APAP. Thus, although APAP has been shown to be both hepato- and nephrotoxic in several in vivo and in vitro systems, the reactive toxic metabolite of APAP is not genotoxic in rat primary hepatocyte cultures.

  5. Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3β axis.

    PubMed

    Rizvi, Fatima; Mathur, Alpana; Kakkar, Poonam

    2015-10-01

    Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3β and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI. PMID:26286854

  6. Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3β axis.

    PubMed

    Rizvi, Fatima; Mathur, Alpana; Kakkar, Poonam

    2015-10-01

    Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3β and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI.

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

    PubMed

    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

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

    PubMed

    Karthivashan, Govindarajan; Kura, Aminu Umar; Arulselvan, Palanisamy; Md Isa, Norhaszalina; Fakurazi, Sharida

    2016-01-01

    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 treatment

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

    PubMed Central

    Karthivashan, Govindarajan; Kura, Aminu Umar; Arulselvan, Palanisamy; Md. Isa, Norhaszalina

    2016-01-01

    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 treatment

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

    PubMed

    Karthivashan, Govindarajan; Kura, Aminu Umar; Arulselvan, Palanisamy; Md Isa, Norhaszalina; Fakurazi, Sharida

    2016-01-01

    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 treatment

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

    MedlinePlus

    ... Careful: Acetaminophen in pain relief medicines can cause liver damage Share Tweet Linkedin Pin it More sharing ... word or may have the abbreviation "APAP." Severe liver damage may occur and may lead to death ...

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

    PubMed

    James, Laura; Yan, Ke; Pence, Lisa; Simpson, Pippa; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda; Kearns, Gregory; Beger, Richard

    2015-01-01

    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. PMID:26208104

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

    PubMed

    James, Laura; Yan, Ke; Pence, Lisa; Simpson, Pippa; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda; Kearns, Gregory; Beger, Richard

    2015-01-01

    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.

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

    SciTech Connect

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

    2014-11-15

    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

  15. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.

    PubMed

    Patterson, Andrew D; Shah, Yatrik M; Matsubara, Tsutomu; Krausz, Kristopher W; Gonzalez, Frank J

    2012-07-01

    Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H(2)O(2) levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation.

  16. Different Contribution of Redox-Sensitive Transient Receptor Potential Channels to Acetaminophen-Induced Death of Human Hepatoma Cell Line

    PubMed Central

    Badr, Heba; Kozai, Daisuke; Sakaguchi, Reiko; Numata, Tomohiro; Mori, Yasuo

    2016-01-01

    Acetaminophen (APAP) is a safe analgesic antipyretic drug at prescribed doses. Its overdose, however, can cause life-threatening liver damage. Though, involvement of oxidative stress is widely acknowledged in APAP-induced hepatocellular death, the mechanism of this increased oxidative stress and the associated alterations in Ca2+ homeostasis are still unclear. Among members of transient receptor potential (TRP) channels activated in response to oxidative stress, we here identify that redox-sensitive TRPV1, TRPC1, TRPM2, and TRPM7 channels underlie Ca2+ entry and downstream cellular damages induced by APAP in human hepatoma (HepG2) cells. Our data indicate that APAP treatment of HepG2 cells resulted in increased reactive oxygen species (ROS) production, glutathione (GSH) depletion, and Ca2+ entry leading to increased apoptotic cell death. These responses were significantly suppressed by pretreatment with the ROS scavengers N-acetyl-L-cysteine (NAC) and 4,5-dihydroxy-1,3-benzene disulfonic acid disodium salt monohydrate (Tiron), and also by preincubation of cells with the glutathione inducer Dimethylfumarate (DMF). TRP subtype-targeted pharmacological blockers and siRNAs strategy revealed that suppression of either TRPV1, TRPC1, TRPM2, or TRPM7 reduced APAP-induced ROS formation, Ca2+ influx, and cell death; the effects of suppression of TRPV1 or TRPC1, known to be activated by oxidative cysteine modifications, were stronger than those of TRPM2 or TRPM7. Interestingly, TRPV1 and TRPC1 were labeled by the cysteine-selective modification reagent, 5,5′-dithiobis (2-nitrobenzoic acid)-2biotin (DTNB-2Bio), and this was attenuated by pretreatment with APAP, suggesting that APAP and/or its oxidized metabolites act directly on the modification target cysteine residues of TRPV1 and TRPC1 proteins. In human liver tissue, TRPV1, TRPC1, TRPM2, and TRPM7 channels transcripts were localized mainly to hepatocytes and Kupffer cells. Our findings strongly suggest that APAP

  17. Isopropanol overdose

    MedlinePlus

    Rubbing alcohol overdose; Isopropyl alcohol overdose ... Isopropyl alcohol can be harmful if it is swallowed or gets in the eyes. ... These products contain isopropanol: Alcohol swabs Cleaning supplies ... Rubbing alcohol Other products may also contain isopropanol.

  18. Estrogen overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002584.htm Estrogen overdose To use the sharing features on this page, please enable JavaScript. Estrogen is a female hormone. Estrogen overdose occurs when ...

  19. Pheniramine overdose

    MedlinePlus

    Pheniramine is a type of medicine called an antihistamine. It helps relieve allergy symptoms. Pheniramine overdose occurs ... recovery are good. Few people die from an antihistamine overdose. With extremely high doses of antihistamines, serious ...

  20. Phenindamine overdose

    MedlinePlus

    Phenindamine is a type of medicine called an antihistamine. It helps relieve allergy symptoms. Phenindamine overdose occurs ... recovery are good. Few people die from an antihistamine overdose. With extremely high doses of antihistamines, serious ...

  1. Dimenhydrinate overdose

    MedlinePlus

    Dimenhydrinate is a type of medicine called an antihistamine. Dimenhydrinate overdose occurs when someone takes more than ... permanent disability. Few people actually die from an antihistamine overdose. Keep all medicines in child-proof bottles ...

  2. Aminophylline overdose

    MedlinePlus

    Theophylline overdose; Xanthine overdose ... Aminophylline and theophylline can be poisonous in large doses. ... Aminophylline and theophylline are found in medicines with these names (with brand names in parentheses): Aminophylline Theophylline (Theo-Dur, Slo-Phyllin, ...

  3. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis

    PubMed Central

    2014-01-01

    Background An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Methods Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). Results In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. Conclusions APAP overdose can cause liver injury. Our result indicate

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

    SciTech Connect

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

    2011-03-15

    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.

  5. Translational biomarkers of acetaminophen-induced acute liver injury.

    PubMed

    Beger, Richard D; Bhattacharyya, Sudeepa; Yang, Xi; Gill, Pritmohinder S; Schnackenberg, Laura K; Sun, Jinchun; James, Laura P

    2015-09-01

    Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

  6. PHLPP2 down regulation influences nuclear Nrf2 stability via Akt-1/Gsk3β/Fyn kinase axis in acetaminophen induced oxidative renal toxicity: Protection accorded by morin.

    PubMed

    Mathur, Alpana; Rizvi, Fatima; Kakkar, Poonam

    2016-03-01

    NF-E2 p45-related factor 2 (Nrf2) is a cap 'n' collar (CNC) basic region-leucine zipper (bZIP) transcription factor that imparts cellular defence against xenobiotic and oxidative stress evoked responses by inducing an array of cytoprotective genes. Essential factors that regulate Nrf2 activity and stability during analgesic nephropathy are incompletely understood. In this study, we demonstrate that acetaminophen (a classic analgesic) posit nephrotoxicity both in vitro and in vivo via PHLPP2 activation. Enhanced PHLPP2 levels down regulate p-Akt by dephosphorylating it at Ser 473 residue leading to Gsk3β activation. APAP subsided Nrf2 nuclear accumulation by activating Gsk3β which phosphorylates Fyn kinase. p-Fyn kinase translocates into the nucleus and phosphorylates Nrf2 (Tyr 568) leading to its nuclear export, ubiquitination and degradation. Therefore, poor prognosis prevails during analgesic nephrotoxicity because of the defects in Akt-1/Gsk3β/Fyn-Nrf2 signaling pathway. Morin, a bioflavonoid given as co- and pre-treatment with acetaminophen significantly prevented the toxicity induced damage by constitutively stabilizing Nrf2 nuclear retention. Diminished Nrf2 levels by APAP overdose imposed severe proximal tubular damage leading to apoptotic cell death. Morin, as a potent Nrf2 inducer accorded protection against acetaminophen induced renal damages by its molecular intervention with Akt-1/Gsk3β/Fyn kinase pathway via PHLPP2 de-activation. PMID:26767949

  7. PHLPP2 down regulation influences nuclear Nrf2 stability via Akt-1/Gsk3β/Fyn kinase axis in acetaminophen induced oxidative renal toxicity: Protection accorded by morin.

    PubMed

    Mathur, Alpana; Rizvi, Fatima; Kakkar, Poonam

    2016-03-01

    NF-E2 p45-related factor 2 (Nrf2) is a cap 'n' collar (CNC) basic region-leucine zipper (bZIP) transcription factor that imparts cellular defence against xenobiotic and oxidative stress evoked responses by inducing an array of cytoprotective genes. Essential factors that regulate Nrf2 activity and stability during analgesic nephropathy are incompletely understood. In this study, we demonstrate that acetaminophen (a classic analgesic) posit nephrotoxicity both in vitro and in vivo via PHLPP2 activation. Enhanced PHLPP2 levels down regulate p-Akt by dephosphorylating it at Ser 473 residue leading to Gsk3β activation. APAP subsided Nrf2 nuclear accumulation by activating Gsk3β which phosphorylates Fyn kinase. p-Fyn kinase translocates into the nucleus and phosphorylates Nrf2 (Tyr 568) leading to its nuclear export, ubiquitination and degradation. Therefore, poor prognosis prevails during analgesic nephrotoxicity because of the defects in Akt-1/Gsk3β/Fyn-Nrf2 signaling pathway. Morin, a bioflavonoid given as co- and pre-treatment with acetaminophen significantly prevented the toxicity induced damage by constitutively stabilizing Nrf2 nuclear retention. Diminished Nrf2 levels by APAP overdose imposed severe proximal tubular damage leading to apoptotic cell death. Morin, as a potent Nrf2 inducer accorded protection against acetaminophen induced renal damages by its molecular intervention with Akt-1/Gsk3β/Fyn kinase pathway via PHLPP2 de-activation.

  8. Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection is Associated with Induction of Flavin-containing Monooxygenase-3 (FMO3) in Hepatocytes

    EPA Science Inventory

    Acetaminophen (APAP) pretreatment with a low hepatotoxic dose in mice results in resistance to a second, higher dose of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in...

  9. Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice

    SciTech Connect

    Tolson, J. Keith; Dix, David J.; Voellmy, Richard W.; Roberts, Stephen M. . E-mail: smr@ufl.edu

    2006-01-15

    The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 {sup o}C water bath immersion for 30 min). Hsp70i knockout mice were more susceptible to APAP-induced hepatotoxicity than controls, as indicated by elevated serum alanine aminotransferase activities 24 and 48 h after the APAP dose. Increased APAP hepatotoxicity in knockout mice was verified by morphological evaluation of liver sections. The difference in toxic response to APAP between knockout and control strain mice could not be attributed to differences in APAP bioactivation, assessed by measurement of CYP2E1 and glutathione S-transferase activities, hepatic nonprotein sulfhydryl content, or covalent binding of reactive APAP metabolites to proteins. Pretreatment with transient hyperthermia to produce a general upregulation of Hsps resulted in decreased APAP hepatotoxicity in both the knockout and control strains. Among thermally-pretreated mice, hepatotoxicity of APAP was greater in the knockouts compared with the control strain. These observations suggest that increased Hsp70i expression in response to APAP acts to limit the extent of tissue injury. Results further suggest that other factors related to heat stress can also contribute to protection against APAP toxicity.

  10. Acetaminophen Pharmacokinetics in Children with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Barshop, Nicole J.; Capparelli, Edmund V.; Sirlin, Claude B.; Schwimmer, Jeffrey B.; Lavine, Joel E

    2010-01-01

    Objectives To evaluate UDP-glucuronyltransferase (UGT) activity and the pharmacokinetics of a single oral dose of acetaminophen (APAP) in children with non-alcoholic fatty liver disease (NAFLD). Methods Twelve boys 10–17 years old with biopsy-proven NAFLD and 12 age and gender-matched controls without NAFLD were recruited. Following administration of a single oral dose of APAP (5mg/kg, maximum 325mg), APAP and its glucuronide metabolite (APAP-G) were measured in plasma, urine, and sputum at various intervals up to 24 hours. The activity of UGT was estimated by the plasma ratio of APAP-G to APAP at 4 hours. Results Following administration of APAP, children with NAFLD had significantly higher concentrations of APAP-G in serum (p=.0071) and urine (p=.0210) compared to controls. No significant differences in APAP pharmacokinetics parameters were observed between the two groups. Conclusions APAP glucuronidation is altered in children with fatty liver disease. Despite the altered disposition of this metabolite, the pharmacokinetics of a single 5 mg/kg dose of APAP is the same in children with NAFLD as in children with normal liver function. PMID:21240014

  11. Establishment of a model of acetaminophen-induced hepatotoxicity in different weekly-aged ICR mice.

    PubMed

    Taguchi, K; Tokuno, M; Yamasaki, K; Kadowaki, D; Seo, H; Otagiri, M

    2015-10-01

    Acetaminophen (APAP), a widely used analgesic and antipyretic drug, has the potential to cause lethal hepatotoxicity. Mice are widely used for developing murine models of APAP-induced hepatotoxicity, and many researchers have used these models for APAP-related studies including the fields of biology, pharmacology and toxicology. Although drug-induced hepatotoxicity is dependent on a number of factors (species, gender and age), very few studies have investigated the effect of aging on APAP hepatotoxicity. In this study, we evaluated the effect of age on APAP-induced hepatotoxicity in different weekly-aged mice to establish a model of APAP-induced hepatotoxicity that is an accurate reflection of general experimental conditions. Male ICR mice 4, 6, 8, 10 and 12 weeks old were given APAP intraperitoneally, and mortality, hepatic damage and the plasma concentration of APAP metabolites were evaluated. It was found that younger male ICR mice were relatively resistant to hepatotoxicity induced by intraperitoneal APAP administration. In addition, the APAP-glucuronide concentration in plasma remained essentially the same among the differently-aged mice, while APAP-sulfate levels were dramatically decreased in an age-dependent manner. Thus, it is recommended that mice of the same ages be used in studies related to APAP-induced hepatotoxixity. These results provide evidence in support of not only the age-related changes in susceptibility to APAP-derived hepatotoxicity in mice but also in developing mouse models for APAP-related studies.

  12. Contac overdose

    MedlinePlus

    ... Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 8. Velez LI, Feng S-Y. Anticholinergics. In: Marx JA, Hockberger RS, Walls RM, et ...

  13. Periactin overdose

    MedlinePlus

    Cyproheptadine hydrochloride overdose ... Cyproheptadine ... The generic drug name for Periactin is cyproheptadine hydrochloride. This medicine may also be sold under the following brand names: Klarivitina Nuran Periatinol This list may not be all-inclusive.

  14. Paracetamol overdose.

    PubMed

    Skinner, Anita

    2015-02-20

    Paracetamol is safe and effective at the therapeutic dose. It is beneficial as an analgesic and is an effective antipyretic. Paracetamol is cheap and easy to buy over the counter, which makes it a common choice in intentional overdose.

  15. Chlorpromazine overdose

    MedlinePlus

    ... other reasons. This medicine may also change the metabolism and the effect of other drugs. Chlorpromazine overdose ... Anticholinergics. In: Marx JA, ed. Rosen's Emergency Medicine: Concepts and Clinical Practice . 8th ed. Philadelphia, PA: Elsevier ...

  16. Iron overdose

    MedlinePlus

    ... MJ, eds. Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 72. Velez LI, O'Connell EJ. Heavy metals. In: Marx JA, Hockberger RS, Walls RM, et ...

  17. Caffeine overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002579.htm Caffeine overdose To use the sharing features on this page, please enable JavaScript. Caffeine is a substance that exists naturally in certain ...

  18. Phencyclidine overdose

    MedlinePlus

    ... is an illegal street drug. It can cause hallucinations and severe agitation. This article discusses overdose due ... does not talk, move, or react) Coma Convulsions Hallucinations High blood pressure Side-to-side eye movements ...

  19. Cyproheptadine overdose

    MedlinePlus

    Cyproheptadine is a type of drug called an antihistamine. These drugs are used to relieve allergy symptoms. ... is likely. Few people actually die from an antihistamine overdose. Very high doses of antihistamines can cause ...

  20. Methadone overdose

    MedlinePlus

    ... strong painkiller. It is also used to treat heroin addiction. Methadone overdose occurs when someone accidentally or ... A.M. Editorial team. Related MedlinePlus Health Topics Heroin Pain Relievers Browse the Encyclopedia A.D.A. ...

  1. Transcriptomic studies on liver toxicity of acetaminophen.

    PubMed

    Toska, Endrit; Zagorsky, Robert; Figler, Bryan; Cheng, Feng

    2014-09-01

    Acetaminophen is widely used as a pain reliever and to reduce fever. At high doses, it can cause severe hepatotoxicity. Acetaminophen overdose has become the leading cause of acute liver failure in the US. The mechanisms for acetaminophen-induced liver injury are unclear. Transcriptomic studies can identify the changes in expression of thousands of genes when exposed to supratherapeutic doses of acetaminophen. These studies elucidated the mechanism of acetaminophen-induced hepatotoxicity and also provide insight into future development of diagnosis and treatment options for acetaminophen-induced acute liver failure. The following is a brief overview of some recent transcriptomic studies and gene-expression-based prediction models on liver toxicity induced by acetaminophen.

  2. Changes in susceptibility to acetaminophen-induced liver injury by the organic anion indocyanine green.

    PubMed

    Silva, V M; Chen, C; Hennig, G E; Whiteley, H E; Manautou, J E

    2001-03-01

    The non-metabolizable organic anion indocyanine green (ICG) has been shown previously to reduce markedly the biliary secretion of acetaminophen, particularly the glutathione conjugate of APAP (APAP-GSH), suggesting that this APAP metabolite may compete with other xenobiotics for excretion into the bile via a canalicular organic anion transport process. This study was conducted to determine whether changes in the biliary disposition of APAP induced by ICG could lead to alterations in susceptibility to APAP hepatotoxicity. To investigate this, groups of overnight-fasted male CD-1 mice received 30 micromol ICG/kg, intravenously, immediately prior to APAP dosing (500 mg/kg, ip). Controls were given propylene glycol vehicle. Mice were killed at 4 h after APAP challenge for immunochemical analysis of cytosolic protein arylation and determination of non-protein sulfhydryl (NPSH) depletion, or at 12 and 24 h for biochemical and histological assessment of liver injury. Elevated plasma sorbitol dehydrogenase activity and centrilobular hepatocellular necrosis was present in control mice receiving APAP at 12 and 24 h. Treatment with ICG did not alter susceptibility to APAP toxicity when measured at 12 h after challenge. However, the severity of histologic lesions in the ICG-APAP group was significantly lower at 24 h after challenge. Furthermore, treatment with ICG did not alter APAP-induced glutathione depletion or cytosolic protein arylation. These data suggest that the organic anion ICG has a protective effect on APAP toxicity that promotes a faster recovery from liver injury.

  3. Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.

    PubMed

    Kim, Sun J; Lee, Min Y; Kwon, Do Y; Kim, Sung Y; Kim, Young C

    2009-10-01

    Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

  4. TRPA1 mediates the hypothermic action of acetaminophen

    PubMed Central

    Gentry, Clive; Andersson, David A.; Bevan, Stuart

    2015-01-01

    Acetaminophen (APAP) is an effective antipyretic and one of the most commonly used analgesic drugs. Unlike antipyretic non-steroidal anti-inflammatory drugs, APAP elicits hypothermia in addition to its antipyretic effect. Here we have examined the mechanisms responsible for the hypothermic activity of APAP. Subcutaneous, but not intrathecal, administration of APAP elicited a dose dependent decrease in body temperature in wildtype mice. Hypothermia was abolished in mice pre-treated with resiniferatoxin to destroy or defunctionalize peripheral TRPV1-expressing terminals, but resistant to inhibition of cyclo-oxygenases. The hypothermic activity was independent of TRPV1 since APAP evoked hypothermia was identical in wildtype and Trpv1−/− mice, and not reduced by administration of a maximally effective dose of a TRPV1 antagonist. In contrast, a TRPA1 antagonist inhibited APAP induced hypothermia and APAP was without effect on body temperature in Trpa1−/− mice. In a model of yeast induced pyrexia, administration of APAP evoked a marked hypothermia in wildtype and Trpv1−/− mice, but only restored normal body temperature in Trpa1−/− and Trpa1−/−/Trpv1−/− mice. We conclude that TRPA1 mediates APAP evoked hypothermia. PMID:26227887

  5. Acetaminophen hepatotoxicity: an updated review.

    PubMed

    Lancaster, Elizabeth M; Hiatt, Jonathan R; Zarrinpar, Ali

    2015-02-01

    As the most common cause of acute liver failure (ALF) in the USA and UK, acetaminophen-induced hepatotoxicity remains a significant public health concern and common indication for emergent liver transplantation. This problem is largely attributable to acetaminophen combination products frequently prescribed by physicians and other healthcare professionals, with unintentional and chronic overdose accounting for over 50 % of cases of acetaminophen-related ALF. Treatment with N-acetylcysteine can effectively reduce progression to ALF if given early after an acute overdose; however, liver transplantation is the only routinely used life-saving therapy once ALF has developed. With the rapid course of acetaminophen-related ALF and limited supply of donor livers, early and accurate diagnosis of patients that will require transplantation for survival is crucial. Efforts in developing novel treatments for acetaminophen-induced ALF are directed toward bridging patients to recovery. These include auxiliary, artificial, and bioartificial support systems. This review outlines the most recent developments in diagnosis and management of acetaminophen-induced ALF.

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

    PubMed

    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. PMID:23927622

  7. Tramadol and acetaminophen tablets for dental pain.

    PubMed Central

    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 400 mg, or placebo. Active control with ibuprofen was used to determine model sensitivity. Pain relief (scale, 0-4) and pain intensity (scale, 0-3) were reported at 30 minutes after the dose and then hourly for 8 hours. Total pain relief over 8 hours (TOTPAR8) and the sum of pain intensity differences (SPID8) were calculated from the hourly scores. Time to onset of pain relief was determined by the double-stopwatch technique, and patients were advised to wait at least 2 hours before taking supplemental analgesia. Patients assessed overall efficacy (scale, 1-5) upon completion. In all, 1197 patients (age range, 16-46 years) were evaluable for efficacy; treatment groups in each study were similar at baseline. Pain relief was superior to placebo (P < or = .0001) for all treatments. Pain relief provided by tramadol/ APAP was superior to that of tramadol or APAP alone, as shown by mean TOT-PAR8 (12.1 vs 6.7 and 8.6, respectively, P < or = .0001) and SPID8 (4.7 vs 0.9 and 2.7, respectively, P < or = .0001). Estimated onset of pain relief was 17 minutes (95% CI, 15-20 minutes) for tramadol/APAP compared with 51 minutes (95% CI, 40-70 minutes) for tramadol, 18 minutes (95% CI, 16-21 minutes) for APAP, and 34 minutes (95% CI, 28-44 minutes) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (P < .05) for the tramadol/APAP group (302 minutes and 3.0, respectively) than for the tramadol (122 minutes and 2.0) or APAP (183 minutes and 2

  8. Mechanism for the primary transformation of acetaminophen in a soil/water system.

    PubMed

    Liang, Chuanzhou; Lan, Zhonghui; Zhang, Xu; Liu, Yingbao

    2016-07-01

    The transformation of acetaminophen (APAP) in a soil/water system was systematically investigated by a combination of kinetic studies and a quantitative analysis of the reaction intermediates. Biotransformation was the predominant pathway for the elimination of APAP, whereas hydrolysis or other chemical transformation, and adsorption processes made almost no contribution to the transformation under a dark incubation. Bacillus aryabhattai strain 1-Sj-5-2-5-M, Klebsiella pneumoniae strain S001, and Bacillus subtilis strain HJ5 were the main bacteria identified in the biotransformation of APAP. The soil-to-water ratio and soil preincubation were able to alter the transformation kinetic pattern. Light irradiation promoted the overall transformation kinetics through enhanced biotransformation and extra photosensitized chemical reactions. The transformation pathways were strongly dependent on the initial concentration of APAP. The main primary transformation products were APAP oligomers and p-aminophenol, with the initial addition of 26.5 and 530 μM APAP, respectively. APAP oligomers accounted for more than 95% of transformed APAP, indicating that almost no bound residues were generated through the transformation of APAP in the soil/water system. The potential environmental risks of APAP could increase following the transformation of APAP in the soil/water system because of the higher toxicity of the transformation intermediates. PMID:27107139

  9. Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity.

    PubMed

    Milesi-Hallé, Alessandra; Abdel-Rahman, Susan M; Brown, Aliza; McCullough, Sandra S; Letzig, Lynda; Hinson, Jack A; James, Laura P

    2011-02-01

    Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl(T)) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl(T) and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.

  10. Indocyanine Green Clearance Varies as a Function of N-Acetylcysteine Treatment in a Murine Model of Acetaminophen Toxicity

    PubMed Central

    Milesi-Hallé, Alessandra; Abdel-Rahman, Susan M.; Brown, Aliza; McCullough, Sandra S.; Letzig, Lynda; Hinson, Jack A.; James, Laura P.

    2011-01-01

    Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment. Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (ClT) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had ClT and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity. PMID:21145883

  11. Acetaminophen hepatotoxicity and HIF-1{alpha} induction in acetaminophen toxicity in mice occurs without hypoxia

    SciTech Connect

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

    2011-05-01

    HIF-1{alpha} 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-1{alpha}. 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-1{alpha} 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-1{alpha} 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-1{alpha} 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-1{alpha} 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.

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

    PubMed

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

    2011-05-01

    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 2h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48h 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; 10mg/kg) reduced HIF-1α induction in APAP treated mice at 1 and 4h 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.

  13. Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation.

    PubMed

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Nafees, Sana; Seth, Amlesh; Ali, Nemat; Rashid, Summya; Sultana, Sarwat

    2012-01-25

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.

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

    SciTech Connect

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

    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.

  15. Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice

    SciTech Connect

    Chaudhuri, Shubhra; McCullough, Sandra S.; Hennings, Leah; Brown, Aliza T.; Li, Shun-Hwa; Simpson, Pippa M.; Hinson, Jack A.; James, Laura P.

    2012-10-15

    Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10 mg/kg, oral gavage) prior to APAP (200 mg/kg IP) and at 7 and 36 h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8 h, compared to the APAP mice. At 24 and 48 h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A{sub 2}, and cytosolic and secretory PLA{sub 2} activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E{sub 2} expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE{sub 2} expression and hepatocyte regeneration, likely through a mechanism involving PLA{sub 2}. -- Highlights: ► Trifluoperazine reduced acetaminophen toxicity and lowered HIF-1α induction. ► Trifluoperazine had no effect on the metabolism of acetaminophen. ► Trifluoperazine reduced hepatocyte regeneration. ► Trifluoperazine reduced phospholipase A{sub 2} activity and prostaglandin E{sub 2} levels.

  16. A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States.

    PubMed

    Blieden, Marissa; Paramore, L Clark; Shah, Dhvani; Ben-Joseph, Rami

    2014-05-01

    Acetaminophen is a commonly-used analgesic in the US and, at doses of more than 4 g/day, can lead to serious hepatotoxicity. Recent FDA and CMS decisions serve to limit and monitor exposure to high-dose acetaminophen. This literature review aims to describe the exposure to and consequences of high-dose acetaminophen among chronic pain patients in the US. Each year in the US, approximately 6% of adults are prescribed acetaminophen doses of more than 4 g/day and 30,000 patients are hospitalized for acetaminophen toxicity. Up to half of acetaminophen overdoses are unintentional, largely related to opioid-acetaminophen combinations and attempts to achieve better symptom relief. Liver injury occurs in 17% of adults with unintentional acetaminophen overdose.

  17. Correlation of MRI findings to histology of acetaminophen toxicity in the mouse.

    PubMed

    Brown, Aliza T; Ou, Xiawei; James, Laura P; Jambhekar, Kedar; Pandey, Tarun; McCullough, Sandra; Chaudhuri, Shubhra; Borrelli, Michael J

    2012-02-01

    Acetaminophen (APAP) toxicity is responsible for approximately half of all cases of acute liver failure in the United States. The mouse model of APAP toxicity is widely used to examine mechanisms of APAP toxicity. Noninvasive approaches would allow for serial measurements in a single animal to study the effects of experimental interventions on the development and resolution of hepatocellular necrosis. The following study examined the time course of hepatic necrosis using small animal magnetic resonance imaging (MRI) following the administration of 200 mg/kg ip APAP given to B6C3F1 male mice. Mice treated with saline served as controls (CON). Other mice received treatment with the clinical antidote N-acetylcysteine (APAP+NAC). Mouse liver pathology was characterized using T1- and T2-weighted sequences at 2, 4, 8 and 24 h following APAP administration. Standard assays for APAP toxicity [serum alanine aminotransaminase (ALT) levels and hematoxylin and eosin (H&E) staining of liver sections] were examined relative to MRI findings. Overall, T2 sequences had a greater sensitivity for necrosis and hemorrhage than T1 (FLASH) images. Liver injury severity scoring of MR images demonstrated increased scores in the APAP mice at 4, 8 and 24 h compared to the CON mice. APAP+NAC mice had MRI scores similar to the CON mice. Semiquantitative analysis of hepatic hemorrhage strongly correlated with serum ALT. Small animal MRI can be used to monitor the evolution of APAP toxicity over time and to evaluate the response to therapy.

  18. Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice.

    PubMed

    Milesi-Hallé, Alessandra; McCullough, Sandra; Hinson, Jack A; Kurten, Richard C; Lamps, Laura W; Brown, Aliza; James, Laura P

    2012-04-01

    Up-regulation of vascular endothelial growth factor (VEGF) is important to hepatocyte regeneration in the late stages of acetaminophen (APAP) toxicity in the mouse. This study was conducted to examine the relationship of hypoxia-inducible factor 1α (HIF-1α) to VEGF and hepatocyte regeneration in APAP toxicity using an inhibitor of HIF-1α DNA-binding activity, echinomycin (EC). B6C3F1 male mice were treated with APAP (200 mg/kg IP), followed by EC (0.15 mg IP) and killed at 4 hr. Serum alanine aminotransferase (ALT), necrosis, hepatic glutathione (GSH) and APAP protein adducts were comparable in the APAP/EC and the APAP/veh mice at 4 hr. Additional studies showed that high dose EC (0.3 mg) reduced hepatic VEGF but also lowered hepatic GSH. Subsequent studies were performed using the 0.15-mg dose of EC. Although EC 0.15 mg had no effect on hepatic VEGF levels at 8 hr, by 24 hr VEGF levels were decreased by 40%. Toxicity (ALT and histopathology) was comparable in the APAP and APAP/EC groups at 24 and 48 hr. Proliferating cell nuclear antigen expression was reduced by both Western blot analysis and immunohistochemical staining in the APAP/EC mice at 48 hr. The data support the hypothesis that induction of HIF-1α, its binding to DNA and subsequent expression of VEGF are important factors in hepatocyte regeneration in APAP toxicity in the mouse.

  19. NQO2 is a reactive oxygen species generating off-target for acetaminophen.

    PubMed

    Miettinen, Teemu P; Björklund, Mikael

    2014-12-01

    The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity.

  20. NQO2 Is a Reactive Oxygen Species Generating Off-Target for Acetaminophen

    PubMed Central

    2014-01-01

    The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity. PMID:25313982

  1. Acetaminophen induces JNK/p38 signaling and activates the caspase-9-3-dependent cell death pathway in human mesenchymal stem cells

    PubMed Central

    YIANG, GIOU-TENG; YU, YUNG-LUNG; LIN, KO-TING; CHEN, JEN-NI; CHANG, WEI-JUNG; WEI, CHYOU-WEI

    2015-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Generally, the therapeutic dose of APAP is clinically safe, however, high doses of APAP can cause acute liver and kidney injury. Therefore, the majority of previous studies have focussed on elucidating the mechanisms of APAP-induced hepatotoxicity and nephrotoxicity, in addition to examining ways to treat these conditions in clinical cases. However, few studies have reported APAP-induced intoxication in human stem cells. Stem cells are important in cell proliferation, differentiation and repair during human development, particularly during fetal and child development. At present, whether APAP causes cytotoxic effects in human stem cells remains to be elucidated, therefore, the present study aimed to investigate the cellular effects of APAP treatment in human stem cells. The results of the present study revealed that high-dose APAP induced more marked cytotoxic effects in human mesenchymal stem cells (hMSCs) than in renal tubular cells. In addition, increased levels of hydrogen peroxide (H2O2), phosphorylation of c-Jun N-terminal kinase and p38, and activation of caspase-9/-3 cascade were observed in the APAP-treated hMSCs. By contrast, antioxidants, including vitamin C reduced APAP-induced augmentations in H2O2 levels, but did not inhibit the APAP-induced cytotoxic effects in the hMSCs. These results suggested that high doses of APAP may cause serious damage towards hMSCs. PMID:26096646

  2. Dual role of acetaminophen in promoting hepatoma cell apoptosis and kidney fibroblast proliferation

    PubMed Central

    YU, YUNG-LUEN; YIANG, GIOU-TENG; CHOU, PEI-LUN; TSENG, HSU-HUNG; WU, TSAI-KUN; HUNG, YU-TING; LIN, PEI-SHIUAN; LIN, SHU-YU; LIU, HSIAO-CHUN; CHANG, WEI-JUNG; WEI, CHYOU-WEI

    2014-01-01

    Acetaminophen (APAP), is a safe analgesic and antipyretic drug at therapeutic dose, and is widely used in the clinic. However, high doses of APAP can induce hepatotoxicity and nephrotoxicity. Most studies have focused on high-dose APAP-induced acute liver and kidney injury. So far, few studies have investigated the effects of the therapeutic dose (1/10 of the high dose) or of the low dose (1/100 of the high dose) of APAP on the cells. The aim of this study was to investigate the cellular effects of therapeutic- or low-dose APAP treatment on hepatoma cells and kidney fibroblasts. As expected, high-dose APAP treatment inhibited while therapeutic and low-dose treatment did not inhibit cell survival of kidney tubular epithelial cells. In addition, therapeutic-dose treatment induced an increase in the H2O2 level, activated the caspase-9/-3 cascade, and induced cell apoptosis of hepatoma cells. Notably, APAP promoted fibroblast proliferation, even at low doses. This study demonstrates that different cellular effects are exerted upon treatment with different APAP concentrations. Our results indicate that treatment with the therapeutic dose of APAP may exert an antitumor activity on hepatoma, while low-dose treatment may be harmful for patients with fibrosis, since it may cause proliferation of fibroblasts. PMID:24682227

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

    PubMed

    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.

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

    PubMed

    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. PMID:26013309

  5. Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death.

    PubMed

    Ahmed, Munzir M E; Al-Obosi, J A S; Osman, H M; Shayoub, M E

    2016-04-01

    Acetaminophen (APAP) a commonly used drug for decrease the fever and pain but is capable to induced hepatotoxicity at over dose. This study was carried out to investigate the effect of APAP on the expression of anti-apoptotic and antioxidative defense genes, and whether aldose reductase over-expressing plasmid capable to protect against APAP-induced oxidative stress and cell death. APAP treatment induced oxidative stress and hepatotoxicity, and significantly increased aldose reductase mRNA and protein expression in mouse hepatocyte (AML-12). Unexpectedly, AML-12 cells over-expressing aldose reductase augmented APAP-induced reduction in cell viability, reactive oxygen species (ROS) production, glutathione (GSH) depletion and glutathione S-transferase A2 expression. Moreover, over-expression of aldose reductase potentiated APAP induced reduction on proliferating cell nuclear antigen, B cell lymphoma-extra large (bcl-xL), catalase, glutathione peroxidase-1 (GPx-1) and abolished APAP-induced B-cell lymphoma 2 (bcl-2) inductions. Further, over-expression of aldose reductase significantly abolished AMP activated protein kinase (AMPK) activity in APAP-treated cells and induced p53 expression. This results demonstrate that APAP induced toxicity in AML-12, increased aldose reductase expression, and over-expression of aldose reductase render this cell more susceptible to APAP induced oxidative stress and cell death, this probably due to inhibition AMPK or bcl-2 activity, or may due to competition between aldose reductase and glutathione reductase for NADPH. PMID:27069324

  6. Anti-Inflammatory Property of Plantago major Leaf Extract Reduces the Inflammatory Reaction in Experimental Acetaminophen-Induced Liver Injury.

    PubMed

    Hussan, Farida; Mansor, Adila Sofea; Hassan, Siti Nazihahasma; Tengku Nor Effendy Kamaruddin, Tg Nurul Tasnim; Budin, Siti Balkis; Othman, Faizah

    2015-01-01

    Hepatic injury induces inflammatory process and cell necrosis. Plantago major is traditionally used for various diseases. This study aimed to determine the anti-inflammatory property of P. major leaf extracts on inflammatory reaction following acetaminophen (APAP) hepatotoxicity. Thirty male Sprague-Dawley rats were divided into 5 groups, namely, normal control (C), APAP, aqueous (APAP + AQ), methanol (APAP + MT), and ethanol (APAP + ET) extract treated groups. All APAP groups received oral APAP (2 g/kg) at day 0. Then, 1000 mg/kg dose of P. major extracts was given for six days. The levels of liver transaminases were measured at day 1 and day 7 after APAP induction. At day 7, the blood and liver tissue were collected to determine plasma cytokines and tissue 11β-HSD type 1 enzyme. The in vitro anti-inflammatory activities of methanol, ethanol, and aqueous extracts were 26.74 ± 1.6%, 21.69 ± 2.81%, and 12.23 ± 3.15%, respectively. The ALT and AST levels were significantly higher in the APAP groups at day 1 whereas the enzyme levels of all groups showed no significant difference at day 7. The extracts treatment significantly reduced the proinflammatory cytokine levels and significantly increased the 11β-HSD type 1 enzyme activity (p < 0.05). In conclusion, the P. major extracts attenuate the inflammatory reaction following APAP-induced liver injury. PMID:26300946

  7. Anti-Inflammatory Property of Plantago major Leaf Extract Reduces the Inflammatory Reaction in Experimental Acetaminophen-Induced Liver Injury.

    PubMed

    Hussan, Farida; Mansor, Adila Sofea; Hassan, Siti Nazihahasma; Tengku Nor Effendy Kamaruddin, Tg Nurul Tasnim; Budin, Siti Balkis; Othman, Faizah

    2015-01-01

    Hepatic injury induces inflammatory process and cell necrosis. Plantago major is traditionally used for various diseases. This study aimed to determine the anti-inflammatory property of P. major leaf extracts on inflammatory reaction following acetaminophen (APAP) hepatotoxicity. Thirty male Sprague-Dawley rats were divided into 5 groups, namely, normal control (C), APAP, aqueous (APAP + AQ), methanol (APAP + MT), and ethanol (APAP + ET) extract treated groups. All APAP groups received oral APAP (2 g/kg) at day 0. Then, 1000 mg/kg dose of P. major extracts was given for six days. The levels of liver transaminases were measured at day 1 and day 7 after APAP induction. At day 7, the blood and liver tissue were collected to determine plasma cytokines and tissue 11β-HSD type 1 enzyme. The in vitro anti-inflammatory activities of methanol, ethanol, and aqueous extracts were 26.74 ± 1.6%, 21.69 ± 2.81%, and 12.23 ± 3.15%, respectively. The ALT and AST levels were significantly higher in the APAP groups at day 1 whereas the enzyme levels of all groups showed no significant difference at day 7. The extracts treatment significantly reduced the proinflammatory cytokine levels and significantly increased the 11β-HSD type 1 enzyme activity (p < 0.05). In conclusion, the P. major extracts attenuate the inflammatory reaction following APAP-induced liver injury.

  8. Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice.

    PubMed

    Chen, C; Hennig, G E; McCann, D J; Manautou, J E

    2000-11-01

    1. The effects of clofibrate (CFB) and indocyanine green (ICG) on the biliary excretion of acetaminophen (APAP) and its metabolites were investigated. 2. Male CD-1 mice were pretreated with 500 mg CFB/kg, i.p. for 10 days. Controls received corn oil vehicle only. After overnight fasting, common bile duct-cannulated mice were challenged with a non-toxic dose of APAP (1 mmol/kg, i.v.). 3. CFB pretreatment did not affect bile flow rate, nor did it affect the cumulative biliary excretion of APAP and its conjugated metabolites. 4. Additional CFB or corn oil pretreated mice were given 30 mumol indocyanine green (ICG)/kg, i.v., immediately before APAP dosing. ICG is a non-metabolizable organic anion that is completely excreted into the bile through a canalicular transport process for organic anions. 5. ICG significantly decreased the bile flow rate and biliary concentration of APAP-glutathione, APAP-glucuronide and APAP-mercapturate within the first hour after dosing without affecting the biliary concentration of APAP. 6. The results indicate that CFB pretreatment does not affect the total amount of APAP and its metabolites excreted in bile. They also suggest that the biliary excretion of several conjugated metabolites of APAP share the same excretory pathway with the organic anion ICG.

  9. Anti-Inflammatory Property of Plantago major Leaf Extract Reduces the Inflammatory Reaction in Experimental Acetaminophen-Induced Liver Injury

    PubMed Central

    Hussan, Farida; Mansor, Adila Sofea; Hassan, Siti Nazihahasma; Tengku Nor Effendy Kamaruddin, Tg. Nurul Tasnim; Budin, Siti Balkis; Othman, Faizah

    2015-01-01

    Hepatic injury induces inflammatory process and cell necrosis. Plantago major is traditionally used for various diseases. This study aimed to determine the anti-inflammatory property of P. major leaf extracts on inflammatory reaction following acetaminophen (APAP) hepatotoxicity. Thirty male Sprague-Dawley rats were divided into 5 groups, namely, normal control (C), APAP, aqueous (APAP + AQ), methanol (APAP + MT), and ethanol (APAP + ET) extract treated groups. All APAP groups received oral APAP (2 g/kg) at day 0. Then, 1000 mg/kg dose of P. major extracts was given for six days. The levels of liver transaminases were measured at day 1 and day 7 after APAP induction. At day 7, the blood and liver tissue were collected to determine plasma cytokines and tissue 11β-HSD type 1 enzyme. The in vitro anti-inflammatory activities of methanol, ethanol, and aqueous extracts were 26.74 ± 1.6%, 21.69 ± 2.81%, and 12.23 ± 3.15%, respectively. The ALT and AST levels were significantly higher in the APAP groups at day 1 whereas the enzyme levels of all groups showed no significant difference at day 7. The extracts treatment significantly reduced the proinflammatory cytokine levels and significantly increased the 11β-HSD type 1 enzyme activity (p < 0.05). In conclusion, the P. major extracts attenuate the inflammatory reaction following APAP-induced liver injury. PMID:26300946

  10. An Amino Acids Mixture Improves the Hepatotoxicity Induced by Acetaminophen in Mice

    PubMed Central

    Rossoni, Giuseppe

    2013-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The aim of this study was to evaluate the protective role of DDM-GSH, a mixture of L-cysteine, L-methionine, and L-serine in a weight ratio of 2 : 1 : 1, in comparison to N-acetylcysteine (NAC), against acetaminophen- (APAP-) induced hepatotoxicity in mice. Toxicity was induced in mice by the intraperitoneal (ip) administration of low dose (2 mmol/kg) or high dose (8 mmol/kg) of APAP. DDM-GSH (0.4 to 1.6 mmol/kg) was given ip to mice 1 h before the APAP administration. The same was done with NAC (0.9 to 3.6 mmol/kg), the standard antidote of APAP toxicity. Mice were sacrificed 8 h after the APAP injection to determine liver weight, serum alanine aminotransferase (ALT), and total glutathione (GSH) depletion and malondialdehyde (MDA) accumulation in liver tissues. DDM-GSH improved mouse survival rates better than NAC against a high dose of APAP. Moreover, DDM-GSH significantly reduced in a dose-dependent manner not only APAP-induced increases of ALT but also APAP-induced hepatic GSH depletion and MDA accumulation. Our results suggest that DDM-GSH may be more potent than NAC in protecting the liver from APAP-induced liver injury. PMID:23878731

  11. Ferroptosis is Involved in Acetaminophen Induced Cell Death.

    PubMed

    Lőrincz, Tamás; Jemnitz, Katalin; Kardon, Tamás; Mandl, József; Szarka, András

    2015-09-01

    The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes.

  12. Ferroptosis is Involved in Acetaminophen Induced Cell Death.

    PubMed

    Lőrincz, Tamás; Jemnitz, Katalin; Kardon, Tamás; Mandl, József; Szarka, András

    2015-09-01

    The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes. PMID:25962350

  13. Calcium carbonate overdose

    MedlinePlus

    Tums overdose; Calcium overdose ... Calcium carbonate can be dangerous in large amounts. ... Some products that contain calcium carbonate are certain: ... and mineral supplements Other products may also contain calcium ...

  14. Methyl salicylate overdose

    MedlinePlus

    Deep heating rubs overdose; Oil of wintergreen overdose ... These products contain methyl salicylate: Deep-heating creams used to relieve sore muscles and joints (Ben Gay, Icy Hot) Oil of wintergreen Solutions for vaporizers Other products may also ...

  15. Pharmacogenomics of acetaminophen in pediatric populations: a moving target

    PubMed Central

    Krasniak, Anne E.; Knipp, Gregory T.; Svensson, Craig K.; Liu, Wanqing

    2014-01-01

    Acetaminophen (APAP) is widely used as an over-the-counter fever reducer and pain reliever. However, the current therapeutic use of APAP is not optimal. The inter-patient variability in both efficacy and toxicity limits the use of this drug. This is particularly an issue in pediatric populations, where tools for predicting drug efficacy and developmental toxicity are not well established. Variability in toxicity between age groups may be accounted for by differences in metabolism, transport, and the genetics behind those differences. While pharmacogenomics has been revolutionizing the paradigm of pharmacotherapy for many drugs, its application in pediatric populations faces significant challenges given the dynamic ontogenic changes in cellular and systems physiology. In this review we focused on the ontogenesis of the regulatory pathways involved in the disposition of APAP and on the variability between pediatric, adolescent, and adult patients. We also summarize important polymorphisms of the pharmacogenes associated with APAP metabolism. Pharmacogenetic studies in pediatric APAP treatment are also reviewed. We conclude that while a consensus in pharmacogenetic management of APAP in pediatric populations has not been achieved, a systems biology based strategy for comprehensively understanding the ontogenic regulatory pathway as well as the interaction between age and genetic variations are particularly necessary in order to address this question. PMID:25352860

  16. A novel defensive mechanism against acetaminophen toxicity in the mouse lateral nasal gland: role of CYP2A5-mediated regulation of testosterone homeostasis and salivary androgen-binding protein expression.

    PubMed

    Zhou, Xin; Wei, Yuan; Xie, Fang; Laukaitis, Christina M; Karn, Robert C; Kluetzman, Kerri; Gu, Jun; Zhang, Qing-Yu; Roberts, Dean W; Ding, Xinxin

    2011-04-01

    To identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial studies established that Cyp2a5-null mice, but not a newly generated strain of Cyp2g1-null mice, were resistant to APAP toxicity in the LNG; therefore, subsequent studies were focused on the Cyp2a5-null mice. Compared with the wild-type (WT) male mouse, the Cyp2a5-null male mouse had intact capability to metabolize APAP to reactive intermediates in the LNG, as well as unaltered circulating levels of APAP, APAP-GSH, APAP-glucuronide, and APAP-sulfate. However, it displayed reduced tissue levels of APAP and APAP-GSH and increased tissue levels of testosterone and salivary androgen-binding protein (ABP) in the LNG. Furthermore, we found that ABP was able to compete with GSH and cellular proteins for adduction with reactive metabolites of APAP in vitro. The amounts of APAP-ABP adducts formed in vivo were greater, whereas the amounts of APAP adducts formed with other cellular proteins were substantially lower, in the LNG of APAP-treated male Cyp2a5-null mice compared with the LNG of APAP-treated male WT mice. We propose that through its critical role in testosterone metabolism, CYP2A5 regulates 1) the bioavailability of APAP and APAP-GSH (presumably through modulation of the rates of xenobiotic excretion from the LNG) and 2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation.

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

    PubMed Central

    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 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 < 0.05). The comet assay revealed increased detaching tail length and DNA concentration during the hepatic toxicity in the acetaminophen group. The malondialdehyde content was inhibited by 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. Conclusions Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats. PMID:26543508

  18. Proteomic Analysis of Acetaminophen-Induced Changes in Mitochondrial Protein Expression Using Spectral Counting

    PubMed Central

    Stamper, Brendan D.; Mohar, Isaac; Kavanagh, Terrance J.; Nelson, Sidney D.

    2011-01-01

    Comparative proteomic analysis following treatment with acetaminophen (APAP) was performed on two different models of APAP-mediated hepatocellular injury in order to both identify common targets for adduct formation and track drug-induced changes in protein expression. Male C57BL/6 mice were used as a model for APAP-mediated liver injury in vivo and TAMH cells were used as a model for APAP-mediated cytotoxicity in vitro. SEQUEST was unable to identify the precise location of sites of adduction following treatment with APAP in either system. However, semiquantitative analysis of the proteomic datasets using spectral counting revealed a downregulation of P450 isoforms associated with APAP bioactivation, and an upregulation of proteins related to the electron transport chain by APAP compared to control. Both mechanisms are likely compensatory in nature as decreased P450 expression is likely to attenuate toxicity associated with N-acetyl-p-quinoneimine (NAPQI) formation, whereas APAP-induced electron transport chain component upregulation may be an attempt to promote cellular bioenergetics. PMID:21329376

  19. Regulatory T cells ameliorate acetaminophen-induced immune-mediated liver injury.

    PubMed

    Wang, Xuefu; Sun, Rui; Chen, Yongyan; Lian, Zhe-Xiong; Wei, Haiming; Tian, Zhigang

    2015-04-01

    The contribution of innate immune cells to acetaminophen (APAP)-induced liver injury has been extensively investigated. However, the roles of T cell populations among adaptive immune cells in APAP-induced liver injury remain to be elucidated. Herein, we found that distinct CD4(+) T cell subsets but not CD8(+) T cells modulated APAP-induced liver injury in mice. After APAP challenge, more CD62L(low)CD44(hi)CD4(+) T cells appeared in the liver, accompanied by increased IFN-γ. The removal of CD4(+) T cells by either antibody depletion or genetic deficiency markedly compromised pro-inflammatory cytokine levels and ameliorated liver injury. Meanwhile, we also found that the frequency and absolute number of Treg cells also increased. Treg cell depletion increased hepatic CD62L(low)CD44(hi)CD4(+) T cells, augmented pro-inflammatory cytokines, and exacerbated liver injury, while adoptive transfer of Treg cells ameliorated APAP-induced liver injury. Furthermore, the recruitment of Treg cells into the liver through specific expression of CXCL10 in the liver could ameliorate APAP-induced liver injury. Our investigation suggests that Th1 and Treg subsets are involved in regulating APAP-induced liver injury. Thus, modulating the Th1/Treg balance may be an effective strategy to prevent and/or treat APAP-induced liver injury.

  20. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    PubMed Central

    Hohmann, Miriam S. N.; Cardoso, Renato D. R.; Pinho-Ribeiro, Felipe A.; Crespigio, Jefferson; Cunha, Thiago M.; Alves-Filho, José C.; da Silva, Rosiane V.; Pinge-Filho, Phileno; Ferreira, Sergio H.; Cunha, Fernando Q.; Casagrande, Rubia; Verri, Waldiceu A.

    2013-01-01

    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. PMID:24288682

  1. Nilotinib interferes with the signalling pathways implicated in acetaminophen hepatotoxicity.

    PubMed

    Shaker, Mohamed E

    2014-03-01

    Nilotinib, a second-generation tyrosine kinase inhibitor, has been recently approved for the treatment for chronic myeloid leukaemia. The objective of this study was to explore the potential effects of clinically relevant doses of nilotinib against acetaminophen (APAP)-induced hepatotoxicity in mice. To simulate the clinical application in human beings, nilotinib (25 and 50 mg/kg) was administered to mice 2 hr after APAP intoxication (500 mg/kg). The results indicated that nilotinib (25 mg/kg) (i) abolished APAP-induced liver injury and necro-inflammation, (ii) increased hepatic-reduced glutathione (GSH) and its related enzymes synthesis, (iii) suppressed hepatic oxidative/nitrosative stress cascades, (iv) decreased neutrophil accumulation in the liver, and (v) prevented the over-expression of B-cell lymphoma-2 (bcl-2), cyclin-D1 and stem cell factor receptor (c-Kit) proteins in the liver. Although nilotinib (50 mg/kg) acted through the same mechanisms, there was severe depletion in hepatic GSH content by nilotinib itself at that dose level, rather than the potent stimulation observed by using a dose of 25 mg/kg. Consequently, the mortality rate after 18 hr was 100% for nilotinib (50 mg/kg) + APAP (750 mg/kg) versus 60% for APAP (750 mg/kg) and 40% for nilotinib (25 mg/kg) + APAP (750 mg/kg) in the survival analysis experiment. In conclusion, nilotinib can counteract the hepatotoxicity produced by a non-lethal dose of APAP. However, there is a risk of aggravating the mortality for a lethal dose of APAP when nilotinib is co-administered at doses relatively high, or near to the clinical range because of hepatic GSH depletion and c-kit inhibition.

  2. Altered protein S-glutathionylation identifies a potential mechanism of resistance to acetaminophen-induced hepatotoxicity.

    PubMed

    McGarry, David J; Chakravarty, Probir; Wolf, C Roland; Henderson, Colin J

    2015-11-01

    Acetaminophen (APAP) is the most commonly used over-the-counter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography-tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2(-/-) mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wild-type mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2(-/-) mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2(-/-) mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity. PMID:26311813

  3. Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis.

    PubMed

    Canet, Mark J; Merrell, Matthew D; Hardwick, Rhiannon N; Bataille, Amy M; Campion, Sarah N; Ferreira, Daniel W; Xanthakos, Stavra A; Manautou, Jose E; A-Kader, H Hesham; Erickson, Robert P; Cherrington, Nathan J

    2015-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

  4. Acute toxicity of mixture of acetaminophen and ibuprofen to Green Neon Shrimp, Neocaridina denticulate.

    PubMed

    Sung, Hung-Hung; Chiu, Yuh-Wen; Wang, Shu-Yin; Chen, Chien-Min; Huang, Da-Ji

    2014-07-01

    In recent years, numerous studies have indicated that various long-term use drugs, such as antibiotics or analgesics, not only cannot be completely decomposed via sewage treatment but also exhibit biological toxicity if they enter the environment; thus, the release of these drugs into the environment can damage ecological systems. This study sought to investigate the acute toxicity of two commonly utilized analgesics, ibuprofen (IBU) and acetaminophen (APAP), to aquatic organisms after these drugs have entered the water. To address this objective, the acute toxicity (median lethal concentration, LC₅₀, for a 96-h exposure) of IBU alone, APAP alone, and mixtures containing different ratios of IBU and APAP in green neon shrimp (Neocaridina denticulata) were measured. The results of four tests revealed that the 96-h LC₅₀ values for IBU and APAP alone were 6.07 mg/L and 6.60 mg/L, respectively. The 96-h LC₅₀ for a 1:1 mixture of IBU and APAP was 6.23 mg/L, and the toxicity of this mixture did not significantly differ from the toxicity of either drug alone (p<0.05). The experimental results for mixtures containing unequal ratios of IBU and APAP indicated that mixtures with high APAP concentrations and low IBU concentrations exhibited markedly greater toxicity in N. denticulata (LC₅₀=4.78 mg/L) than APAP or IBU alone. However, mixtures with high IBU concentrations and low APAP concentrations exhibited lower toxicity in N. denticulata (LC₅₀=6.78 mg/L) than IBU or APAP alone. This study demonstrated that different mixtures of IBU and APAP were associated with different toxic effects in green neon shrimp. PMID:24860956

  5. Resistance to acetaminophen-induced hepatotoxicity in glutathione S-transferase Mu 1-null mice.

    PubMed

    Arakawa, Shingo; Maejima, Takanori; Fujimoto, Kazunori; Yamaguchi, Takashi; Yagi, Masae; Sugiura, Tomomi; Atsumi, Ryo; Yamazoe, Yasushi

    2012-01-01

    We investigated the role of glutathione S-transferases Mu 1 (GSTM1) in acetaminophen (APAP)-induced hepatotoxicity using Gstm1-null mice. A single oral administration of APAP resulted in a marked increase in plasma alanine aminotransferase accompanied by hepatocyte necrosis 24 hr after administration in wild-type mice, but its magnitude was unexpectedly attenuated in Gstm1-null mice. Therefore, it is suggested that Gstm1-null mice are resistant to APAP-induced hepatotoxicity. To examine the mechanism of this resistance in Gstm1-null mice, we measured phosphorylation of c-jun N-terminal kinase (JNK), which mediates the signal of APAP-induced hepatocyte necrosis, by Western blot analysis 2 and 6 hr after APAP administration. A marked increase in phosphorylated JNK was observed in wild-type mice, but the increase was markedly suppressed in Gstm1-null mice. Therefore, it is suggested that suppressed phosphorylation of JNK may be a main mechanism of the resistance to APAP-induced hepatotoxicity in Gstm1-null mice, although other possibilities of the mechanism cannot be eliminated. Additionally, phosphorylation of glycogen synthase kinase-3β and mitogen-activated protein kinase kinase 4, which are upstream kinases of JNK in APAP-induced hepatotoxicity, were also suppressed in Gstm1-null mice. A decrease in liver total glutathione 2 hr after APAP administration, which is an indicator for exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of APAP, were similar in wild-type and Gstm1-null mice. In conclusion, Gstm1-null mice are considered to be resistant to APAP-induced hepatotoxicity perhaps by the suppression of JNK phosphorylation. This study indicates the novel role of GSTM1 as a factor mediating the cellular signal for APAP-induced hepatotoxicity.

  6. Acute toxicity of mixture of acetaminophen and ibuprofen to Green Neon Shrimp, Neocaridina denticulate.

    PubMed

    Sung, Hung-Hung; Chiu, Yuh-Wen; Wang, Shu-Yin; Chen, Chien-Min; Huang, Da-Ji

    2014-07-01

    In recent years, numerous studies have indicated that various long-term use drugs, such as antibiotics or analgesics, not only cannot be completely decomposed via sewage treatment but also exhibit biological toxicity if they enter the environment; thus, the release of these drugs into the environment can damage ecological systems. This study sought to investigate the acute toxicity of two commonly utilized analgesics, ibuprofen (IBU) and acetaminophen (APAP), to aquatic organisms after these drugs have entered the water. To address this objective, the acute toxicity (median lethal concentration, LC₅₀, for a 96-h exposure) of IBU alone, APAP alone, and mixtures containing different ratios of IBU and APAP in green neon shrimp (Neocaridina denticulata) were measured. The results of four tests revealed that the 96-h LC₅₀ values for IBU and APAP alone were 6.07 mg/L and 6.60 mg/L, respectively. The 96-h LC₅₀ for a 1:1 mixture of IBU and APAP was 6.23 mg/L, and the toxicity of this mixture did not significantly differ from the toxicity of either drug alone (p<0.05). The experimental results for mixtures containing unequal ratios of IBU and APAP indicated that mixtures with high APAP concentrations and low IBU concentrations exhibited markedly greater toxicity in N. denticulata (LC₅₀=4.78 mg/L) than APAP or IBU alone. However, mixtures with high IBU concentrations and low APAP concentrations exhibited lower toxicity in N. denticulata (LC₅₀=6.78 mg/L) than IBU or APAP alone. This study demonstrated that different mixtures of IBU and APAP were associated with different toxic effects in green neon shrimp.

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

    PubMed

    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. PMID:26454079

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

    PubMed

    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.

  9. Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice.

    PubMed

    Thiele, Kristin; Solano, M Emilia; Huber, Samuel; Flavell, Richard A; Kessler, Timo; Barikbin, Roja; Jung, Roman; Karimi, Khalil; Tiegs, Gisa; Arck, Petra C

    2015-10-01

    Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans. PMID:26254283

  10. Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice.

    PubMed

    Thiele, Kristin; Solano, M Emilia; Huber, Samuel; Flavell, Richard A; Kessler, Timo; Barikbin, Roja; Jung, Roman; Karimi, Khalil; Tiegs, Gisa; Arck, Petra C

    2015-10-01

    Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.

  11. Acetaminophen Injection

    MedlinePlus

    ... injection is also used in combination with opioid (narcotic) medications to relieve moderate to severe pain. Acetaminophen is in a class of medications called analgesics (pain relievers) and antipyretics (fever reducers). It works by changing ...

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

    PubMed Central

    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

  13. Effects of administration of subtoxic doses of acetaminophen on liver and blood levels of insulin-like growth factor-1 in rats.

    PubMed

    Ozdemir, Durgul; Aksu, Ilkay; Baykara, Basak; Ates, Mehmet; Sisman, Ali Riza; Kiray, Muge; Buyuk, Arzu; Uysal, Nazan

    2016-01-01

    Acetaminophen (APAP) is widely used in the treatment of pain. Toxic doses of APAP cause acute liver failure, but therapeutic doses are believed to be safe. The purpose of this study is to investigate the effects of administration of subtoxic doses of APAP on liver and blood levels of insulin-like growth factor-1 (IGF-1) in rats. Low dose (100 mg/kg) and high dose (250 mg/kg) of APAP were intraperitoneally injected into Wistar albino rats. Following administration of therapeutic doses of APAP, there were no significant changes in serum transaminases and liver glutathione levels. Both doses of APAP induced a decrease in liver and blood levels of IGF-1 when compared with the controls. There was no significant difference in liver IGF-1 levels between the high-dose and low-dose APAP groups; however, there was a significant difference in blood IGF-1 levels between both the groups. The histological examination showed that low dose of APAP induced mild degree of structural change, while high dose of APAP induced severe structural damage. In conclusion, these results suggest that blood IGF-1 levels may have a value in predicting hepatic damage resulting from therapeutic doses of APAP.

  14. Studies of acetaminophen and metabolites in urine and their correlations with toxicity using metabolomics.

    PubMed

    Sun, Jinchun; Schnackenberg, Laura K; Beger, Richard D

    2009-08-01

    A LC/MS-based metabolomic assay was utilized to investigate a drug's excretion kinetic profile in urine so that the drug toxicity information could be obtained. Groups of 10 male Sprague-Dawley rats per dose were orally gavaged with a single dose of 0.2% carboxymethylcellulose, 400 mg acetaminophen (APAP)/kg body weight or 1600 mg APAP/kg. UPLC/MS and NMR were used to evaluate the excretion kinetics of major drug metabolites. N-acetyl-L-cysteine acetaminophen (APAP-NAC) had statistically significant correlations with clinical chemistry data, endogenous metabolite concentrations and histopathology data. The potential toxicity of a drug can be assessed through the study of the drug's metabolite profiles.

  15. Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes*

    PubMed Central

    Mobasher, Maysa Ahmed; de Toro-Martín, Juan; González-Rodríguez, Águeda; Ramos, Sonia; Letzig, Lynda G.; James, Laura P.; Muntané, Jordi; Álvarez, Carmen; Valverde, Ángela M.

    2014-01-01

    Many drugs are associated with the development of glucose intolerance or deterioration in glycemic control in patients with pre-existing diabetes. We have evaluated the cross-talk between signaling pathways activated by acetaminophen (APAP) and insulin signaling in hepatocytes with or without expression of the protein-tyrosine phosphatase 1B (PTP1B) and in wild-type and PTP1B-deficient mice chronically treated with APAP. Human primary hepatocytes, Huh7 hepatoma cells with silenced PTP1B, mouse hepatocytes from wild-type and PTP1B-deficient mice, and a mouse model of chronic APAP treatment were used to examine the mechanisms involving PTP1B in the effects of APAP on glucose homeostasis and hepatic insulin signaling. In APAP-treated human hepatocytes at concentrations that did not induce death, phosphorylation of JNK and PTP1B expression and enzymatic activity were increased. APAP pretreatment inhibited activation of the early steps of insulin signaling and decreased Akt phosphorylation. The effects of APAP in insulin signaling were prevented by suramin, a PTP1B inhibitor, or rosiglitazone that decreased PTP1B levels. Likewise, PTP1B deficiency in human or mouse hepatocytes protected against APAP-mediated impairment in insulin signaling. These signaling pathways were modulated in mice with chronic APAP treatment, resulting in protection against APAP-mediated hepatic insulin resistance and alterations in islet alpha/beta cell ratio in PTP1B−/− mice. Our results demonstrate negative cross-talk between signaling pathways triggered by APAP and insulin signaling in hepatocytes, which is in part mediated by PTP1B. Moreover, our in vivo data suggest that chronic use of APAP may be associated with insulin resistance in the liver. PMID:25204659

  16. Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice.

    PubMed

    Chaudhuri, Shubhra; McCullough, Sandra S; Hennings, Leah; Brown, Aliza T; Li, Shun-Hwa; Simpson, Pippa M; Hinson, Jack A; James, Laura P

    2012-10-15

    Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10mg/kg, oral gavage) prior to APAP (200mg/kg IP) and at 7 and 36h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8h, compared to the APAP mice. At 24 and 48h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A(2), and cytosolic and secretory PLA(2) activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E(2) expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE(2) expression and hepatocyte regeneration, likely through a mechanism involving PLA(2).

  17. Essential role of protein-tyrosine phosphatase 1B in the modulation of insulin signaling by acetaminophen in hepatocytes.

    PubMed

    Mobasher, Maysa Ahmed; de Toro-Martín, Juan; González-Rodríguez, Águeda; Ramos, Sonia; Letzig, Lynda G; James, Laura P; Muntané, Jordi; Álvarez, Carmen; Valverde, Ángela M

    2014-10-17

    Many drugs are associated with the development of glucose intolerance or deterioration in glycemic control in patients with pre-existing diabetes. We have evaluated the cross-talk between signaling pathways activated by acetaminophen (APAP) and insulin signaling in hepatocytes with or without expression of the protein-tyrosine phosphatase 1B (PTP1B) and in wild-type and PTP1B-deficient mice chronically treated with APAP. Human primary hepatocytes, Huh7 hepatoma cells with silenced PTP1B, mouse hepatocytes from wild-type and PTP1B-deficient mice, and a mouse model of chronic APAP treatment were used to examine the mechanisms involving PTP1B in the effects of APAP on glucose homeostasis and hepatic insulin signaling. In APAP-treated human hepatocytes at concentrations that did not induce death, phosphorylation of JNK and PTP1B expression and enzymatic activity were increased. APAP pretreatment inhibited activation of the early steps of insulin signaling and decreased Akt phosphorylation. The effects of APAP in insulin signaling were prevented by suramin, a PTP1B inhibitor, or rosiglitazone that decreased PTP1B levels. Likewise, PTP1B deficiency in human or mouse hepatocytes protected against APAP-mediated impairment in insulin signaling. These signaling pathways were modulated in mice with chronic APAP treatment, resulting in protection against APAP-mediated hepatic insulin resistance and alterations in islet alpha/beta cell ratio in PTP1B(-/-) mice. Our results demonstrate negative cross-talk between signaling pathways triggered by APAP and insulin signaling in hepatocytes, which is in part mediated by PTP1B. Moreover, our in vivo data suggest that chronic use of APAP may be associated with insulin resistance in the liver. PMID:25204659

  18. Crystallization of poly(ethylene oxide) with acetaminophen--a study on solubility, spherulitic growth, and morphology.

    PubMed

    Yang, Min; Gogos, Costas

    2013-11-01

    A simple, sensitive, efficient, and novel method analyzing the number of spherulitic nuclei was proposed to estimate the solubility of a model drug acetaminophen (APAP) in poly(ethylene oxide) (PEO). At high crystallization temperature (323 K), 10% APAP-PEO had the same low number of spherulitic nuclei as pure PEO, indicating that APAP and PEO were fully miscible. At low crystallization temperature (303 K), the number of nuclei for 10% APAP-PEO was significantly higher, suggesting that APAP was oversaturated and therefore recrystallized and acted as a nucleating agent. Based on the results obtained, the solubility of APAP in PEO is possibly between the concentration of 0.1% and 1% at 303 K. The spherulitic growth rate G of PEO was found to decrease with increasing APAP concentration, suggesting that APAP is most likely functioning as a chemical defect and is either rejected from or included in the PEO crystals during chain folding. APAP could possibly locate in the inter-spherulitic, inter-fibrillar, inter-lamellar, or intra-lamellar regions of PEO. At 323 K, the morphology of 10% APAP-PEO is more dendritic than spherulitic with large unfilled space in between dendrites and spherulites, which is a sign of one or the combination of the four modes of segregation. An extensive spherulitic nucleation and growth kinetics study using the classical theoretical relationships, for example, the Hoffman-Lauritzen (HL) and Avrami theories, was conducted. Both microscopic and differential scanning calorimetric (DSC) analysis yielded similar values for the nucleation constant Kg as well as the fold surface free energy σe and work of chain folding q. The values of σe and q increased with APAP concentration, indicating that the chain folding of PEO was hindered by APAP.

  19. Hypothermic activity of acetaminophen; involvement of GABAA receptor, theoretical and experimental studies

    PubMed Central

    Ahangar, Nematollah; Esam, Zohreh; Bekhradnia, Ahmadreza; Ebrahimzadeh, Mohammad Ali

    2016-01-01

    Objective(s): The mechanism of hypothermia action of acetaminophen (APAP) remains unclear even 125 years after its synthesis. Acetaminophen produces hypothermia. The mechanism of this reduction in core body temperature is not clear but evidence shows that it is not dependent on opioid and cannabinoid receptors. Because of strong documents about the roles of GABA and benzodiazepine receptors in hypothemic activity of some drugs such as diazepam, we determined if these receptors also contributes to the hypothermic effect of APAP. Materials and Methods: Diazepam (5 mg/kg, IP) was used for induction of hypothermia. Flumazenil (10 mg/kg, IP) or picrotoxin (2 mg/kg, IP) used for reversal of this effect. Rats injected with APAP (100, 200 or 300 mg/kg, IP). Baseline temperature measurements were taken with a digital thermometer via rectum. To evaluate the structural correlation between APAP and benzodiazepine receptor ligands, numerous models are selected and studied at HF/6-31G* level of theory. Relative energies, enthalpies and Gibbs free energies were calculated for all selected drugs. Results Diazepam induced hypothermia was reversed by flumazenil or picrotoxin. Rats injected with APAP displayed dose- and time-related hypothermia. For combined administration, the hypothermic effect of APAP (200 mg/kg) was strongly reduced by pretreatment with picrotoxin or flumazenil P<0.0001and P<0.01, respectively. Selective structural data, bond length, dihedral angles, and related distance in pharmacophore of APAP and BZDR models were the same. Some significant structural analogues were obtained between these drugs. Conclusion: Results suggest hypothermic action of acetaminophen may be mediate by its effect at GABAA benzodiazepine receptor. PMID:27403252

  20. Barbiturate intoxication and overdose

    MedlinePlus

    Intoxication - barbiturates ... Symptoms of barbiturate intoxication and overdose include: Altered level of consciousness Difficulty in thinking Drowsiness or coma Faulty judgment Lack of coordination Shallow ...

  1. Baking soda overdose

    MedlinePlus

    Soda loading ... Baking soda contains sodium bicarbonate. ... Symptoms of baking soda overdose include: Constipation Convulsions Diarrhea Feeling of being full Frequent urination Irritability Muscle spasms Muscle weakness Vomiting

  2. Nephroprotective effect of jaggery against acute and subchronic toxicity of acetaminophen in Wistar rats.

    PubMed

    Sharma, Chandra Kant; Sharma, Vinay

    2012-01-01

    The present investigation was planned to evaluate the nephroprotective activity of jaggery against acetaminophen (APAP)-induced renal damage in rats. The protective activity of jaggery at different doses (250, 500, and 750 mg/kg, orally) was evaluated against oxidative damage induced by APAP administration (2 g/kg, once orally in acute exposure; 20 mg/kg, orally for 21 days in subchronic exposure) in rats. APAP administration significantly increased the levels of serum urea, creatinine, and renal lipid peroxidation (LPO), whereas substantial decreases were observed in levels of glutathione (GSH), adenosine triphosphatase (ATPase), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) enzymatic activities after APAP administration. Administration of jaggery significantly moved the studied parameters toward normal levels and also reversed the histopathologic alterations. Thus, jaggery can be used to reduce renal damage and may serve as an alternative medicine in the treatment of renal etiologies.

  3. Organochlorines inhibit acetaminophen glucuronidation by redirecting UDP-glucuronic acid towards the D-glucuronate pathway

    SciTech Connect

    Chan, Tom S. Wilson, John X.; Selliah, Subajini; Bilodeau, Marc; Zwingmann, Claudia; Poon, Raymond; O'Brien, Peter J.

    2008-11-01

    Industry-derived organochlorines are persistent environmental pollutants that are a continuing health concern. The effects of these compounds on drug metabolism are not well understood. In the current study we present evidence that the inhibition of acetaminophen (APAP) glucuronidation by minute concentrations of organochlorines correlates well with their ability to stimulate the D-glucuronate pathway leading to ascorbate synthesis. A set of 6 arylated organochlorines, including 5 PCB (polychlorinated biphenyl) congeners, were assessed for their effects on APAP glucuronidation in isolated hepatocytes from male Sprague-Dawley rats. The capacity of each organochlorine to inhibit APAP glucuronidation was found to be directly proportional to its capacity to stimulate ascorbate synthesis. PCB153, PCB28 and bis-(4-chlorophenyl sulfone) (BCPS) in increasing order were the most effective organochlorines for inhibiting APAP glucuronidation and stimulating the D-glucuronate pathway. None of the 3 inhibitors of APAP glucuronidation were able to alter the expression of UGT1A6, UGT1A7 and UGT1A8 (the major isoforms responsible for APAP glucuronidation in the rat), however, their efficacy at inhibiting APAP glucuronidation was proportional to their capacity to deplete UDP-glucuronic acid (UDPGA). BCPS-mediated inhibition of APAP glucuronidation in isolated hepatocytes had non-competitive characteristics and was insensitive to the inactivation of cytochrome P450. The effective organochlorines were also able to selectively stimulate the hydrolysis of UDPGA to UDP and glucuronate in isolated microsomes, but could not inhibit APAP glucuronidation in microsomes when UDPGA was in excess. We conclude that organochlorines are able to inhibit APAP glucuronidation in hepatocytes by depleting UDPGA via redirecting UDPGA towards the D-glucuronate pathway. Because the inhibition is non-competitive, low concentrations of these compounds could have long term inhibitory effects on the

  4. Buccal acetaminophen provides fast analgesia: two randomized clinical trials in healthy volunteers

    PubMed Central

    Pickering, Gisèle; Macian, Nicolas; Libert, Frédéric; Cardot, J Michel; Coissard, Séverine; Perovitch, Philippe; Maury, Marc; Dubray, Claude

    2014-01-01

    Background Acetaminophen (APAP) by oral or intravenous (iv) routes is used for mild to moderate pain but may take time to be effective. When fast relief is required and/or oral or iv routes are not available because of the patient’s condition, the transmucosal route may be an alternative. Methodology A new transmucosal/buccal (b) pharmaceutical form of APAP dissolved in 50% wt alcohol is compared with other routes of administration. Two consecutive randomized, crossover, double-blind clinical trials (CT1: NCT00982215 and CT2: NCT01206985) included 16 healthy volunteers. CT1 compared the pharmacology of 250 mg bAPAP with 1 g iv APAP. CT2 compared the pharmacodynamics of 125 mg bAPAP with 1 g iv and 125 mg sublingual (s) APAP. Mechanical pain thresholds are recorded in response to mechanical stimuli applied on the forearm several times during 120 minutes. The objective is to compare the time of onset of antinociception and the antinociception (area under the curve) between the routes of administration with analysis of variance (significance P<0.05). Results bAPAP has a faster time of antinociception onset (15 minutes, P<0.01) and greater antinociception at 50 minutes (P<0.01, CT1) and 30 minutes (P<0.01, CT2) than ivAPAP and sAPAP. All routes are similar after 50 minutes. Conclusion bAPAP has a faster antinociceptive action in healthy volunteers. This attractive alternative to other routes would be useful in situations where oral or iv routes are not available. This finding must now be confirmed in patients suffering from acute pain of mild and moderate intensity. PMID:25302017

  5. Influence of acetaminophen vehicle on regulation of transporter gene expression during hepatotoxicity.

    PubMed

    Aleksunes, Lauren M; Augustine, Lisa M; Cherrington, Nathan J; Manautou, José E

    2007-11-01

    Researchers who study acetaminophen (APAP) hepatotoxicity use either a 50% propylene glycol solution or saline as a diluent. Previous studies demonstrated differential expression of hepatobiliary transporter mRNA in mice treated with a toxic dose of APAP dissolved in 50% propylene glycol. The purpose of this study was to determine whether using saline as a diluent for APAP alters regulation of transporter gene expression during hepatotoxicity. Male C57BL/6J mice received acetaminophen (APAP 400 mg/kg, i.p. in saline) or saline (20 ml/kg). Plasma and liver samples were collected at 24 and 48 h for assessment of alanine aminotransferase (ALT) activity and gene expression. It was determined that plasma ALT activity was elevated at 24 and 48 h after APAP administration. Using the branched DNA signal amplification assay, reductions in organic anion-transporting polypeptides Oatp1a1, Oatp1b2, sodium/taurocholate-cotransporting polypeptide (Ntcp), and bile salt export pump (Bsep) mRNA were observed in APAP-treated mice. In contrast, multidrug resistance-associated proteins Mrp1, Mrp2, Mrp3, and Mrp4, as well as multidrug resistance proteins Mdr1a and Mdr1b genes, were increased following APAP. No changes in Oatp1a4, Mdr2, or breast cancer resistance protein (Bcrp) mRNA were observed. Alterations in transporter gene expression in this study were similar to those reported previously using propylene glycol as diluent. With the exceptions of Oatp1a1, Ntcp, and Mrp1, these data mirror previous results suggesting that the solution used to dissolve APAP may alter the susceptibility of mice to hepatotoxicity, but only minimally change the regulation of transporter gene expression.

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

    PubMed Central

    González-Ponce, Herson Antonio; Martínez-Saldaña, María Consolación; Rincón-Sánchez, Ana Rosa; Sumaya-Martínez, María Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juárez, 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 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 (800 mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20 mmol/L APAP, 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. PMID:27782042

  7. Therapeutic efficacy of Wuzhi tablet (Schisandra sphenanthera Extract) on acetaminophen-induced hepatotoxicity through a mechanism distinct from N-acetylcysteine.

    PubMed

    Fan, Xiaomei; Chen, Pan; Jiang, Yiming; Wang, Ying; Tan, Huasen; Zeng, Hang; Wang, Yongtao; Qu, Aijuan; Gonzalez, Frank J; Huang, Min; Bi, Huichang

    2015-03-01

    Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury.

  8. Risk of Acute Kidney Injury and Long-Term Outcome in Patients With Acetaminophen Intoxication: A Nationwide Population-Based Retrospective Cohort Study.

    PubMed

    Chen, Yu-Guang; Lin, Cheng-Li; Dai, Ming-Shen; Chang, Ping-Ying; Chen, Jia-Hong; Huang, Tzu-Chuan; Wu, Yi-Ying; Kao, Chia-Hung

    2015-11-01

    Acetaminophen (APAP) intoxication is a common cause of hepatic toxicity and life-threatening hepatic failure. However, few studies have investigated the possible association between APAP intoxication and acute kidney injury (AKI). We constructed a retrospective cohort study to clarify the relationship between APAP intoxication and the risk of AKI.We identified patients with APAP intoxication and selected a comparison cohort that was 1:4 frequency matched according to age, sex, and year of APAP intoxication diagnosis from the Taiwan National Health Insurance Research Database from 1998 to 2010. We analyzed the risks of AKI for patients with APAP intoxication by using Cox proportional hazards regression models.In this study, 2914 patients with APAP intoxication and 11,656 controls were included. The overall risks of developing AKI were 2.41-fold in the patients with APAP intoxication compared with the comparison cohort. After we excluded APAP intoxication patients with coexisting AKI and hepatic failure/hepatitis, the overall risks of developing AKI were still 2.22-fold in the patients with APAP intoxication. There were 2 patients who had end-stage renal disease (ESRD) following APAP intoxication-related AKI. Limitations include retrospective review, selection bias, and absence of data on detail medications used, laboratory investigations and dosage of APAP intoxication.Our long-term cohort study results showed that AKI is a possible adverse effect among patients with APAP intoxication, regardless of whether patients have presented with hepatic toxicity. However, additional studies are necessary to clarify whether such patients can progress to ESRD. PMID:26579812

  9. Acquired resistance to acetaminophen hepatotoxicity is associated with induction of multidrug resistance-associated protein 4 (Mrp4) in proliferating hepatocytes.

    PubMed

    Aleksunes, Lauren M; Campion, Sarah N; Goedken, Michael J; Manautou, José E

    2008-08-01

    Treatment with hepatotoxicants such as acetaminophen (APAP) causes resistance to a second, higher dose of the same toxicant (autoprotection). APAP induces hepatic mRNA and protein levels of the multidrug resistance-associated proteins (Mrp) transporters in mice and humans. Basolateral efflux transporters Mrp3 and Mrp4 are the most significantly induced. We hypothesized that upregulation of Mrp3 and Mrp4 is one mechanism by which hepatocytes become resistant to a subsequent higher dose of APAP by limiting accumulation of xeno-, endobiotics, and byproducts of hepatocellular injury. The purpose of this study was to evaluate Mrp3 and Mrp4 expression in proliferating hepatocytes in a mouse model of APAP autoprotection. Plasma and livers were collected from male C57BL/6J mice treated with APAP 400 mg/kg for determination of hepatotoxicity and protein expression. Maximal Mrp3 and Mrp4 induction occurred 48 h after APAP. Mrp4 upregulation occurred selectively in proliferating hepatocytes. Additional groups of APAP-pretreated mice were challenged 48 h later with a second, higher dose of APAP. APAP-pretreated mice had reduced hepatotoxicity after APAP challenge compared to those pretreated with vehicle. A more rapid recovery of glutathione (GSH) in APAP-pretreated mice corresponded with increases in GSH synthetic enzymes. Interestingly, mice pretreated and challenged with APAP had dramatic increases in Mrp4 expression as well as enhanced hepatocyte proliferation. Inhibition of hepatocyte replication with colchicine not only restored sensitivity of APAP-pretreated mice to injury, but also blocked Mrp4 induction. Mrp4 overexpression may be one phenotypic property of proliferating hepatocytes that protects against subsequent hepatotoxicant exposure by mechanisms that are presently unknown. PMID:18468992

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

    PubMed

    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.

  11. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPAR{alpha} with clofibrate

    SciTech Connect

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

    2008-08-01

    The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPAR{alpha} 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. {sup 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 {sup 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 PPAR{alpha} was tested. PPAR{alpha} was downregulated in NASH. To investigate whether downregulation of PPAR{alpha} in NASH is the critical mechanism of compromised liver tissue repair, PPAR{alpha} 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 PPAR{alpha} expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.

  12. Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity.

    PubMed

    Donahower, Brian C; McCullough, Sandra S; Hennings, Leah; Simpson, Pippa M; Stowe, Cindy D; Saad, Ali G; Kurten, Richard C; Hinson, Jack A; James, Laura P

    2010-07-01

    We reported previously that vascular endothelial growth factor (VEGF) was increased in acetaminophen (APAP) toxicity in mice and treatment with a VEGF receptor inhibitor reduced hepatocyte regeneration. The effect of human recombinant VEGF (hrVEGF) on APAP toxicity in the mouse was examined. In early toxicity studies, B6C3F1 mice received hrVEGF (50 microg s.c.) or vehicle 30 min before receiving APAP (200 mg/kg i.p.) and were sacrificed at 2, 4, and 8 h. Toxicity was comparable at 2 and 4 h, but reduced in the APAP/hrVEGF mice at 8 h (p < 0.05) compared with the APAP/vehicle mice. Hepatic glutathione (GSH) and APAP protein adduct levels were comparable between the two groups of mice, with the exception that GSH was higher at 8 h in the hrVEGF-treated mice. Subsequently, mice received two doses (before and 10 h) or three doses (before and 10 and 24 h) of hrVEGF; alanine aminotransferase values and necrosis were reduced at 24 and 36 h, respectively, in the APAP/hrVEGF mice (p < 0.05) compared with the APAP/vehicle mice. Proliferating cell nuclear antigen expression was enhanced, and interleukin-6 expression was reduced in the mice that received hrVEGF (p < 0.05) compared with the APAP/vehicle mice. In addition, treatment with hrVEGF lowered plasma hyaluronic acid levels and neutrophil counts at 36 h. Cumulatively, the data show that treatment with hrVEGF reduced toxicity and increased hepatocyte regeneration in APAP toxicity in the mouse. Attenuation of sinusoidal cell endothelial dysfunction and changes in neutrophil dynamics may be operant mechanisms in the hepatoprotection mediated by hrVEGF in APAP toxicity.

  13. Prescription Acquired Acetaminophen Use and the Risk of Asthma in Adults: A Case Control Study

    PubMed Central

    Kelkar, Mugdha; Cleves, Mario A.; Foster, Howell R.; Hogan, William R.; James, Laura P.

    2013-01-01

    Background Studies have examined the association between acetaminophen (APAP) use and asthma; however, their interpretation is limited by a number of methodological issues. Objective We sought to investigate the association between recent and chronic prescription acquired acetaminophen use and asthma. Methods This was a retrospective case control study using a 10% random sample of the IMS LifeLink commercial claims data from 1997 to 2009. Cases had to have at least 1 incident claim of asthma. 3:1 controls matched on age, gender, and region were randomly chosen. APAP exposure, dose and duration were measured in the 7 and 30 days (recent) and in the 1-year (chronic) look-back period. Multivariable conditional logistic regression was used to estimate the risk of asthma associated with acetaminophen use adjusted for comorbidities, other drugs increasing asthma risk, and health system factors. Results There were 28,892 cases and 86,676 controls with mean age 42.7 years and 37.7% were males. 22.6% cases and 18.2% controls had APAP exposure in the pre-index year with mean cumulative doses of 78.7 gm and 59.8 gm respectively. There was no significant association between recent prescription APAP exposure and asthma (7 days: OR = 1.02, p = 0.74; 30 days: OR = 0.97, p = 0.38). Cumulative prescription APAP dose in the year prior increased asthma risk compared to APAP nonusers (<=1 kg: OR = 1.09, p <0.001 and >1 kg: OR = 1.60, p=0.02). Duration of prescription APAP use >30 days was associated with elevated asthma risk (OR = 1.39, p <0.001). Conclusion Chronic prescription-acquired APAP use was associated with an increased risk of asthma while recent use was not. However, over the counter APAP use was not captured in this study and further epidemiologic research with complete APAP exposure ascertainment and research on pathophysiological mechanisms is needed to confirm these relationships. PMID:23170033

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

    SciTech Connect

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

    2012-03-15

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

    SciTech Connect

    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.

  16. Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) compared with immediate-release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen

    PubMed Central

    Devarakonda, Krishna; Kostenbader, Kenneth; Giuliani, Michael J; Young, Jim L

    2015-01-01

    Objective To characterize the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP), IR HB/ibuprofen, and IR tramadol HCl/APAP. Methods In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1) a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose) on day 1, followed by two tablets every 12 hours (q12h) beginning on day 3; 2) a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6), followed by one tablet every 6 hours (q6h) beginning on day 3; 3) a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6), followed by one tablet q6h beginning on day 3; and 4) a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose) on day 1, a three-tablet initial dose at 48 hours followed by two-tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady-state PK were assessed. Adverse events were monitored. Results The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg) vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures were similar between treatments. Adverse events were similar for each treatment and typical of low-dose combination opioid analgesics. With dosing q12h, IR/ER HB/APAP had half as many concentration peaks and troughs as the comparators treated q6h. Conclusion With dosing q12h, IR/ER HB/APAP provided similar peak and total steady-state hydrocodone

  17. Peppermint oil overdose

    MedlinePlus

    Peppermint oil is an oil made from the peppermint plant. Peppermint oil overdose occurs when someone swallows more than ... Menthol is the ingredient in peppermint oil that can be poisonous in large amounts.

  18. Campho-Phenique overdose

    MedlinePlus

    Campho-Phenique contains both camphor and phenol. For information on products containing camphor alone, see camphor overdose . ... Both camphor and phenol are in Campho-Phenique. However, camphor and phenol may be found separately in other products.

  19. Zinc oxide overdose

    MedlinePlus

    Zinc oxide is an ingredient in many products. Some of these are certain creams and ointments used ... prevent or treat minor skin burns and irritation. Zinc oxide overdose occurs when someone eats one of ...

  20. Fenoprofen calcium overdose

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/002649.htm Fenoprofen calcium overdose To use the sharing features on this page, please enable JavaScript. Fenoprofen calcium is a type of medicine called a nonsteroidal ...

  1. Sports cream overdose

    MedlinePlus

    Sports creams are creams or ointments used to treat aches and pains. Sports cream overdose can occur if someone uses this ... Two ingredients in sports creams that can be poisonous are: Menthol Methyl salicylate

  2. Bacitracin zinc overdose

    MedlinePlus

    ... Small amounts of bacitracin zinc are dissolved in petroleum jelly to create antibiotic ointments. Bacitracin zinc overdose ... is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation ...

  3. Diclofenac sodium overdose

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/002630.htm Diclofenac sodium overdose To use the sharing features on this page, please enable JavaScript. Diclofenac sodium is a prescription medicine used to relieve pain ...

  4. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

    SciTech Connect

    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya; Okada, Norihiko; Yoshida, Saori; Yamamoto, Junya; Ohkubo, Rika; Abiko, Yumi; Yamada, Hidenori; Akahoshi, Noriyuki; Kasahara, Tadashi; Kumagai, Yoshito; Ishii, Isao

    2015-01-15

    The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs{sup +/−} or Cth{sup +/−}) and homozygous (Cth{sup −/−}) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth{sup −/−} mice at 150 mg/kg dose, and also in Cbs{sup +/−} or Cth{sup +/−} mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth{sup −/−} mice but not wild-type mice, although glutamate–cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth{sup −/−} mice with lower K{sub m} values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth{sup −/−} mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200–300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. - Highlights: • Cbs{sup +/−}, Cth{sup +/−}, and

  5. Hydrocodone/oxycodone overdose

    MedlinePlus

    Hydrocodone and oxycodone belong to a class of narcotic medicines called opiates. These medicines are man-made ... medicines may also be combined with the non-narcotic medicine, acetaminophen (Tylenol).

  6. Analysis of Changes in Hepatic Gene Expression in a Murine Model of Tolerance to Acetaminophen Hepatotoxicity (Autoprotection)

    PubMed Central

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

    2013-01-01

    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 hr later with 600 mg APAP/kg. Livers were obtained 4 or 24 hr 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. PMID:24126418

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

    PubMed

    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 (400mg/kg) and then challenged 48h later with 600mg APAP/kg. Livers were obtained 4 or 24h 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. PMID:24126418

  8. Hepatoprotective Effect of Silymarin (Silybum marianum) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats.

    PubMed

    Freitag, Abel Felipe; Cardia, Gabriel Fernando Esteves; da Rocha, Bruno Ambrósio; Aguiar, Rafael Pazzinatto; Silva-Comar, Francielli Maria de Souza; Spironello, Ricardo Alexandre; Grespan, Renata; Caparroz-Assef, Silvana Martins; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2015-01-01

    This study was aimed to investigate the effect of Silymarin (SLM) on the hypertension state and the liver function changes induced by acetaminophen (APAP) in spontaneously hypertensive rat (SHR). Animals normotensive (N) or hypertensive (SHR) were treated or not with APAP (3 g/kg, oral) or previously treated with SLM. Twelve hours after APAP administration, plasmatic levels of liver function markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), gamma glutamyl transferase (γ-GT), and alkaline phosphatase (ALP) of all groups, were determined. Liver injury was assessed using histological studies. Samples of their livers were then used to determine the myeloperoxidase (MPO) activity and nitric oxide (NO) production and were also sectioned for histological analysis. No differences were observed for ALT, γ-GT, and GLU levels between SHR and normotensive rats groups. However, AST and ALP levels were increased in hypertensive animals. APAP treatment promoted an increase in ALT and AST in both SHR and N. However, only for SHR, γ-GT levels were increased. The inflammatory response evaluated by MPO activity and NO production showed that SHR was more susceptible to APAP effect, by increasing leucocyte infiltration. Silymarin treatment (Legalon) restored the hepatocyte functional and histopathological alterations induced by APAP in normotensive and hypertensive animals.

  9. Hepatoprotective Effect of Silymarin (Silybum marianum) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats

    PubMed Central

    Cardia, Gabriel Fernando Esteves; da Rocha, Bruno Ambrósio; Aguiar, Rafael Pazzinatto; Spironello, Ricardo Alexandre; Caparroz-Assef, Silvana Martins; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2015-01-01

    This study was aimed to investigate the effect of Silymarin (SLM) on the hypertension state and the liver function changes induced by acetaminophen (APAP) in spontaneously hypertensive rat (SHR). Animals normotensive (N) or hypertensive (SHR) were treated or not with APAP (3 g/kg, oral) or previously treated with SLM. Twelve hours after APAP administration, plasmatic levels of liver function markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), gamma glutamyl transferase (γ-GT), and alkaline phosphatase (ALP) of all groups, were determined. Liver injury was assessed using histological studies. Samples of their livers were then used to determine the myeloperoxidase (MPO) activity and nitric oxide (NO) production and were also sectioned for histological analysis. No differences were observed for ALT, γ-GT, and GLU levels between SHR and normotensive rats groups. However, AST and ALP levels were increased in hypertensive animals. APAP treatment promoted an increase in ALT and AST in both SHR and N. However, only for SHR, γ-GT levels were increased. The inflammatory response evaluated by MPO activity and NO production showed that SHR was more susceptible to APAP effect, by increasing leucocyte infiltration. Silymarin treatment (Legalon) restored the hepatocyte functional and histopathological alterations induced by APAP in normotensive and hypertensive animals. PMID:25821491

  10. Hepatoprotective action of celery (Apium graveolens) leaves in acetaminophen-fed freshwater fish (Pangasius sutchi).

    PubMed

    Shivashri, C; Rajarajeshwari, T; Rajasekar, P

    2013-10-01

    Acetaminophen (APAP)-induced liver damage is one of the most common problems among the population. Therefore, the study was aimed to investigate the hepatoprotective effect of celery leaves on APAP-induced toxicity in a freshwater fish, Pangasius sutchi. Fish were divided into four experimental groups of 6 fish each. Group 1 served as control. Group 2 fish were exposed to APAP (500 mg/kg) for 24 h. Groups 3 and 4 fish were exposed to APAP + celery leaf powder (CE) (500 mg/kg) and CE for 24 h, respectively. The severity of liver damage, hepatic lipid, glycogen, ions status and histological alterations was examined. The characterization of CE extract was also performed. APAP-exposed fish showed elevated levels of both circulating and tissue hepatotoxic markers (AST, ALT and ALP), reduced hepatic glycogen and lipid contents (TG and cholesterol), increased tissue lipid peroxidation markers (TBARS, LHP and PCO), altered tissue levels of enzymatic (SOD, CAT, GPx and GST) and non-enzymatic (GSH) antioxidants and cellular thiol levels (T-SH, P-SH and NP-SH), and reduced hepatic ions (Na(+), K(+) and Ca(2+)) and abnormal liver histology. The abnormalities associated with APAP exposure were reversed on treatment with CE. The TLC separation and HPLC quantification of petroleum ether/acetone extract of CE showed the peaks for highly efficient flavonoids such as rutein, quercetin and luteolin. The observed hepatoprotective effect of CE might be due to its rich flavonoids.

  11. Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.

    PubMed

    Eakins, R; Walsh, J; Randle, L; Jenkins, R E; Schuppe-Koistinen, I; Rowe, C; Starkey Lewis, P; Vasieva, O; Prats, N; Brillant, N; Auli, M; Bayliss, M; Webb, S; Rees, J A; Kitteringham, N R; Goldring, C E; Park, B K

    2015-01-01

    Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury. PMID:26607827

  12. Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome

    PubMed Central

    Eakins, R.; Walsh, J.; Randle, L.; Jenkins, R. E.; Schuppe-Koistinen, I.; Rowe, C.; Starkey Lewis, P.; Vasieva, O.; Prats, N.; Brillant, N.; Auli, M.; Bayliss, M.; Webb, S.; Rees, J. A.; Kitteringham, N. R.; Goldring, C. E.; Park, B. K.

    2015-01-01

    Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10–15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury. PMID:26607827

  13. Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.

    PubMed

    Eakins, R; Walsh, J; Randle, L; Jenkins, R E; Schuppe-Koistinen, I; Rowe, C; Starkey Lewis, P; Vasieva, O; Prats, N; Brillant, N; Auli, M; Bayliss, M; Webb, S; Rees, J A; Kitteringham, N R; Goldring, C E; Park, B K

    2015-11-26

    Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.

  14. Evaluation of the degradation of acetaminophen by the filamentous fungus Scedosporium dehoogii using carbon-based modified electrodes.

    PubMed

    Mbokou, Serge Foukmeniok; Pontié, Maxime; Razafimandimby, Bienvenue; Bouchara, Jean-Philippe; Njanja, Evangéline; Tonle Kenfack, Ignas

    2016-08-01

    The nonpathogenic filamentous fungus Scedosporium dehoogii was used for the first time to study the electrochemical biodegradation of acetaminophen (APAP). A carbon fiber microelectrode (CFME) modified by nickel tetrasulfonated phthalocyanine (p-NiTSPc) and a carbon paste electrode (CPE) modified with coffee husks (CH) were prepared to follow the kinetics of APAP biodegradation. The electrochemical response of APAP at both electrodes was studied by cyclic voltammetry and square wave voltammetry. p-NiTSPc-CFME was suitable to measure high concentrations of APAP, whereas CH-CPE gave rise to high current densities but was subject to the passivation phenomenon. p-NiTSPc-CFME was then successfully applied as a sensor to describe the kinetics of APAP biodegradation: this was found to be of first order with a kinetics constant of 0.11 day(-1) (at 25 °C) and a half-life of 6.30 days. APAP biodegradation by the fungus did not lead to the formation of p-aminophenol (PAP) and hydroquinone (HQ) that are carcinogenic, mutagenic, and reprotoxic (CMR). Graphical Abstract The kinetics of APAP biodegradation, followed by a poly-nickel tetrasulfonated phtalocyanine modified carbon fiber microelectrode. PMID:27349916

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

    PubMed

    Vulcano, L A Denzoin; Confalonieri, O; Franci, R; Tapia, M O; Soraci, A L

    2013-01-01

    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. PMID:26623313

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

    PubMed Central

    Vulcano, L.A. Denzoin; Confalonieri, O.; Franci, R.; Tapia, M.O.; Soraci, A.L.

    2013-01-01

    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. PMID:26623313

  17. Alpha-lipoic acid treatment of acetaminophen-induced rat liver damage.

    PubMed

    Mahmoud, Y I; Mahmoud, A A; Nassar, G

    2015-01-01

    Acetaminophen (paracetamol) is a well-tolerated analgesic and antipyretic drug when used at therapeutic doses. Overdoses, however, cause oxidative stress, which leads to acute liver failure. Alpha lipoic acid is an antioxidant that has proven effective for ameliorating many pathological conditions caused by oxidative stress. We evaluated the effect of alpha lipoic acid on the histological and histochemical alterations of liver caused by an acute overdose of acetaminophen in rats. Livers of acetaminophen-intoxicated rats were congested and showed centrilobular necrosis, vacuolar degeneration and inflammatory cell infiltration. Necrotic hepatocytes lost most of their carbohydrates, lipids and structural proteins. Liver sections from rats pre-treated with lipoic acid showed fewer pathological changes; the hepatocytes appeared moderately vacuolated with moderate staining of carbohydrates and proteins. Nevertheless, alpha lipoic acid at the dose we used did not protect the liver fully from acetaminophen-induced acute toxicity. PMID:26179071

  18. Alpha-lipoic acid treatment of acetaminophen-induced rat liver damage.

    PubMed

    Mahmoud, Y I; Mahmoud, A A; Nassar, G

    2015-01-01

    Acetaminophen (paracetamol) is a well-tolerated analgesic and antipyretic drug when used at therapeutic doses. Overdoses, however, cause oxidative stress, which leads to acute liver failure. Alpha lipoic acid is an antioxidant that has proven effective for ameliorating many pathological conditions caused by oxidative stress. We evaluated the effect of alpha lipoic acid on the histological and histochemical alterations of liver caused by an acute overdose of acetaminophen in rats. Livers of acetaminophen-intoxicated rats were congested and showed centrilobular necrosis, vacuolar degeneration and inflammatory cell infiltration. Necrotic hepatocytes lost most of their carbohydrates, lipids and structural proteins. Liver sections from rats pre-treated with lipoic acid showed fewer pathological changes; the hepatocytes appeared moderately vacuolated with moderate staining of carbohydrates and proteins. Nevertheless, alpha lipoic acid at the dose we used did not protect the liver fully from acetaminophen-induced acute toxicity.

  19. Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes.

    PubMed

    Nafisi, Sara; Heidari, Reza; Ghaffarzadeh, Mohammad; Ziaee, Mojtaba; Hamzeiy, Hossein; Garjani, Alireza; Eghbal, Mohammad Ali

    2014-06-01

    Acetaminophen (N-acetyl para amino phenol, APAP) is a widely used antipyretic and analgesic drug responsible for various drug-induced liver injuries. This study evaluated APAP-induced toxicity in isolated rat hepatocytes alongside the protective effects of silafibrate and N-acetyl cysteine (NAC). Hepatocytes were isolated from male Sprague-Dawley rats by collagenase enzyme perfusion via the portal vein. This technique is based on liver perfusion with collagenase after removing calcium ions (Ca2+) with a chelator. Cells were treated with different concentrations of APAP, silafibrate, and NAC. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial depolarisation were measured as toxicity markers. ROS formation and lipid peroxidation occurred after APAP administration to rat hepatocytes. APAP caused mitochondrial depolarisation in isolated cells. Administration of silafibrate (200 μmol L-1) and/or NAC (200 μmol L-1) reduced the ROS formation, lipid peroxidation, and mitochondrial depolarisation caused by APAP. Cytotoxicity induced by APAP in rat hepatocytes was mediated by oxidative stress. In addition, APAP seemed to target cellular mitochondria during hepatocyte damage. The protective properties of silafibrate and/or NAC against APAP‑induced hepatic injury may have involved the induction of antioxidant enzymes, protection against oxidative stress and inflammatory responses, and alteration in cellular glutathione content.

  20. Comparison of acetaminophen toxicity in primary hepatocytes isolated from transgenic mice with different appolipoprotein E alleles.

    PubMed

    Mezera, V; Kucera, O; Moravcova, A; Peterova, E; Rousar, T; Rychtrmoc, D; Sobotka, O; Cervinkova, Z

    2015-12-01

    The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, important for combating electrophilic and oxidative stress in the liver and other organs. This encompasses detoxification of hepatotoxic drugs, including acetaminophen (APAP). Recently, an association between apolipoprotein E (ApoE) genotype and Nrf2 expression was described. We compared the toxicity of APAP on primary culture hepatocytes isolated from transgenic mice carrying two different human ApoE alleles and wild-type controls. The cells were exposed to APAP in concentrations from 0.5 to 4 mM for up to 24 hours. APAP led to a dose-dependent hepatotoxicity from 1 mM after 16 h exposure in all mice tested. The toxicity was higher in hepatocytes isolated from both transgenic strains than in wild-type controls and most pronounced in ApoE3 mice. Concurrently, there was a decline in mitochondrial membrane potential, especially in ApoE3 hepatocytes. The formation of reactive oxygen species was increased after 24 hours with 2.5 mM APAP in hepatocytes of all strains tested, with the highest increase being in the ApoE3 genotype. The activity of caspases 3 and 7 did not differ among groups and was minimal after 24 hour incubation with 4 mM APAP. We observed higher lipid accumulation in hepatocytes isolated from both transgenic strains than in wild-type controls. The expression of Nrf2-dependent genes was higher in ApoE3 than in ApoE4 hepatocytes and some of these genes were induced by APAP treatment. In conclusion, transgenic mice with ApoE4 and ApoE3 alleles displayed higher susceptibility to acute APAP toxicity in vitro than wild-type mice. Of the two transgenic genotypes tested, ApoE3 allele carriers were more prone to injury. PMID:26769836

  1. Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney.

    PubMed

    Richie, J P; Lang, C A; Chen, T S

    1992-07-01

    Glutathione (GSH) plays an essential role in the detoxification of acetaminophen (APAP) and the prevention of APAP-induced toxicity in the kidney. Our previous results demonstrated that a GSH deficiency is a general property of aging tissues, including the kidney, suggesting a hypothesis that senescent organisms are at greater risk to APAP-induced renal damage. To test this, C57BL/6NIA mice of different ages through the life span were injected with various doses of APAP, and the extent of GSH and cysteine (Cys) depletion and recovery were determined. At time intervals up to 24 hr, kidney cortex samples were obtained, processed and analyzed for glutathione status, namely GSH, glutathione disulfide (GSSG), Cys and cystine, using an HPLC method with dual electrochemical detection. In the uninjected controls, GSH and Cys concentrations decreased about 30% in the aging mouse, but the GSSG and cystine levels were unchanged during the life span. APAP administration depleted the kidney GSH and Cys contents in a dose- and time-dependent manner. Four hours after APAP administration, GSH levels of the young, growing (3- to 6-month) and the mature (12-month) mice decreased 34 and 58%, respectively, and recovered to near control values by 24 hr (95 and 98%). In contrast, the extent of depletion in old (31-month) mice was greater (64%) and the 24-hr recovery was less, returning only to 56%. Likewise, Cys levels of the young and mature mice decreased 49 and 65%, respectively, 4 hr following APAP, and increased to 99 and 85% by 24 hr. In contrast, in old mice, there was a 78% depletion after 4 hr followed by a recovery of only 65% by 24 hr. These results demonstrated clearly that in the aging mouse kidney, a GSH and Cys deficiency occurs that is accompanied by an impaired APAP detoxification capacity. PMID:1632827

  2. Comparison of acetaminophen toxicity in primary hepatocytes isolated from transgenic mice with different appolipoprotein E alleles.

    PubMed

    Mezera, V; Kucera, O; Moravcova, A; Peterova, E; Rousar, T; Rychtrmoc, D; Sobotka, O; Cervinkova, Z

    2015-12-01

    The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, important for combating electrophilic and oxidative stress in the liver and other organs. This encompasses detoxification of hepatotoxic drugs, including acetaminophen (APAP). Recently, an association between apolipoprotein E (ApoE) genotype and Nrf2 expression was described. We compared the toxicity of APAP on primary culture hepatocytes isolated from transgenic mice carrying two different human ApoE alleles and wild-type controls. The cells were exposed to APAP in concentrations from 0.5 to 4 mM for up to 24 hours. APAP led to a dose-dependent hepatotoxicity from 1 mM after 16 h exposure in all mice tested. The toxicity was higher in hepatocytes isolated from both transgenic strains than in wild-type controls and most pronounced in ApoE3 mice. Concurrently, there was a decline in mitochondrial membrane potential, especially in ApoE3 hepatocytes. The formation of reactive oxygen species was increased after 24 hours with 2.5 mM APAP in hepatocytes of all strains tested, with the highest increase being in the ApoE3 genotype. The activity of caspases 3 and 7 did not differ among groups and was minimal after 24 hour incubation with 4 mM APAP. We observed higher lipid accumulation in hepatocytes isolated from both transgenic strains than in wild-type controls. The expression of Nrf2-dependent genes was higher in ApoE3 than in ApoE4 hepatocytes and some of these genes were induced by APAP treatment. In conclusion, transgenic mice with ApoE4 and ApoE3 alleles displayed higher susceptibility to acute APAP toxicity in vitro than wild-type mice. Of the two transgenic genotypes tested, ApoE3 allele carriers were more prone to injury.

  3. Acute acetaminophen intoxication leads to hepatic iron loading by decreased hepcidin synthesis.

    PubMed

    van Swelm, Rachel P L; Laarakkers, Coby M M; Blous, Linda; Peters, Janny G P; Blaney Davidson, Esmeralda N; van der Kraan, Peter M; Swinkels, Dorine W; Masereeuw, Rosalinde; Russel, Frans G M

    2012-09-01

    Acetaminophen (APAP), a major cause of acute liver injury in the Western world, is mediated by metabolism and oxidative stress. Recent studies have suggested a role for iron in potentiating APAP-induced liver injury although its regulatory mechanism is not completely understood. The current study was designed to unravel the iron-regulating pathways in mice after APAP-induced hepatotoxicity. Mice with severe injury showed a significant increase in liver iron concentration and oxidative stress. Concurrently, the plasma concentration of hepcidin, the key regulator in iron metabolism, and hepatic hepcidin antimicrobial peptide (Hamp) mRNA expression levels were significantly reduced. We showed that hepcidin transcription was inhibited via several hepcidin-regulating factors, including the bone morphogenetic protein/small mother against decapentaplegic (BMP/SMAD) pathway, CCAAT/enhancer-binding protein α (C/EBPα), and possibly also via erythropoietin (EPO). Downregulation of the BMP/SMAD signaling pathway was most likely caused by hypoxia-inducible factor 1α (HIF-1α), which was increased in mice with severe APAP-induced liver injury. HIF-1α stimulates cleaving of hemojuvelin, the cofactor of the BMP receptor, thereby blocking BMP-induced signaling. In addition, gene expression levels of C/ebpα were significantly reduced, and Epo mRNA expression levels were significantly increased after APAP intoxication. These factors are regulated through HIF-1α during oxidative stress and suggest that HIF-1α is a key modulator in reduced hepcidin transcription after APAP-induced hepatotoxicity. In conclusion, acute APAP-induced liver injury leads to activation of HIF-1α, which results in a downregulation in hepcidin expression through a BMP/SMAD signaling pathway and through C/EBPα inhibition. Eventually, this leads to hepatic iron loading associated with APAP cytotoxicity. PMID:22610607

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

    PubMed Central

    Omidi, Arash; Riahinia, Narges; Montazer Torbati, Mohammad Bagher; Behdani, Mohammad-Ali

    2014-01-01

    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. PMID:25386395

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

    SciTech Connect

    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.

    2012-03-15

    classic clinical chemistry tests. ► Metabolomic analyses led to the detection of five new acetaminophen metabolites. ► Low dose APAP changed immune and oxidative stress related gene expression in blood. ► APAP-induced full-genome human blood miRNA profiles were assessed for the first time.

  6. Errors inducing radiation overdoses.

    PubMed

    Grammaticos, Philip C

    2013-01-01

    There is no doubt that equipments exposing radiation and used for therapeutic purposes should be often checked for possibly administering radiation overdoses to the patients. Technologists, radiation safety officers, radiologists, medical physicists, healthcare providers and administration should take proper care on this issue. "We must be beneficial and not harmful to the patients", according to the Hippocratic doctrine. Cases of radiation overdose are often reported. A series of cases of radiation overdoses have recently been reported. Doctors who were responsible, received heavy punishments. It is much better to prevent than to treat an error or a disease. A Personal Smart Card or Score Card has been suggested for every patient undergoing therapeutic and/or diagnostic procedures by the use of radiation. Taxonomy may also help. PMID:24251304

  7. Role of nicotinamide (vitamin B3) in acetaminophen-induced changes in rat liver: Nicotinamide effect in acetaminophen-damged liver.

    PubMed

    Mahmoud, Yomna I; Mahmoud, Asmaa A

    2016-06-01

    Acetaminophen is a widely used analgesic and antipyretic agent, which is safe at therapeutic doses. However, overdoses of acetaminophen induce severe oxidative stress, which leads to acute liver failure. Nicotinamide has proven effective in ameliorating many pathological conditions that occur due to oxidative stress. This study verifies the prophylactic and therapeutic effects of nicotinamide against the hepatic pathophysiological and ultrastructural alterations induced by acetaminophen. Wistar rats intoxicated with an acute overdose of acetaminophen (5g/kg b.wt) were given a single dose of nicotinamide (500mg/kg b.wt) either before or after intoxication. Acetaminophen caused significant elevation in the liver functions and lipid peroxidation marker, and decline in the activities of the hepatic antioxidant enzymes. This oxidative injury was associated with hepatic centrilobular necrosis, hemorrage, vacuolar degeneration, lipid accumulation and mitochondrial alterations. Treating intoxicated rats with nicotinamide (500mg/kg) significantly ameliorated acetaminophen-induced biochemical changes and pathological injuries. However, administering the same dose of nicotinamide to healthy animals or prior to acetaminophen-intoxication induced hepatotoxicity. Caution should be taken when administering high doses of NAM because of its possible hepatotoxicity. Considering the wide use of nicotinamide, there is an important need for monitoring nicotinamide tolerance, safety and efficacy in healthy and diseased subjects. PMID:27211843

  8. Cevimeline (Evoxac ®) overdose.

    PubMed

    Voskoboynik, Berenika; Babu, Kavita; Hack, Jason B

    2011-03-01

    Cevimeline (Evoxac ®) is an oral muscarinic agent that has been recently approved for the treatment of xerostomia in the setting of Sjogren's syndrome. Its toxicity in overdose has not been reported in the medical literature to date. We report a previously healthy patient who intentionally ingested approximately 10 mg/kg of cevimeline and presented with symptoms of muscarinic excess and mental status depression. The patient recovered uneventfully after receiving activated charcoal and supportive care. This report describes the first documented cevimeline overdose.

  9. Acetaminophen Induces Apoptosis in Rat Cortical Neurons

    PubMed Central

    Posadas, Inmaculada; Santos, Pablo; Blanco, Almudena; Muñoz-Fernández, Maríangeles; Ceña, Valentín

    2010-01-01

    Background Acetaminophen (AAP) is widely prescribed for treatment of mild pain and fever in western countries. It is generally considered a safe drug and the most frequently reported adverse effect associated with acetaminophen is hepatotoxicity, which generally occurs after acute overdose. During AAP overdose, encephalopathy might develop and contribute to morbidity and mortality. Our hypothesis is that AAP causes direct neuronal toxicity contributing to the general AAP toxicity syndrome. Methodology/Principal Findings We report that AAP causes direct toxicity on rat cortical neurons both in vitro and in vivo as measured by LDH release. We have found that AAP causes concentration-dependent neuronal death in vitro at concentrations (1 and 2 mM) that are reached in human plasma during AAP overdose, and that are also reached in the cerebrospinal fluid of rats for 3 hours following i.p injection of AAP doses (250 and 500 mg/Kg) that are below those required to induce acute hepatic failure in rats. AAP also increases both neuronal cytochrome P450 isoform CYP2E1 enzymatic activity and protein levels as determined by Western blot, leading to neuronal death through mitochondrial–mediated mechanisms that involve cytochrome c release and caspase 3 activation. In addition, in vivo experiments show that i.p. AAP (250 and 500 mg/Kg) injection induces neuronal death in the rat cortex as measured by TUNEL, validating the in vitro data. Conclusions/Significance The data presented here establish, for the first time, a direct neurotoxic action by AAP both in vivo and in vitro in rats at doses below those required to produce hepatotoxicity and suggest that this neurotoxicity might be involved in the general toxic syndrome observed during patient APP overdose and, possibly, also when AAP doses in the upper dosing schedule are used, especially if other risk factors (moderate drinking, fasting, nutritional impairment) are present. PMID:21170329

  10. [Use of acetaminophen in the community].

    PubMed

    Guberman, D

    1990-01-01

    Acetaminophen (Acamol) is one of the most widely used medications in children. The recommended dose is 10-15 mg/kg every 4 hours, and up to 5 doses a day. In a prospective study in an outpatient clinic, 101 parents of children 5 years old or younger were asked to describe their use of acetaminophen for their children, including dose, mode administration and maximal frequency of administration for fever. 2/3 used the syrup and 1/3 used suppositories. The average single dose was 13.8 +/- 5.5 mg/kg. Only 61% of the children received reasonable quantities of acetaminophen per dose. While 12% got an overdose of 20 mg/kg or more, 27% got an underdose of less than 10 mg/kg. Treatment was as often as every 2-3 hours in 13% of the children but only once every 8-24 hours in 22%. To overcome inadequate administration of acetaminophen, parents must be properly educated. PMID:2303194

  11. Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346-Insensitive Nuclear Translocation of GAPDH.

    PubMed

    Snider, Natasha T; Portney, Daniel A; Willcockson, Helen H; Maitra, Dhiman; Martin, Hope C; Greenson, Joel K; Omary, M Bishr

    2016-01-01

    The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals during cellular stress via several post-translational modifications that change its folding properties, protein-protein interactions and sub-cellular localization. We examined GAPDH properties in acute mouse liver injury due to ethanol and/or acetaminophen (APAP) treatment. Synergistic robust and time-dependent nuclear accumulation and aggregation of GAPDH were observed only in combined, but not individual, ethanol/APAP treatments. The small molecule GAPDH-targeting compound TCH346 partially attenuated liver damage possibly via mitochondrial mechanisms, and independent of nuclear accumulation and aggregation of GAPDH. These findings provide a novel potential mechanism for hepatotoxicity caused by combined alcohol and acetaminophen exposure. PMID:27513663

  12. Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346-Insensitive Nuclear Translocation of GAPDH

    PubMed Central

    Snider, Natasha T.; Portney, Daniel A.; Willcockson, Helen H.; Maitra, Dhiman; Martin, Hope C.; Greenson, Joel K.; Omary, M. Bishr

    2016-01-01

    The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals during cellular stress via several post-translational modifications that change its folding properties, protein-protein interactions and sub-cellular localization. We examined GAPDH properties in acute mouse liver injury due to ethanol and/or acetaminophen (APAP) treatment. Synergistic robust and time-dependent nuclear accumulation and aggregation of GAPDH were observed only in combined, but not individual, ethanol/APAP treatments. The small molecule GAPDH-targeting compound TCH346 partially attenuated liver damage possibly via mitochondrial mechanisms, and independent of nuclear accumulation and aggregation of GAPDH. These findings provide a novel potential mechanism for hepatotoxicity caused by combined alcohol and acetaminophen exposure. PMID:27513663

  13. Relationship between serum acetaminophen concentration and N-acetylcysteine-induced adverse drug reactions.

    PubMed

    Zyoud, Sa'ed H; Awang, Rahmat; Sulaiman, Syed Azhar Syed; Khan, Halilol Rahman Mohamed; Sawalha, Ansam F; Sweileh, Waleed M; Al-Jabi, Samah W

    2010-09-01

    Intravenous N-acetylcysteine is usually regarded as a safe antidote. However, during the infusion of the loading dose, different types of adverse drug reactions (ADR) may occur. The objective of this study was to investigate the relation between the incidence of different types of ADR and serum acetaminophen concentration in patients presenting to the hospital with acetaminophen overdose. This is a retrospective study of patients admitted to the hospital for acute acetaminophen overdose over a period of 5 years (1 January 2004 to 31 December 2008). Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis. Of 305 patients with acetaminophen overdose, 146 (47.9%) were treated with intravenous N-acetylcysteine and 139 (45.6%) were included in this study. Different types of ADR were observed in 94 (67.6%) patients. Low serum acetaminophen concentrations were significantly associated with cutaneous anaphylactoid reactions but not other types of ADR. Low serum acetaminophen concentration was significantly associated with flushing (p < 0.001), rash (p < 0.001) and pruritus (p < 0.001). However, there were no significant differences in serum acetaminophen concentrations between patients with and without the following ADR: gastrointestinal reactions (p = 0.77), respiratory reactions (p = 0.96), central nervous reactions (p = 0.82) and cardiovascular reactions (p = 0.37). In conclusion, low serum acetaminophen concentrations were associated with higher cutaneous anaphylactoid reactions. Such high serum acetaminophen concentrations may be protective against N-acetylcysteine-induced cutaneous ADR. PMID:20374238

  14. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice.

    PubMed

    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 by acetaminophen (APAP). Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw) followed by 24 h urine collection. Doses of ≥275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT) values (p<0.0001). Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001), including superoxide dismutase 1 (SOD1), carbonic anhydrase 3 (CA3) and calmodulin (CaM), as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001) in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury.

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

    SciTech Connect

    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{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

  16. Sassafras oil overdose

    MedlinePlus

    Sassafras oil comes from the root bark of the sassafras tree. Sassafras oil overdose occurs when someone swallows more than ... Safrole is the poisonous ingredient in sassafras oil. It is a clear or ... yellow oily liquid. It can be dangerous in large amounts.

  17. Protective effect of allyl methyl disulfide on acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Zhang, Yongchun; Zhang, Fang; Wang, Kaiming; Liu, Guangpu; Yang, Min; Luan, Yuxia; Zhao, Zhongxi

    2016-04-01

    Multiple sulfur compounds of garlic have shown versatile medicinal activities in the prevention and treatment of various diseases. Allyl methyl disulfide (AMDS) was identified as one of the bioactive components in fresh garlic paste in our previous study. The purpose of this study was to investigate the hepatoprotective effect of AMDS against acetaminophen (APAP)-induced acute liver damage in mice. Results reveal that AMDS significantly alleviates APAP-induced elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in mice. Furthermore, AMDS significantly (p < 0.05) reduced the maleic dialdehyde (MDA) level in liver tissues and restored the activities of antioxidant enzymes SOD, GSH-PX and GSH towards normal levels. IL-6 and TNF-alpha (TNF-α) levels in the serum and liver were clearly increased by acetaminophen-damage (p < 0.05) and AMDS intake significantly suppressed acetaminophen-induced increase of the two cytokines (p < 0.05). The immunohistochemical and pathological analyses showed that AMDS could ameliorate the liver injury through the strong attenuation of the CD45 expression and HNE formation. All the results indicate that AMDS had the ability to protect hepatocytes from APAP-induced liver damage.

  18. Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity.

    PubMed

    Wang, Kun-Peng; Bai, Yu; Wang, Jian; Zhang, Jin-Zhen

    2014-05-01

    Schisandra chinensis is a well-known traditional medicinal herb. Acetaminophen is a commonly used over-the-counter analgesic and overdose of acetaminophen was the most frequent cause of acute liver failure. However, no studies have demonstrated the role of Schisandra chinensis in acetaminophen-induced acute liver failure to the best of our knowledge. In this study, an acute liver injury model was established in mice using acetaminophen. The protective role of Schisandra chinensis was detected by histopathological analysis, and measurement of the serum transaminase levels and hepatic Cyp activity levels in the mouse model. Subsequently, hepatocytes were isolated from the livers of the mouse model. The cell cycle, apoptosis, mitochondrial membrane potential and reactive oxygen species were determined using flow cytometry. Cell proliferation and 26S proteasome activity were determined using spectrophotometry. Schisandra chinensis was found to resist acetaminophen-induced hepatotoxicity by protecting mitochondria and lysosomes and inhibiting the phosphor-c-Jun N-terminal kinase signaling pathway. These findings provide a novel application of Schisandra chinensis against acetaminophen-induced acute liver failure.

  19. Role of connexin 32 in acetaminophen toxicity in a knockout mice model.

    PubMed

    Igarashi, Isao; Maejima, Takanori; Kai, Kiyonori; Arakawa, Shingo; Teranishi, Munehiro; Sanbuissho, Atsushi

    2014-03-01

    Gap junctional intercellular communication (GJIC), by which glutathione (GSH) and inorganic ions are transmitted to neighboring cells, is recognized as being largely involved in toxic processes of chemicals. We examined acetaminophen (APAP)-induced hepatotoxicity clinicopathologically using male wild-type mice and mice lacking the gene for connexin32, a major gap junction protein in the liver [knockout (Cx32KO) mice]. When APAP was intraperitoneally administered at doses of 100, 200, or 300mg/kg, hepatic centrilobular necrosis with elevated plasma aminotransferase activities was observed in wild-type mice receiving 300mg/kg, and in Cx32KO mice given 100mg/kg or more. At 200mg/kg or more, hepatic GSH and GSSG contents decreased significantly and the effect was more severe in wild-type mice than in Cx32KO mice. On the other hand, markedly decreased GSH staining was observed in the hepatic centrilobular zones of Cx32KO mice compared to that of wild-type mice. These results demonstrate that Cx32KO mice are more susceptible to APAP hepatotoxicity than wild-type mice, and indicate that the distribution of GSH of the centrilobular zones in the hepatic lobules, rather than GSH and GSSG contents in the liver, is important in APAP hepatotoxicity. In conclusion, Cx32 protects against APAP-induced hepatic centrilobular necrosis in mice, which may be through the GSH transmission to neighboring hepatocytes by GJIC.

  20. Fluorometric assessment of acetaminophen-induced toxicity in rat hepatocyte spheroids seeded on micro-space cell culture plates.

    PubMed

    Sanoh, Seigo; Santoh, Masataka; Takagi, Masashi; Kanayama, Tatsuya; Sugihara, Kazumi; Kotake, Yaichiro; Ejiri, Yoko; Horie, Toru; Kitamura, Shigeyuki; Ohta, Shigeru

    2014-09-01

    Hepatotoxicity induced by the metabolic activation of drugs is a major concern in drug discovery and development. Three-dimensional (3-D) cultures of hepatocyte spheroids may be superior to monolayer cultures for evaluating drug metabolism and toxicity because hepatocytes in spheroids maintain the expression of various metabolizing enzymes and transporters, such as cytochrome P450 (CYP). In this study, we examined the hepatotoxicity due to metabolic activation of acetaminophen (APAP) using fluorescent indicators of cell viability and intracellular levels of glutathione (GSH) in rat hepatocyte spheroids grown on micro-space cell culture plates. The mRNA expression levels of some drug-metabolizing enzymes were maintained during culture. Additionally, this culture system was compatible with microfluorometric imaging under confocal laser scanning microscopy. APAP induced a decrease in intracellular ATP at 10mM, which was blocked by the CYP inhibitor 1-aminobenzotriazole (ABT). APAP (10mM, 24h) decreased the levels of both intracellular ATP and GSH, and GSH-conjugated APAP (APAP-GSH) were formed. All three effects were blocked by ABT, confirming a contribution of APAP metabolic activation by CYP to spheroid toxicity. Fluorometric imaging of hepatocyte spheroids on micro-space cell culture plates may allow the screening of drug-induced hepatotoxicity during pharmaceutical development.

  1. Validation of ICD-9-CM codes for identification of acetaminophen-related emergency department visits in a large pediatric hospital

    PubMed Central

    2013-01-01

    Background Acetaminophen overdose is a major concern among the pediatric population. Our objective was to assess the validity of International Classification of Disease (ICD-9-CM) codes for identification of pediatric emergency department (ED) visits resulting from acetaminophen exposure or overdose. Methods We conducted a retrospective medical record review of ED visits at Texas Children’s Hospital in Houston, Texas, between January 1, 2005, and December 31, 2010. Visits coded with 1 or more ICD-9 codes for poisoning (965, 977, and their subcodes and supplemental E-codes E850, E858, E935, E947, and E950 and their subcodes) were identified from an administrative database, and further review of the medical records was conducted to identify true cases of acetaminophen exposure or overdose. We then examined the sensitivity, positive predictive value, and percentage of false positives identified by various codes and code combinations to establish which codes most accurately identified acetaminophen exposure or overdose. Results Of 1,215 ED visits documented with 1 or more of the selected codes, 316 (26.0%) were a result of acetaminophen exposure or overdose. Sensitivity was highest (87.0%) for the combination of codes 965.4 (poisoning by aromatic analgesics, not elsewhere classified) and E950.0 (suicide and self-inflicted poisoning by analgesics, antipyretics, and antirheumatics), with a positive predictive value of 86.2%. Code 965.4 alone yielded a sensitivity of 85.1%, with a positive predictive value of 92.8%. Code performance varied among age groups and depending on the type of exposure (intentional or unintentional). Conclusion ICD-9 codes are useful for ascertaining which ED visits are a result of acetaminophen exposure or overdose within the pediatric population. However, because ICD-9 coding differs by age group and depending on the type of exposure, hypothesis-driven strategies must be utilized for each pediatric age group to avoid misclassification. PMID

  2. Overuse, Overdose, Overdiagnosis… Overreaction?

    PubMed Central

    Ho, ELM

    2010-01-01

    When x-rays were first discovered, the harmful effects of radiation had to be manifest in the early users before they were known. Today, radiation protection and safety have been established and the effects of radiation, as well as its risks, are known. Even so, medical radiation, in particular the growth in the use of computed tomography (CT), has resulted in soaring radiation doses received by the population in general. Inappropriate use has resulted in overuse, overdose and, perhaps, overdiagnosis, especially when used in screening. In the quest to control and curb the use of procedures involving radiation, however, we must be careful not to provoke a pandemic of irrational fear of radiation. Overreaction to the overuse and overdose of radiation might deter patients from life-saving procedures. PMID:21611049

  3. Cholestasis induced by model organic anions protects from acetaminophen hepatotoxicity in male CD-1 mice.

    PubMed

    Silva, Vanessa M; Hennig, Gayle E; Manautou, José E

    2006-01-25

    Administration of the non-metabolizable organic anion indocyanine green (ICG) prior to a toxic dose of acetaminophen (4-acetamidophenol; APAP) reduces liver injury 24h after dosing. ICG also produces a dose-dependent decrease in bile flow in mice and rats. Studies in bile duct-cannulated rats suggest that cholestasis can play a role in this protection. This study was conducted to determine if the ability of model organic anions to produce cholestasis is relevant to the protection against APAP hepatotoxicity afforded by ICG. In these studies, overnight fasted male CD-1 mice were dosed (i.v.) with the cholestatic dyes bromcresol green (BCG, 30 micromol/kg) and rose bengal (RB, 60 micromol/kg) immediately prior APAP administration (500 mg/kg, i.p.). Other groups of mice received the non-cholestatic dyes dibromosulphthalein (DBSP, 150 micromol/kg) and amaranth (AM, 300 micromol/kg) prior to APAP. Controls were given vehicle only. Hepatocellular necrosis was evident at 24 h in control mice receiving APAP. Pretreatment with the cholestatic dyes BCG and RB decreased the severity of hepatocellular necrosis induced by APAP. However, administration of the non-cholestatic dyes DBSP and AM did not alter APAP-induced liver damage. Glutathione replenishment was not altered by pretreatment with any of these dyes. Furthermore, ICG protected mice against carbon tetrachloride (CCl4) hepatotoxicity. Since CCl4 undergoes minimal biliary excretion and does not compete for biliary transport function, this finding supports the notion that cholestasis itself rather than competition for canalicular transporters is central to the hepatoprotection by ICG and other cholephilic dyes.

  4. Is There a Causal Relation between Maternal Acetaminophen Administration and ADHD?

    PubMed Central

    Saad, Antonio; Hegde, Shruti; Kechichian, Talar; Gamble, Phyllis; Rahman, Mahbubur; Stutz, Sonja J.; Anastasio, Noelle C.; Alshehri, Wael; Lei, Jun; Mori, Susumu; Kajs, Bridget; Cunningham, Kathryn A.; Saade, George; Burd, Irina; Costantine, Maged

    2016-01-01

    Objective Recent epidemiological studies reported an association between maternal intake of acetaminophen (APAP) and attention deficit hyperactivity disorder (ADHD) in their children. However, none of these studies demonstrated causality. Our objective was to determine whether exposure to APAP during pregnancy result in hyperkinetic dysfunctions in offspring, using a murine model. Material and Methods Pregnant CD1 mice (N = 8/group) were allocated to receive by gavage either APAP (150 mg/kg/day, equivalent to the FDA-approved maximum human clinical dose), or 0.5% carboxymethylcellulose (control group), starting on embryonic day 7 until delivery. Maternal serum APAP and alanine transaminase (ALT) concentrations were determined by ELISA and kinetic colorimetric assays, respectively. Open field locomotor activity (LMA) in the 30-day old mouse offspring was quantified using Photobeam Activity System. Mouse offspring were then sacrificed, whole brains processed for magnetic resonance imaging (MRI; 11.7 Tesla magnet) and for neuronal quantification using Nissl stain. The association between APAP exposure and LMA in mouse offspring was analyzed using a mixed effects Poisson regression model that accounted for mouse offspring weight, gender, random selection, and testing time and day. We corrected for multiple comparisons and considered P<0.008 as statistically significant. Results Maternal serum APAP concentration peaked 30 minutes after gavage, reaching the expected mean of 117 μg/ml. Serum ALT concentrations were not different between groups. There were no significant differences in vertical (rearing), horizontal, or total locomotor activity between the two rodent offspring groups at the P level fixed to adjust for multiple testing. In addition, no differences were found in volumes of 29 brain areas of interest on MRI or in neuronal quantifications between the two groups. Conclusion This study refutes that hypothesis that prenatal exposure to APAP causes hyperkinetic

  5. Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

    PubMed Central

    Peter, Inga; Hazarika, Suwagmani; Vasiadi, Magdalini; Greenblatt, David J.; Lee, William M.

    2014-01-01

    Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a single-time-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophen-metabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1–4.9; P = 0.034) compared with all other ALF patients. This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0–17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminophen-induced ALF. PMID:24104197

  6. Acetaminophen-induced liver injury: Implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway.

    PubMed

    Suciu, Maria; Gruia, Alexandra T; Nica, Dragos V; Azghadi, Seyed M R; Mic, Ani A; Mic, Felix A

    2015-12-01

    Acetaminophen is a commonly used drug that induces serious hepatotoxicity when overdosed, leading to increased levels of serum aminotransferases. However, little knowledge exists linking acetaminophen to liver free fatty acids and the eicosanoid-mediated signaling pathway. To this end, adult NMRI mice injected with a dose of 400 mg/kg acetaminophen were monitored for one week post-treatment. Consistent changes were observed in serum transaminases, profile of hepatic free fatty acids, expression of cyclooxygenase, elongase, lipogenesis, and lipolysis genes; as well as in expression patterns of cyclooxygenase-1 and -2 in the liver. Both linoleic acid and arachidonic acid--substrates in eicosanoid biosynthesis--were significantly influenced by overdose, and the latter peaked first among the free fatty acids examined here. There was a close similarity between the temporal dynamics of linoleic acid and aspartate aminotransferases. Moreover, serum transaminases were reduced by cyclooxygenase-2 inhibitors, but not by cyclooxygenase-1 inhibitors. Our results hence attest to the hazard of acetaminophen overdose on the temporal homeostasis of hepatic concentrations of free fatty acids and expression of key genes underlying liver lipid metabolism. There is also evidence for activation of a cyclooxygenase-mediated signaling pathway, especially the cyclooxygenase 2-prostanoid pathway, during acetaminophen-induced liver injury. Therefore, the results of the present study should provide valuable information to a wide audience, working to understand the health hazard of this drug and the implications of the eicosanoid signaling pathway in liver pathophysiology.

  7. Protective effect of acetaminophen against colon cancer initiation effects of 3,2'-dimethyl-4-aminobiphenyl in rats.

    PubMed

    Williams, G M; Iatropoulos, M J; Jeffrey, A M; Shirai, T

    2002-02-01

    A previous investigation demonstrated the anticarcinogenicity of acetaminophen (APAP) against colon carcinogenesis in rats induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB was selected as a structurally related surrogate for heterocyclic amines, formed during cooking of protein, which are believed to be involved in human colon cancer. The objective of the present study was to ascertain whether the early initiating effects of this colon carcinogen are inhibited by APAP. Six groups of male F344 rats were treated over a 6-week period as follows: (1) vehicle (corn oil) for 6 weeks; (2) APAP in the diet at 1000 ppm daily for 6 weeks; (3) 50 mg/kg DMAB by gavage once a week for the last 4 weeks; (4) 5 mg/kg DMAB as for (3); (5) 1000 ppm APAP for 6 weeks and 50 mg/kg DMAB for the last 4 weeks; and (6) 1000 ppm APAP and 5 mg/kg DMAB as for (5). Colonic tissue was within normal limits in the control and APAP groups. In the APAP only group, apical enterocytic hypertrophy and hyperaemia over the entire surface epithelium was present. In the high-dose DMAB group, in the lower third of the crypts, foci of enlarged glands with hypertrophic cells exhibiting karyomegaly and anisokaryosis (FHE) of 3+ degree of severity were evident in 100% of the animals. Also, there were increases in periglandular fibrocytes, matrix and mononuclear cells (PF). In the low-dose DMAB group both FHE and PF changes with the same degree of severity were reduced. In rats given the low dose of DMAB plus APAP, FHE and PF with the same degree of severity (3+) was absent. Both DMAB exposures increased significantly the replicating fraction of colonic enterocytes in an exposure-related fashion and the replicating fractions were significantly reduced by APAP. In 32P-postlabelling of colon, liver and urinary bladder DNA, high-dose DMAB produced 2-6 distinct dose-related spots reflecting DNA adducts. These spots were reduced or were no longer detectable in all three tissues when APAP was given 2 weeks

  8. UGT1A6 and UGT2B15 Polymorphisms and Acetaminophen Conjugation in Response to a Randomized, Controlled Diet of Select Fruits and Vegetables

    PubMed Central

    Navarro, Sandi L.; Chen, Yu; Li, Lin; Li, Shuying S.; Chang, Jyh-Lurn; Schwarz, Yvonne; King, Irena B.; Potter, John D.; Bigler, Jeannette

    2011-01-01

    Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP-glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed in part to polymorphisms in UGT1As. However, evidence suggests that UGT2B15 may also be important. We evaluated, in a controlled feeding trial, whether APAP conjugation differed by UGT1A6 and UGT2B15 genotypes and whether supplementation of known dietary inducers of UGT (crucifers, soy, and citrus) modulated APAP glucuronidation compared with a diet devoid of fruits and vegetables (F&V). Healthy adults (n = 66) received 1000 mg of APAP orally on days 7 and 14 of each 2-week feeding period and collected saliva and urine over 12 h. Urinary recovery of the percentage of the APAP dose as free APAP was higher (P = 0.02), and the percentage as APAP glucuronide (APAPG) was lower (P = 0.004) in women. The percentage of APAP was higher among UGT1A6*1/*1 genotypes, relative to *1/*2 and *2/*2 genotypes (P = 0.045). For UGT2B15, the percentage of APAPG decreased (P < 0.0001) and that of APAP sulfate increased (P = 0.002) in an allelic dose-dependent manner across genotypes from *1/*1 to *2/*2. There was a significant diet × UGT2B15 genotype interaction for the APAPG ratio (APAPG/total metabolites × 100) (P = 0.03), with *1/*1 genotypes having an approximately 2-fold higher F&V to basal diet difference in response compared with *1/*2 and *2/*2 genotypes. Salivary APAP maximum concentration (Cmax) was significantly higher in women (P = 0.0003), with F&V (P = 0.003), and among UGT1A6*2/*2 and UGT2B15*1/*2 genotypes (P = 0.02 and 0.002, respectively). APAP half-life was longer in UGT2B15*2/*2 genotypes with F&V (P = 0.009). APAP glucuronidation was significantly influenced by the UGT2B15*2 polymorphism, supporting a role in vivo for UGT2B15 in APAP glucuronidation, whereas the contribution of UGT1A6*2 was modest. Selected F&V known to affect UGT activity led to greater glucuronidation and less

  9. Characteristics of Drug Overdose in Young Suicide Attempters

    PubMed Central

    Kweon, Yong-Sil; Hwang, Sunyoung; Yeon, Bora; Choi, Kyoung Ho; Oh, Youngmin; Lee, Hae-Kook; Lee, Chung Tai

    2012-01-01

    Objective Few studies have focused on the characteristic features of drug overdose in children and adolescents who have attempted suicide in Korea. The present study examined the characteristics of drug overdose in children and adolescents who visited the emergency room following drug ingestion for a suicide attempt. Methods The medical records of 28 patients who were treated in the emergency room following a drug overdose from January 2008 to March 2011 were analyzed. Demographic and clinical variables related to the suicide attempts were examined. Results The mean age of the patients was 16.6±1.7 years (range 11-19 years), and 20 of the patients (71.4%) were female. Most of the patients (n=23, 82.1%) overdosed on a single drug; acetaminophen-containing analgesics were the most common (n=12, 42.9%). Depression was the most common psychiatric disorder (n=22, 78.6%), and interpersonal conflict was the most common precipitating factor of the suicide attempts (n=11, 39.3%). This was the first suicide attempt for approximately 80% of the patients. About one fourth of the patients (n=7, 25%) had follow-up visits at the psychiatric outpatient clinic. Conclusion Early screening and psychiatric intervention for depression may be an important factor in preventing childhood and adolescent suicide attempts. Developing coping strategies to manage interpersonal conflicts may also be helpful. Moreover, policies restricting the amount and kind of drugs purchased by teenagers may be necessary to prevent drug overdose in this age group. PMID:23430317

  10. Wuzhi tablet (Schisandra Sphenanthera extract) protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of NRF2-ARE and p53/p21 pathways.

    PubMed

    Fan, Xiaomei; Jiang, Yiming; Wang, Ying; Tan, Huasen; Zeng, Hang; Wang, Yongtao; Chen, Pan; Qu, Aijuan; Gonzalez, Frank J; Huang, Min; Bi, Huichang

    2014-12-01

    Schisandra sphenanthera is widely used as a tonic and restorative in many countries to enhance the function of liver and other organs. Wuzhi tablet (WZ) is a preparation of an ethanol extract of Schisandra sphenanthera. Our previous study demonstrated that WZ exerted a protective effect toward acetaminophen (APAP)-induced hepatotoxicity. However, the molecular mechanisms of this protection remain unclear. This study aimed to determine what molecular pathways contributed to the hepatoprotective effects of WZ against APAP toxicity. Administration of WZ 3 days before APAP treatment significantly attenuated APAP hepatotoxicity in a dose-dependent manner and reduced APAP-induced JNK activation. Treatment with WZ resulted in potent inhibition of CYP2E1, CYP3A11, and CYP1A2 activities and then caused significant inhibition of the formation of the oxidized APAP metabolite N-acetyl-p-benzoquinone imine-reduced glutathione. The expression of NRF2 was increased after APAP and/or WZ treatment, whereas KEAP1 levels were decreased. The protein expression of NRF2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was significantly increased by WZ treatment. Furthermore, APAP increased the levels of p53 and its downstream gene p21 to trigger cell cycle arrest and apoptosis, whereas WZ pretreatment could inhibit p53/p21 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, PCNA, and ALR to promote hepatocyte proliferation. This study demonstrated that WZ prevented APAP-induced liver injury by inhibition of cytochrome P450-mediated APAP bioactivation, activation of the NRF2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the p53, p21, cyclin D1, CDK4, PCNA, and ALR to facilitate liver regeneration after APAP-induced liver injury.

  11. Electrochemical properties of the acetaminophen on the screen printed carbon electrode towards the high performance practical sensor applications.

    PubMed

    Karikalan, Natarajan; Karthik, Raj; Chen, Shen-Ming; Velmurugan, Murugan; Karuppiah, Chelladurai

    2016-12-01

    Acetaminophen is a non-steroidal anti-inflammatory drug used as an antipyretic agent for the alternative to aspirin. Conversely, the overdoses of acetaminophen can cause hepatic toxicity and kidney damage. Hence, the determination of acetaminophen receives much more attention in biological samples and also in pharmaceutical formulations. Here, we report a rapid and sensitive detection of the acetaminophen based on the bare (unmodified) screen printed carbon electrode (BSPCE) and its electrochemistry was studied in various pHs. From the observed results, the mechanism of the electro-oxidation of acetaminophen was derived for various pHs. The acetaminophen is not stable in strong acidic and strong alkaline media, which is hydrolyzed and hydroxylated. However, it is stable in intermediate pHs due to the dimerization of acetaminophen. The kinetics of the acetaminophen oxidation was briefly studied and documented in the schemes. In addition, the surface morphology and disorders of BSPCE was probed by scanning electron microscope (SEM) and Raman spectroscopy. Moreover, the BSPCE determined the acetaminophen with the linear concentration ranging from 0.05 to 190μM and the lower detection limit of 0.013μM. Besides that it reveals the good recoveries towards the pharmaceutical samples and shows the excellent selectivity, sensitivity and stability. To the best of our knowledge, this is the better performance compare to the previously reported unmodified acetaminophen sensors. PMID:27552419

  12. Using aquatic fungi for pharmaceutical bioremediation: Uptake of acetaminophen by Mucor hiemalis does not result in an enzymatic oxidative stress response.

    PubMed

    Esterhuizen-Londt, Maranda; Schwartz, Katrin; Pflugmacher, Stephan

    2016-10-01

    The increasing anthropogenic pollution of aquatic environments and fresh water scarcity worldwide have prompted the development of low-cost and effective water treatment alternatives. One example of a highly released anthropogenic xenobiotics is acetaminophen (APAP), which has been detected in surface waters at concentrations as high as 5 μg L(-1). To date, traditional water treatment plants were unable to remove all pharmaceutical xenobiotics and as in the case with APAP, the breakdown products are toxic. Phytoremediation has proved to remove xenobiotics efficiently producing no toxic breakdown products, however, they are often restrained in their application range. Therefore, it was necessary to find alternate remediation tools to extend and complement the application ranges of existing bioremediation techniques. With the success of mycoremediation as well as the adaptability of fungi, Mucor hiemalis was investigated in terms of its APAP uptake capabilities. The investigation included the examination of concentration- and time-dependent uptake studies to examine the effects of each of these parameters independently. Additionally, the extracellular peroxidase activity of M. hiemalis was measured with exposure to APAP to evaluate possible breakdown and the antioxidative stress enzymes, catalase, glutathione peroxidase, and glutathione reductase, were assayed to investigate whether APAP caused oxidative stress. The results showed that M. hiemalis was able to internalize between 1 and 2 μg APAP per g dried fungal biomass when exposed to 5, 10, 50 and 100 ng mL(-1) APAP for 24-48 h, but not beyond this time frame. Further, exposure to APAP did not result in elevated extracellular peroxidase activity or oxidative stress. The findings led to the conclusion that M. hiemalis could be integrated in bioremediation systems, for short-term degradation at low concentrations of APAP with effective management. PMID:27647241

  13. Using aquatic fungi for pharmaceutical bioremediation: Uptake of acetaminophen by Mucor hiemalis does not result in an enzymatic oxidative stress response.

    PubMed

    Esterhuizen-Londt, Maranda; Schwartz, Katrin; Pflugmacher, Stephan

    2016-10-01

    The increasing anthropogenic pollution of aquatic environments and fresh water scarcity worldwide have prompted the development of low-cost and effective water treatment alternatives. One example of a highly released anthropogenic xenobiotics is acetaminophen (APAP), which has been detected in surface waters at concentrations as high as 5 μg L(-1). To date, traditional water treatment plants were unable to remove all pharmaceutical xenobiotics and as in the case with APAP, the breakdown products are toxic. Phytoremediation has proved to remove xenobiotics efficiently producing no toxic breakdown products, however, they are often restrained in their application range. Therefore, it was necessary to find alternate remediation tools to extend and complement the application ranges of existing bioremediation techniques. With the success of mycoremediation as well as the adaptability of fungi, Mucor hiemalis was investigated in terms of its APAP uptake capabilities. The investigation included the examination of concentration- and time-dependent uptake studies to examine the effects of each of these parameters independently. Additionally, the extracellular peroxidase activity of M. hiemalis was measured with exposure to APAP to evaluate possible breakdown and the antioxidative stress enzymes, catalase, glutathione peroxidase, and glutathione reductase, were assayed to investigate whether APAP caused oxidative stress. The results showed that M. hiemalis was able to internalize between 1 and 2 μg APAP per g dried fungal biomass when exposed to 5, 10, 50 and 100 ng mL(-1) APAP for 24-48 h, but not beyond this time frame. Further, exposure to APAP did not result in elevated extracellular peroxidase activity or oxidative stress. The findings led to the conclusion that M. hiemalis could be integrated in bioremediation systems, for short-term degradation at low concentrations of APAP with effective management.

  14. Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: clinical and animal model applications.

    PubMed

    Cook, Sarah F; King, Amber D; Chang, Yan; Murray, Gordon J; Norris, Hye-Ryun K; Dart, Richard C; Green, Jody L; Curry, Steven C; Rollins, Douglas E; Wilkins, Diana G

    2015-03-15

    The aims of this study were to develop, validate, and apply a high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method for quantification of protein-derived 3-(cystein-S-yl)-acetaminophen (APAP-Cys) in human serum. Formation of acetaminophen (APAP) protein adducts is thought to be a critical, early event in the development of APAP-induced hepatotoxicity, and quantification of these protein adducts in human serum represents a valuable tool for assessment of APAP exposure, metabolism, and toxicity. In the reported procedure, serum samples were first dialyzed or passed through gel filtration columns to remove APAP-Cys not covalently bound to proteins. Serum eluates were then subjected to enzymatic protease digestion to liberate protein-bound APAP-Cys. Norbuprenorphine-D3 was utilized as an internal standard (IS). APAP-Cys and IS were recovered from digested serum by protein precipitation with acetonitrile, and sample extracts were analyzed by HPLC-ESI-MS/MS. The method was validated by assessment of intra- and inter-assay accuracy and imprecision on two different analytical instrument platforms. APAP-Cys could be accurately quantified from 0.010 to 10μM, and intra- and inter-assay imprecision were <15% on both analytical instruments. APAP-Cys was stable in human serum for three freeze-thaw cycles and for 24h at ambient temperature. Extracted samples were stable when stored in refrigerated autosamplers for the typical duration of analysis or when stored at -20°C for six days. Results from process efficiency and matrix effect experiments indicated adequate recovery from human serum and insignificant ion suppression or enhancement. The utility and sensitivity of the reported procedure were illustrated by analysis of clinical samples collected from subjects taking chronic, therapeutic doses of APAP. Applicability to other biological matrices was also demonstrated by measurement of protein-derived APAP-Cys in plasma

  15. Hepatoprotective Potential of Prosopis farcta Beans Extracts against Acetaminophen-induced Hepatotoxicity in Wister Rats

    PubMed Central

    Asadollahi, Akram; Sarir, Hadi; Omidi, Arash; Torbati, Mohammad Bagher Montazar

    2014-01-01

    Background: Hepatotoxicity by acetaminophen is the most frequent cause of acute liver failure in many countries. Prosopis farcta beans extract (PFE) has some antioxidant property and may alleviate hepatotoxicity. Therefore, the aim of this study was to evaluate effects of PFE against acetaminophen-induced hepatotoxicity. Methods: Thirty-six male Wistar albino rats weighing 220 ± 30 g were distributed into six groups. Two groups were pretreated with PFE (50 and 75 mg/kg) for 7 days before administration of acetaminophen (600 mg/kg). Two were given acetaminophen or PFE (50 and 75 mg/kg) alone, and the control received normal saline. One day after acetaminophen, administration blood samples were collected by cardiac puncture to determine liver function enzymes markers; aspartate aminotransferase and alanine aminotransferase (AST and ALT), cholesterol, triglyceride (TG), high, low, and very low density lipoproteins (LDL and VLDL). Results: In acetaminophen-treated rat plasma AST (314 ± 18.54 vs. 126.37 ± 4.13), ALT (304 ± 49.24 vs. 187.33 ± 3.71), cholesterol, TG, LDL, and VLDL were increased by 149, 160, 37, 92, 60, and 94%, respectively. PFE at both doses significantly (P < 0.05) attenuated the above biochemical indices to near normal. Conclusions: Prosopis farcta beans extract (50 and 75 mg/kg) exhibited hepatoprotective activity against APAP. PMID:25400887

  16. Reactive nitrogen species in acetaminophen-induced mitochondrial damage and toxicity in mouse hepatocytes.

    PubMed

    Burke, Angela S; MacMillan-Crow, Lee Ann; Hinson, Jack A

    2010-07-19

    Acetaminophen (APAP) toxicity in primary mouse hepatocytes occurs in two phases. The initial phase (0-2 h) occurs with metabolism to N-acetyl-p-benzoquinoneimine which depletes glutathione, and covalently binds to proteins, but little toxicity is observed. Subsequent washing of hepatocytes to remove APAP and reincubating in media alone (2-5 h) results in toxicity. We previously reported that the reincubation phase occurs with mitochondrial permeability transition (MPT) and increased oxidative stress (dichlorodihydrofluorescein fluorescence) (DCFH(2)). Since DCFH(2) may be oxidized by multiple oxidative mechanisms, we investigated the role of reactive nitrogen species (RNS) leading to 3-nitrotyrosine in proteins by ELISA and by immunoblots. Incubation of APAP with hepatocytes for 2 h did not result in toxicity or protein nitration; however, washing hepatocytes and reincubating in media alone (2-5 h) resulted in protein nitration which correlated with toxicity. Inclusion of the MPT inhibitor, cyclosporine A, in the reincubation media eliminated toxicity and protein nitration. The general nitric oxide synthase (NOS) inhibitor L-NMMA and the neuronal NOS (NOS1) inhibitor, 7-nitroindazole, added in the reincubation media decreased toxicity and protein nitration; however, neither the inducible NOS (NOS2) inhibitors L-NIL (N6-(1-iminoethyl)-L-lysine) nor SAIT (S-(2-aminoethyl)isothiourea) decreased protein nitration or toxicity. The RNS scavengers, N-acetylcysteine, and high concentrations of APAP, added in the reincubation phase decreased toxicity and protein nitration. 7-Nitroindazole and cyclosporine A inhibited the APAP-induced loss of mitochondrial membrane potential when added in the reincubation phase. The data indicate a role for RNS in APAP induced toxicity.

  17. Acetaminophen and Codeine

    MedlinePlus

    The combination of acetaminophen and codeine comes as a tablet, capsule, and liquid to take by mouth. It usually is taken every 6 ... explain any part you do not understand. Take acetaminophen and codeine exactly as directed.Codeine can be ...

  18. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice.

    PubMed

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-03-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  19. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice

    PubMed Central

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-01-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  20. Evaluation of nephroprotective, diuretic, and antioxidant activities of plectranthus amboinicus on acetaminophen-induced nephrotoxic rats.

    PubMed

    Palani, S; Raja, S; Naresh, R; Kumar, B Senthil

    2010-05-01

    Plectranthus amboinicus (PA), commonly known as country borage, is a folkoric medicinal plant. Juice from its leaves is commonly used for illnesses including liver and renal conditions in the Asian sub-continent. Acetaminophen (APAP), used as an analgesic, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective, diuretic, and antioxidant activities of the ethanol extract of PA at two doses of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. This study shows that APAP significantly increases the levels of serum urea (UR), hemoglobin (Hb), total leukocyte count, creatinine, raised body weight, and reduced levels of neutrophils, granulocytes, uric acid, and platelet concentration. Ethanol extract of PA rescued these phenotypes by increasing anti-oxidative responses as assessed by biochemistry and histopathology. In addition, the ethanol extract of PA at two doses showed a significant diuretic activity by increased levels of total urine output and urinary elerolytes such as sodium and potassium. In conclusion, these data suggest that the ethanol extract of PA possess nephroprotective and antioxidant effects against APAP-induced nephrotoxicity and strong diuretics effect in rats. PMID:20367443

  1. Protective Effect of Sundarban Honey against Acetaminophen-Induced Acute Hepatonephrotoxicity in Rats

    PubMed Central

    Tanvir, E. M.; Gan, Siew Hua; Parvez, Mashud; Aminul Islam, Md.; Khalil, Md. Ibrahim

    2014-01-01

    Honey, a supersaturated natural product of honey bees, contains complex compounds with antioxidant properties and therefore has a wide a range of applications in both traditional and modern medicine. In the present study, the protective effects of Sundarban honey from Bangladesh against acetaminophen- (APAP-) induced hepatotoxicity and nephrotoxicity in experimental rats were investigated. Adult male Wistar rats were pretreated with honey (5 g/kg) for 4 weeks, followed by the induction of hepatotoxicity and nephrotoxicity via the oral administration of a single dose of APAP (2 g/kg). Organ damage was confirmed by measuring the elevation of serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), total protein (TP), total bilirubin (TB), urea, creatinine, and malondialdehyde (MDA). Histopathological alterations observed in the livers and the kidneys further confirmed oxidative damage to these tissues. Animals pretreated with Sundarban honey showed significantly markedly reduced levels of all of the investigated parameters. In addition, Sundarban honey ameliorated the altered hepatic and renal morphology in APAP-treated rats. Overall, our findings indicate that Sundarban honey protects against APAP-induced acute hepatic and renal damage, which could be attributed to the honey's antioxidant properties. PMID:25530774

  2. H2 receptor antagonists overdose

    MedlinePlus

    ... Saunders; 2015:chap 138. Kirk MA, Baer AB. Anticholinergics and antihistamines. In: Shannon MW, Borron SW, Burns MJ, eds. Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007: ...

  3. [The message from heroin overdoses].

    PubMed

    Pap, Ágota; Hegedűs, Katalin

    2015-03-01

    Drug use can be defined as a kind of self destruction, and it is directly linked to attitudes toward death and suicide occurring in a significant number of users of different narcotics. The aim of the authors was to look for the background of this relationship between drug and death and examine the origin, development, and motives behind heroin overdose based on an analysis of previous studies. It seems clear that pure heroin overdose increased gradually over the years. The fear of the police is the inhibitory factor of the overdose prevention and notification of emergency health care service. Signs of suicide could be the own home as the chosen location for heroin overdose and the presence of partners ("moment of death companion"). Interventions should include simple techniques such as first aid, naloxone administration, resuscitation, prevention of relapse of prisoners and social network extension involving maintenance programs.

  4. Calcium carbonate with magnesium overdose

    MedlinePlus

    The combination of calcium carbonate and magnesium is commonly found in antacids. These medicines provide heartburn relief. Calcium carbonate with magnesium overdose occurs when someone takes more than the ...

  5. Ranolazine overdose-induced seizures.

    PubMed

    Akil, Nour; Bottei, Edward; Kamath, Sameer

    2015-12-01

    Ranolazine is a new anti-anginal medication that was approved by the US Food and Drug Administration (FDA) in 2006 for patients with symptomatic chronic angina despite optimized therapy. This paper presents a case report of a fifteen year old male patient admitted to the pediatric intensive care unit after ranolazine overdose ingestion. He had recurrent new onset seizures that are most likely due to ranolazine overdose. Seizures have never been reported with ranolazine use or abuse. PMID:26072257

  6. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    PubMed

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18-55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant.

  7. Timescale analysis of a mathematical model of acetaminophen metabolism and toxicity.

    PubMed

    Reddyhoff, Dennis; Ward, John; Williams, Dominic; Regan, Sophie; Webb, Steven

    2015-12-01

    Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the different timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose. PMID:26348886

  8. Timescale analysis of a mathematical model of acetaminophen metabolism and toxicity.

    PubMed

    Reddyhoff, Dennis; Ward, John; Williams, Dominic; Regan, Sophie; Webb, Steven

    2015-12-01

    Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the different timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose.

  9. Inactivation of glyceraldehyde-3-phosphate dehydrogenase by a reactive metabolite of acetaminophen and mass spectral characterization of an arylated active site peptide.

    PubMed

    Dietze, E C; Schäfer, A; Omichinski, J G; Nelson, S D

    1997-10-01

    Acetaminophen (4'-hydroxyacetanilide, APAP) is a widely used analgesic and antipyretic drug that can cause hepatic necrosis under some circumstances via cytochrome P450-mediated oxidation to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Although the mechanism of hepatocellular injury caused by APAP is not fully understood, it is known that NAPQI forms covalent adducts with several hepatocellular proteins. Reported here is the identification of one of these proteins as glyceraldehyde-3-phosphate dehydrogenase [GAPDH, D-glyceraldehyde-3-phosphate: NAD+ oxidoreductase (phosphorylating), EC 1.2.1.12]. Two hours after the administration of hepatotoxic doses of [14C]APAP to mice, at a time prior to overt cell damage, hepatocellular GAPDH activity was significantly decreased concurrent with the formation of a 14C-labeled GAPDH adduct. A nonhepatotoxic regioisomer of APAP, 3'-hydroxyacetanilide (AMAP), was found to decrease GAPDH activity to a lesser extent than APAP, and radiolabel from [14C]AMAP bound to a lesser extent to GAPDH at a time when its overall binding to hepatocellular proteins was almost equivalent to that of APAP. In order to determine the nature of the covalent adduct between GAPDH and APAP, its major reactive and toxic metabolite, NAPQI, was incubated with purified porcine muscle GAPDH. Microsequencing analysis and fast atom bombardment mass spectrometry (FAB-MS) with collision-induced dissociation (CID) were used to characterize one of the adducts as APAP bound to the cysteinyl sulfhydryl group of Cys-149 in the active site peptide of GAPDH. PMID:9348431

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

    PubMed

    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

    2016-01-01

    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

  11. Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS.

    PubMed

    Sun, Jinchun; Schnackenberg, Laura K; Holland, Ricky D; Schmitt, Thomas C; Cantor, Glenn H; Dragan, Yvonne P; Beger, Richard D

    2008-08-15

    Urinary metabolic perturbations associated with acute and chronic acetaminophen-induced hepatotoxicity were investigated using nuclear magnetic resonance (NMR) spectroscopy and ultra performance liquid chromatography/mass spectrometry (UPLC/MS) metabonomics approaches to determine biomarkers of hepatotoxicity. Acute and chronic doses of acetaminophen (APAP) were administered to male Sprague-Dawley rats. NMR and UPLC/MS were able to detect both drug metabolites and endogenous metabolites simultaneously. The principal component analysis (PCA) of NMR or UPLC/MS spectra showed that metabolic changes observed in both acute and chronic dosing of acetaminophen were similar. Histopathology and clinical chemistry studies were performed and correlated well with the PCA analysis and magnitude of metabolite changes. Depletion of antioxidants (e.g. ferulic acid), trigonelline, S-adenosyl-L-methionine, and energy-related metabolites indicated that oxidative stress was caused by acute and chronic acetaminophen administration. Similar patterns of metabolic changes in response to acute or chronic dosing suggest similar detoxification and recovery mechanisms following APAP administration.

  12. Connexin32: a mediator of acetaminophen-induced liver injury?

    PubMed

    Maes, Michaël; McGill, Mitchell R; da Silva, Tereza Cristina; Lebofsky, Margitta; Maria Monteiro de Araújo, Cintia; Tiburcio, Taynã; Veloso Alves Pereira, Isabel; Willebrords, Joost; Crespo Yanguas, Sara; Farhood, Anwar; Zaidan Dagli, Maria Lucia; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2016-02-01

    Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity. PMID:26739117

  13. Hepatoprotective Property of Oral Silymarin is Comparable to N-Acetyl Cysteine in Acetaminophen Poisoning

    PubMed Central

    Kazemifar, Amir Mohammad; Hajaghamohammadi, Ali Akbar; Samimi, Rasoul; Alavi, Zohreh; Abbasi, Esmail; Asl, Marjan Nasiri

    2012-01-01

    Background N-Acetyl Cysteine (NAC) is usually used as antidote for prevention of acetaminophen-induced hepatotoxicity. In present study we have evaluated efficacy of oral silymarin in its prevention in rats intoxicated with lethal dose of acetaminophen. Methods A total of 50 Male Sprague-Dawley rats were randomly divided into five groups. The first group received only vehicle of acetaminophen and served as control. The second group was given 800 mg/kg acetaminophen by gavage with an orogastric canula. The third, fourth and fifth groups were given 300 mg/kg NAC and 150 and 300 mg/kg silymarin respectively. Analysis of serum AST, ALT, and ALP and liver histopathology were employed for assessment of hepatotoxicity. Results Mean serum ALT levels were significantly increased in the APAP group rats. The mean serum ALT levels returned to normal in both NAC treated and silymarin treated groups. Silymarin (150 mg/kg) had prevented hepatocytes necrosis similar to NAC. No severe hepatotoxicity were seen in groups 3 and 4; while it is seen in 70% of animals in group 2. Conclusion We found that a single dose of orally administered silymarin (150 mg/kg) significantly attenuated acetaminophen-induced liver damage in rat. Oral silymarin can be used in these patients instead of NAC.

  14. A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione.

    PubMed

    Klopčič, Ivana; Poberžnik, Matic; Mavri, Janez; Dolenc, Marija Sollner

    2015-12-01

    Acetaminophen (APAP) forms some reactive metabolites that can react with DNA. APAP is a potentially genotoxic drug and is classified as a Group 3 drug according to International Agency for Research on Cancer (IARC). One of the possible mechanisms of APAP genotoxicity after long term of use is that its reactive quinone imine (QI) metabolite of acetaminophen (NAPQI), can chemically react with DNA after glutathione (GSH) depletion. A quantum chemical study of the reactions between the NAPQI and deoxyguanosine (dG) or GSH was performed. Activation energies (ΔG(ǂ)) for the reactions associated with the 1, 4-Michael addition were calculated on the M062X/6-311++G (d,p) level of theory. We modeled the reaction with dG as a multi-step process. The first step is rate-limiting (ΔG(ǂ) = 26.7 kcal/mol) and consists of formation of a C-N bond between the C3 atom of the QI moiety and the N7 atom of dG. The second step involves proton transfer from the C3 moiety to the nitrogen atom of the QI with ΔG(ǂ) of 13.8 kcal/mol. The depurination reaction that follows has a ΔG(ǂ) of 25.7 kcal/mol. The calculated ΔG(ǂ) for the nucleophilic attack of the deprotonated S atom of GSH on the C3 atom of the NAPQI is 12.9 kcal/mol. Therefore, the QI will react with GSH much faster than with DNA. Our study gives mechanistic insight into the genotoxicity of the APAP metabolite and will be useful for estimating the genotoxic potential of existing drugs with a QI moiety. Our results show that clinical application of APAP is safe, while in the case of severely depleted GSH levels APAP should be administered with caution. PMID:26551927

  15. A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione.

    PubMed

    Klopčič, Ivana; Poberžnik, Matic; Mavri, Janez; Dolenc, Marija Sollner

    2015-12-01

    Acetaminophen (APAP) forms some reactive metabolites that can react with DNA. APAP is a potentially genotoxic drug and is classified as a Group 3 drug according to International Agency for Research on Cancer (IARC). One of the possible mechanisms of APAP genotoxicity after long term of use is that its reactive quinone imine (QI) metabolite of acetaminophen (NAPQI), can chemically react with DNA after glutathione (GSH) depletion. A quantum chemical study of the reactions between the NAPQI and deoxyguanosine (dG) or GSH was performed. Activation energies (ΔG(ǂ)) for the reactions associated with the 1, 4-Michael addition were calculated on the M062X/6-311++G (d,p) level of theory. We modeled the reaction with dG as a multi-step process. The first step is rate-limiting (ΔG(ǂ) = 26.7 kcal/mol) and consists of formation of a C-N bond between the C3 atom of the QI moiety and the N7 atom of dG. The second step involves proton transfer from the C3 moiety to the nitrogen atom of the QI with ΔG(ǂ) of 13.8 kcal/mol. The depurination reaction that follows has a ΔG(ǂ) of 25.7 kcal/mol. The calculated ΔG(ǂ) for the nucleophilic attack of the deprotonated S atom of GSH on the C3 atom of the NAPQI is 12.9 kcal/mol. Therefore, the QI will react with GSH much faster than with DNA. Our study gives mechanistic insight into the genotoxicity of the APAP metabolite and will be useful for estimating the genotoxic potential of existing drugs with a QI moiety. Our results show that clinical application of APAP is safe, while in the case of severely depleted GSH levels APAP should be administered with caution.

  16. The Canberra Christmas overdoses mystery.

    PubMed

    Bammer, G; Sengoz, A

    1995-01-01

    Our investigation of a cluster of three fatal overdoses casts doubt on the conventional wisdom that overdoses result from unregulated changes in the purity of street heroin. Use of alcohol or other sedatives can make an otherwise safe dose of heroin (or other opioids) lethal. In addition users can knowingly increase their dose, usually as an indulgence. Some media reporting of this cluster of deaths was accurate, but there was also sensationalization, perpetuating stereotypes about the drug market that may be untrue. Information flow within the using community was relatively accurate, but slow, possibly because it was the holiday season. Larger studies to substantiate our findings are needed. In addition, introduction of a user-organization-based epidemiological monitoring system for overdoses would be a valuable public health measure.

  17. Withaferin-A Reduces Acetaminophen-Induced Liver Injury in Mice.

    PubMed

    Jadeja, Ravirajsinh N; Urrunaga, Nathalie H; Dash, Suchismita; Khurana, Sandeep; Saxena, Neeraj Kumar

    2015-09-01

    Withaferin-A (WA) has anti-oxidant activities however, its therapeutic potential in acetaminophen (APAP) hepatotoxicity is unknown. We performed a proof-of-concept study to assess the therapeutic potential of WA in a mouse model that mimics APAP-induced liver injury (AILI) in humans. Overnight fasted C57BL/6NTac (5-6 wk. old) male mice received 200 mg/kg APAP intraperitoneally (i.p.). After 1 h mice were treated with 40 mg/kg WA or vehicle i.p., and euthanized 4 and 16 h later; their livers were harvested and serum collected for analysis. At 4 h, compared to vehicle-treated mice, WA-treated mice had reduced serum ALT levels, hepatocyte necrosis and intrahepatic hemorrhage. All APAP-treated mice had reduced hepatic glutathione (GSH) levels however, reduction in GSH was lower in WA-treated when compared to vehicle-treated mice. Compared to vehicle-treated mice, livers from WA-treated mice had reduced APAP-induced JNK activation, mitochondrial Bax translocation, and nitrotyrosine generation. Compared to vehicle-treated mice, WA-treated mice had increased hepatic up-regulation of Nrf2, Gclc and Nqo1, and down-regulation of Il-6 and Il-1β. The hepatoprotective effect of WA persisted at 16 h. Compared to vehicle-treated mice, WA-treated mice had reduced hepatocyte necrosis and hepatic expression of Il-6, Tnf-α and Il-1β, increased hepatic Gclc and Nqo1 expression and GSH levels, and reduced lipid peroxidation. Finally, in AML12 hepatocytes, WA reduced H₂O₂-induced oxidative stress and necrosis by preventing GSH depletion. Collectively, these data show mechanisms whereby WA reduces necrotic hepatocyte injury, and demonstrate that WA has therapeutic potential in AILI.

  18. Charcoal hemoperfusion in bupropion overdose.

    PubMed

    Akdemir, Hızır Ufuk; Calışkan, Fatih; Duran, Latif; Katı, Celal; Güngörer, Bülent; Ocak, Metin

    2014-10-01

    Bupropion is a relatively new and popular medication for depression, with seizures as its major side effect. In the literature, there are insufficient data about hemodialysis following bupropion overdose. A 23-year-old female patient was brought to our emergency department with acute change in mental status and seizure after deliberate self-poisoning with approximately 25-30 tablets of bupropion hydrochloride. Her Glasgow coma scale score was 8/15. The patient underwent hemodialysis about 4 hours later. After 4 hours of extracorporeal treatment, she became conscious and was extubated. We present a case of full recovery after charcoal hemoperfusion following a bupropion overdose.

  19. Variability in Acetaminophen Labeling Practices: a Missed Opportunity to Enhance Patient Safety.

    PubMed

    King, Jennifer P; McCarthy, Danielle M; Serper, Marina; Jacobson, Kara L; Mullen, Rebecca J; Parker, Ruth M; Wolf, Michael S

    2015-12-01

    Confusion regarding a drug's active ingredient may lead to simultaneous use of multiple acetaminophen-containing prescriptions and increase the risk of unintentional overdose. The objective of this study was to examine prescription labeling practices for commonly prescribed acetaminophen-containing analgesics, specifically focusing on how active ingredient information and concomitant use warnings were conveyed. Patients with new acetaminophen-containing prescriptions were recruited upon discharge from an emergency department in Chicago or at an outpatient, hospital-based pharmacy in Atlanta. Label information was transcribed from prescription bottles and patients' knowledge of active ingredient was assessed by in-person interviews. Among the 245 acetaminophen-containing prescriptions, hydrocodone was the most common second active ingredient (n = 208, 84.8 %) followed by oxycodone (n = 28, 11.4 %). Acetaminophen was identified by its full name on 6.9 % (n = 17) of labels; various abbreviations were used in 93.1 % of cases. One hundred forty-seven bottles used auxiliary warning labels with the majority of labels (n = 130, 88.4 %) warning about maximum dose and 11.5 % (n = 17) about concomitant use. Most of the study participants (n = 177, 72.2 %) were not able to identify acetaminophen as an active ingredient in their prescription. There was no significant association between the use of unabbreviated labels including warning information and patients' awareness of acetaminophen as an active ingredient (36.4 vs. 27.3 %, p = 0.50). We noted high variability in labeling practices and warning information conveyed to patients receiving acetaminophen-containing prescriptions. Missed opportunities to adequately convey risk information may contribute to the burden of acetaminophen-related liver injury.

  20. Variability in Acetaminophen Labeling Practices: a Missed Opportunity to Enhance Patient Safety.

    PubMed

    King, Jennifer P; McCarthy, Danielle M; Serper, Marina; Jacobson, Kara L; Mullen, Rebecca J; Parker, Ruth M; Wolf, Michael S

    2015-12-01

    Confusion regarding a drug's active ingredient may lead to simultaneous use of multiple acetaminophen-containing prescriptions and increase the risk of unintentional overdose. The objective of this study was to examine prescription labeling practices for commonly prescribed acetaminophen-containing analgesics, specifically focusing on how active ingredient information and concomitant use warnings were conveyed. Patients with new acetaminophen-containing prescriptions were recruited upon discharge from an emergency department in Chicago or at an outpatient, hospital-based pharmacy in Atlanta. Label information was transcribed from prescription bottles and patients' knowledge of active ingredient was assessed by in-person interviews. Among the 245 acetaminophen-containing prescriptions, hydrocodone was the most common second active ingredient (n = 208, 84.8 %) followed by oxycodone (n = 28, 11.4 %). Acetaminophen was identified by its full name on 6.9 % (n = 17) of labels; various abbreviations were used in 93.1 % of cases. One hundred forty-seven bottles used auxiliary warning labels with the majority of labels (n = 130, 88.4 %) warning about maximum dose and 11.5 % (n = 17) about concomitant use. Most of the study participants (n = 177, 72.2 %) were not able to identify acetaminophen as an active ingredient in their prescription. There was no significant association between the use of unabbreviated labels including warning information and patients' awareness of acetaminophen as an active ingredient (36.4 vs. 27.3 %, p = 0.50). We noted high variability in labeling practices and warning information conveyed to patients receiving acetaminophen-containing prescriptions. Missed opportunities to adequately convey risk information may contribute to the burden of acetaminophen-related liver injury. PMID:25697756

  1. Visualization of acetaminophen-induced liver injury by time-of-flight secondary ion mass spectrometry.

    PubMed

    Murayama, Yohei; Satoh, Shuya; Hashiguchi, Akinori; Yamazaki, Ken; Hashimoto, Hiroyuki; Sakamoto, Michiie

    2015-11-01

    Time-of-flight secondary ion mass spectrometry (MS) provides secondary ion images that reflect distributions of substances with sub-micrometer spatial resolution. To evaluate the use of time-of-flight secondary ion MS to capture subcellular chemical changes in a tissue specimen, we visualized cellular damage showing a three-zone distribution in mouse liver tissue injured by acetaminophen overdose. First, we selected two types of ion peaks related to the hepatocyte nucleus and cytoplasm using control mouse liver. Acetaminophen-overdosed mouse liver was then classified into three areas using the time-of-flight secondary ion MS image of the two types of peaks, which roughly corresponded to established histopathological features. The ion peaks related to the cytoplasm decreased as the injury became more severe, and their origin was assumed to be mostly glycogen based on comparison with periodic acid-Schiff staining images and reference compound spectra. This indicated that the time-of-flight secondary ion MS image of the acetaminophen-overdosed mouse liver represented the chemical changes mainly corresponding to glycogen depletion on a subcellular scale. In addition, this technique also provided information on lipid species related to the injury. These results suggest that time-of-flight secondary ion MS has potential utility in histopathological applications.

  2. The effect of acetaminophen nanoparticles on liver toxicity in a rat model.

    PubMed

    Biazar, Esmaeil; Rezayat, S Mahdi; Montazeri, Naser; Pourshamsian, Khalil; Zeinali, Reza; Asefnejad, Azadeh; Rahimi, Mehdi; Zadehzare, Mohammadmajid; Mahmoudi, Mehran; Mazinani, Rohollah; Ziaei, Mehdi

    2010-04-07

    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.

  3. Phyllanthus urinaria extract attenuates acetaminophen induced hepatotoxicity: involvement of cytochrome P450 CYP2E1.

    PubMed

    Hau, Desmond Kwok Po; Gambari, Roberto; Wong, Raymond Siu Ming; Yuen, Marcus Chun Wah; Cheng, Gregory Yin Ming; Tong, Cindy Sze Wai; Zhu, Guo Yuan; Leung, Alexander Kai Man; Lai, Paul Bo San; Lau, Fung Yi; Chan, Andrew Kit Wah; Wong, Wai Yeung; Kok, Stanton Hon Lung; Cheng, Chor Hing; Kan, Chi Wai; Chan, Albert Sun Chi; Chui, Chung Hin; Tang, Johnny Cheuk On; Fong, David Wang Fun

    2009-08-01

    Acetaminophen is a commonly used drug for the treatment of patients with common cold and influenza. However, an overdose of acetaminophen may be fatal. In this study we investigated whether mice, administered intraperitoneally with a lethal dose of acetaminophen, when followed by oral administration of Phyllanthus urinaria extract, may be prevented from death. Histopathological analysis of mouse liver sections showed that Phyllanthus urinaria extract may protect the hepatocytes from acetaminophen-induced necrosis. Therapeutic dose of Phyllanthus urinaria extract did not show any toxicological phenomenon on mice. Immunohistochemical staining with the cytochrome P450 CYP2E1 antibody revealed that Phyllanthus urinaria extract reduced the cytochrome P450 CYP2E1 protein level in mice pre-treated with a lethal dose of acetaminophen. Phyllanthus urinaria extract also inhibited the cytochrome P450 CYP2E1 enzymatic activity in vitro. Heavy metals, including arsenic, cadmium, mercury and lead, as well as herbicide residues were not found above their detection limits. High performance liquid chromatography identified corilagin and gallic acid as the major components of the Phyllanthus urinaria extract. We conclude that Phyllanthus urinaria extract is effective in attenuating the acetaminophen induced hepatotoxicity, and inhibition of cytochrome P450 CYP2E1 enzyme may be an important factor for its therapeutic mechanism.

  4. Medication Overdoses at a Public Emergency Department in Santiago, Chile

    PubMed Central

    Aguilera, Pablo; Garrido, Marcela; Lessard, Eli; Swanson, Julian; Mallon, William K.; Saldias, Fernando; Basaure, Carlos; Lara, Barbara; Swadron, Stuart P.

    2016-01-01

    Introduction While a nationwide poison control registry exists in Chile, reporting to the center is sporadic and happens at the discretion of the treating physician or by patients’ self-report. Moreover, individual hospitals do not monitor accidental or intentional poisoning in a systematic manner. The goal of this study was to identify all cases of intentional medication overdose (MO) that occurred over two years at a large public hospital in Santiago, Chile, and examine its epidemiologic profile. Methods This study is a retrospective, explicit chart review conducted at Hospital Sótero del Rio from July 2008 until June 2010. We included all cases of identified intentional MO. Alcohol and recreational drugs were included only when they were ingested with other medications. Results We identified 1,557 cases of intentional MO and analyzed a total of 1,197 cases, corresponding to 0.51% of all emergency department (ED) presentations between July 2008 and June 2010. The median patient age was 25 years. The majority was female (67.6%). Two peaks were identified, corresponding to the spring of each year sampled. The rate of hospital admission was 22.2%. Benzodiazepines, selective serotonin reuptake inhibitors, and tricyclic antidepressants (TCA) were the causative agents most commonly found, comprising 1,044 (87.2%) of all analyzed cases. Acetaminophen was involved in 81 (6.8%) cases. More than one active substance was involved in 35% of cases. In 7.3% there was ethanol co-ingestion and in 1.0% co-ingestion of some other recreational drug (primarily cocaine). Of 1,557 cases, six (0.39%) patients died. TCA were involved in two of these deaths. Conclusion Similar to other developed and developing nations, intentional MO accounts for a significant number of ED presentations in Chile. Chile is unique in the region, however, in that its spectrum of intentional overdoses includes an excess burden of tricyclic antidepressant and benzodiazepine overdoses, a relatively low rate

  5. Aconitum carmichaelii protects against acetaminophen-induced hepatotoxicity via B-cell lymphoma-2 protein-mediated inhibition of mitochondrial dysfunction.

    PubMed

    Park, Gunhyuk; Kim, Ki Mo; Choi, Songie; Oh, Dal-Seok

    2016-03-01

    We previously reported the clinical profile of processed Aconitum carmichaelii (AC, Aconibal(®)), which included inhibition of cytochrome P450 (CYP) 2E1 activity in healthy male adults. CYP2E1 is recognized as the enzyme that initiates the cascade of events leading to acetaminophen (APAP)-induced toxicity. However, no studies have characterized its role in APAP-induced hepatic injury. Here, we investigated the protective effects of AC on APAP-induced hepatotoxicity via mitochondrial dysfunction. AC (5-500 μg/mL) significantly inhibited APAP-induced reduction of glutathione. In addition, AC decreased mitochondrial membrane potential (Δψm) and B-cell lymphoma 2 (Bcl-2)-associated X protein levels (% change 46.63) in mitochondria. Moreover, it increased Bcl-2 (% change 55.39) and cytochrome C levels (% change 38.33) in mitochondria, measured using immunofluorescence or a commercial kit. Furthermore, cell membrane integrity was preserved and nuclear fragmentation inhibited by AC. These results demonstrate that AC protects hepatocytes against APAP-induced toxicity by inhibiting mitochondrial dysfunction. PMID:26895385

  6. Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

    PubMed Central

    Thompson, Brandon J.; Sanchez-Covarrubias, Lucy; Zhang, Yifeng; Laracuente, Mei-Li; Vanderah, Todd W.; Ronaldson, Patrick T.; Davis, Thomas P.

    2013-01-01

    Effective pharmacologic treatment of pain with opioids requires that these drugs attain efficacious concentrations in the central nervous system (CNS). A primary determinant of CNS drug permeation is P-glycoprotein (P-gp), an endogenous blood-brain barrier (BBB) efflux transporter that is involved in brain-to-blood transport of opioid analgesics (i.e., morphine). Recently, the nuclear receptor constitutive androstane receptor (CAR) has been identified as a regulator of P-gp functional expression at the BBB. This is critical to pharmacotherapy of pain/inflammation, as patients are often administered acetaminophen (APAP), a CAR-activating ligand, in conjunction with an opioid. Our objective was to investigate, in vivo, the role of CAR in regulation of P-gp at the BBB. Following APAP treatment, P-gp protein expression was increased up to 1.4–1.6-fold in a concentration-dependent manner. Additionally, APAP increased P-gp transport of BODIPY-verapamil in freshly isolated rat brain capillaries. This APAP-induced increase in P-gp expression and activity was attenuated in the presence of CAR pathway inhibitor okadaic acid or transcriptional inhibitor actinomycin D, suggesting P-gp regulation is CAR-dependent. Furthermore, morphine brain accumulation was enhanced by P-gp inhibitors in APAP-treated animals, suggesting P-gp–mediated transport. A warm-water (50°C) tail-flick assay revealed a significant decrease in morphine analgesia in animals treated with morphine 3 or 6 hours after APAP treatment, as compared with animals treated concurrently. Taken together, our data imply that inclusion of APAP in a pain treatment regimen activates CAR at the BBB and increases P-gp functional expression, a clinically significant drug-drug interaction that modulates opioid analgesic efficacy. PMID:24019224

  7. Impact of amending the acetylcysteine marketing authorisation on treatment of paracetamol overdose.

    PubMed

    Thompson, G; Fatima, S B; Shah, N; Kitching, G; Waring, W S

    2013-01-01

    In September 2012, the Medicines and Healthcare products Regulatory Agency (MHRA) substantially amended the Marketing Authorisation for acetylcysteine following an extensive review. The present study examined the impact of this license change on patterns of acetylcysteine use in patients presenting to hospital after paracetamol (acetaminophen) overdose. Between September 2011 and April 2013, 785 consecutive patients presented to York Hospital due to paracetamol overdose, and a before-after analysis was used to compare outcomes. There were 483 patients before and 302 patients after the license amendment, and age, gender, acute or staggered overdose pattern, and dose were similar in both groups. In the patients with paracetamol concentrations between the "100-line" and "200-line," a significantly higher proportion received acetylcysteine treatment (51% before versus 98% after, P = 0.0029), as expected. A modest increase was also observed in relation to late or staggered overdose or cases where the time of ingestion was uncertain (53% versus 74%, P = 0.0430). The median duration of hospital stay increased across the entire study population, from 15 to 24 hours (P = 0.0159) due to the increased proportion of patients requiring acetylcysteine treatment. The findings indicate that the MHRA amendment is a financially costly intervention, and further studies are needed to examine clinical outcomes so that its cost effectiveness might be addressed. PMID:23956882

  8. Acetaminophen and NAPQI are Toxic to Auditory Cells via Oxidative and Endoplasmic Reticulum Stress-dependent Pathways

    PubMed Central

    Kalinec, Gilda M.; Thein, Pru; Parsa, Arya; Yorgason, Joshua; Luxford, William; Urrutia, Raul; Kalinec, Federico

    2014-01-01

    Pain relievers containing N-acetyl-para-aminophenol, also called APAP, acetaminophen or paracetamol, in combination with opioid narcotics are top-selling pharmaceuticals in the U.S. Individuals who abuse these drugs for as little as sixty days can develop tinnitus and progressive bilateral sensorineural hearing loss. Recently published studies indicate that APAP and its metabolic product N-acetyl-p-benzoquinoneimine (NAPQI) are the primary ototoxic agents in this type of pain relievers. However, the mechanisms underlying the deleterious effects of these drugs on auditory cells remain to be fully characterized. In this study, we report cellular, genomic, and proteomic experiments revealing that cytotoxicity by APAP and NAPQI involves two different pathways in Immortomouse™-derived HEI-OC1 cells, implicating ROS overproduction, alterations in ER morphology, redistribution of intra-cisternal chaperones, activation of the eIF2α-CHOP pathway, as well as changes in ER stress and protein folding response markers. Thus, both oxidative and ER stress are part of the cellular and molecular mechanisms that contribute to the cytotoxic effects of APAP and NAPQI in these cells. We suggest that these in vitro findings should be taken into consideration when designing pharmacological strategies aimed at preventing the toxic effects of these drugs on the auditory system. PMID:24793116

  9. Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

    SciTech Connect

    Bourdi, Mohammed Korrapati, Midhun C.; Chakraborty, Mala; Yee, Steven B.; Pohl, Lance R.

    2008-09-12

    Recent studies in mice suggest that stress-activated c-Jun N-terminal protein kinase 2 (JNK2) plays a pathologic role in acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure (ALF). In contrast, we present evidence that JNK2 can have a protective role against AILI. When male C57BL/6J wild type (WT) and JNK2{sup -/-} mice were treated with 300 mg APAP/kg, 90% of JNK2{sup -/-} mice died of ALF compared to 20% of WT mice within 48 h. The high susceptibility of JNK2{sup -/-} mice to AILI appears to be due in part to deficiencies in hepatocyte proliferation and repair. Therefore, our findings are consistent with JNK2 signaling playing a protective role in AILI and further suggest that the use of JNK inhibitors as a potential treatment for AILI, as has been recommended by other investigators, should be reconsidered.

  10. Acetaminophen cytotoxicity is ameliorated in a human liver organotypic co-culture model.

    PubMed

    Nelson, Leonard J; Navarro, Maria; Treskes, Philipp; Samuel, Kay; Tura-Ceide, Olga; Morley, Steven D; Hayes, Peter C; Plevris, John N

    2015-01-01

    Organotypic liver culture models for hepatotoxicity studies that mimic in vivo hepatic functionality could help facilitate improved strategies for early safety risk assessment during drug development. Interspecies differences in drug sensitivity and mechanistic profiles, low predictive capacity, and limitations of conventional monocultures of human hepatocytes, with high attrition rates remain major challenges. Herein, we show stable, cell-type specific phenotype/cellular polarity with differentiated functionality in human hepatocyte-like C3A cells (enhanced CYP3A4 activity/albumin synthesis) when in co-culture with human vascular endothelial cells (HUVECs), thus demonstrating biocompatibility and relevance for evaluating drug metabolism and toxicity. In agreement with in vivo studies, acetaminophen (APAP) toxicity was most profound in HUVEC mono-cultures; whilst in C3A:HUVEC co-culture, cells were less susceptible to the toxic effects of APAP, including parameters of oxidative stress and ATP depletion, altered redox homeostasis, and impaired respiration. This resistance to APAP is also observed in a primary human hepatocyte (PHH) based co-culture model, suggesting bidirectional communication/stabilization between different cell types. This simple and easy-to-implement human co-culture model may represent a sustainable and physiologically-relevant alternative cell system to PHHs, complementary to animal testing, for initial hepatotoxicity screening or mechanistic studies of candidate compounds differentially targeting hepatocytes and endothelial cells. PMID:26632255

  11. Application of Physiologically Based Pharmacokinetic Modeling to Predict Acetaminophen Metabolism and Pharmacokinetics in Children

    PubMed Central

    Jiang, X-L; Zhao, P; Barrett, J S; Lesko, L J; Schmidt, S

    2013-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that undergoes extensive phase I and II metabolism. To better understand the kinetics of this process and to characterize the dynamic changes in metabolism and pharmacokinetics (PK) between children and adults, we developed a physiologically based PK (PBPK) model for APAP integrating in silico, in vitro, and in vivo PK data into a single model. The model was developed and qualified for adults and subsequently expanded for application in children by accounting for maturational changes from birth. Once developed and qualified, it was able to predict clinical PK data in neonates (0–28 days), infants (29 days to <2 years), children (2 to <12 years), and adolescents (12–17 years) following intravenous and orally administered APAP. This approach represents a general strategy for projecting drug exposure in children, in the absence of pediatric PK information, using previous drug- and system-specific information of adults and children through PBPK modeling. PMID:24132164

  12. Incorporation of acetaminophen as an active pharmaceutical ingredient into porous lactose.

    PubMed

    Ebrahimi, Amirali; Saffari, Morteza; Dehghani, Fariba; Langrish, Timothy

    2016-02-29

    A new formulation method for solid dosage forms with drug loadings from 0.65 ± 0.03% to 39 ± 1% (w/w) of acetaminophen (APAP) as a model drug has been presented. The proposed method involves the production of highly-porous lactose with a BET surface area of 20 ± 1 m(2)/g as an excipient using a templating method and the incorporation of drug into the porous structure by adsorption from a solution of the drug in ethanol. Drug deposition inside the carrier particles, rather than being physically distributed between them, eliminated the potential drug/carrier segregation, which resulted in excellent blend uniformities with relative standard deviations of less than 3.5% for all drug formulations. The results of DSC and XRD tests have shown deposition of nanocrystals of APAP inside the nanopores of lactose due the nanoconfinement phenomenon. FTIR spectroscopy has revealed no interaction between the adsorbed drug and the surface of lactose. The final loaded lactose particles had large BET surface areas and high porosities, which significantly increased the crushing strengths of the produced tablets. In vitro release studies in phosphate buffer (pH 5.8) have shown an acceptable delivery performance of 85% APAP release within 7 minutes for loaded powders filled in gelatin capsules. PMID:26768724

  13. Human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with JNK activation and protein adduct formation

    PubMed Central

    Guldiken, Nurdan; Zhou, Qin; Kucukoglu, Ozlem; Rehm, Melanie; Levada, Kateryna; Gross, Annika; Kwan, Raymond; James, Laura P.; Trautwein, Christian; Omary, M. Bishr; Strnad, Pavel

    2015-01-01

    Background and aims Keratins 8 and 18 (K8/K18) are the intermediate filaments proteins of simple-type digestive epithelia, and provide important cytoprotective function. K8/K18 variants predispose humans to chronic liver disease progression and to poor outcomes in acute acetaminophen (APAP)-related liver failure. Given that K8 G62C and R341H/R341C are common K8 variants in European and North American populations, we studied their biological significance using transgenic mice. Methods Mice that overexpress the human K8 variants R341H or R341C were generated and used together with previously described mice that overexpress wild-type (WT) K8 or K8 G62C. Mice were injected with 600 mg/kg APAP, or underwent bile duct ligation (BDL). Livers were evaluated by microarray analysis, quantitative RT-PCR, immunoblotting, histological and immunological staining, and biochemical assays. Results Under basal conditions, the K8 G62C/R341H/R341C variant-expressing mice did not show an obvious liver phenotype or altered keratin filament distribution, while K8 G62C/R341C animals had aberrant disulphide-crosslinked keratins. Animals carrying the K8 variants displayed limited gene expression changes but had lower nicotinamide N-methyl transferase (NNMT) levels and were predisposed to APAP-induced hepatotoxicity. NNMT represents a novel K8/K18-associated protein that becomes upregulated after K8/K18 transfection. The more pronounced liver damage was accompanied by increased and prolonged JNK activation; elevated APAP protein adducts; K8 hyperphosphorylation at S74/S432 with enhanced K8 solubility; and prominent pericentral keratin network disruption. No differences in APAP serum levels, glutathione or ATP levels were noted. BDL resulted in similar liver injury and biliary fibrosis in all mouse genotypes. Conclusion Expression of human K8 variants G62C, R341H, or R341C in mice predisposes to acute acetaminophen hepatotoxicity, thereby providing direct evidence for the importance of these

  14. [Analgesic/Antipyretic treatment: ibuprofen or acetaminophen? An update].

    PubMed

    Olive, Georges

    2006-01-01

    Because of the adverse effects associated with aspirin, especially Reye's syndrome in children, practitioners currently use as first line therapy drugs such as ibuprofen or acetaminophen. Their pharmacokinetic characteristics are not quite identical: both are absorbed rapidly and have high bioavailability, however, unlike acetaminophen, ibuprofen is characterized by high plasma protein binding and a limited distribution volume. Both drugs are metabolized essentially in the liver into inactive hydroxylated or glucoronidated metabolites by conjugation but acetaminophen is also transformed into an oxidation compound--normally reduced by glutathione--which, in the case of acute overdosing with depletion of endogenous glutathione stores, may lead to severe hepatotoxicity. Old age and light to moderate renal or hepatic failure do not significantly modify their pharmacokinetic parameters, and thus do not call for dose adjustment. Clinical trials have shown both drugs to have comparable efficacy on pain and fever, with perhaps a slight advantage for ibuprofen. In practice, the choice will depend on the prescription habits of the practitioner, patient's (or parents') preferences and, above all, the pathological context and possible contra-indications. PMID:16886709

  15. Hepatoprotective and anti-oxidant activities of Glossogyne tenuifolia against acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Tien, Yu-Hsiu; Chen, Bing-Huei; Wang Hsu, Guoo-Shyng; Lin, Wan-Teng; Huang, Jui-Hua; Lu, Yi-Fa

    2014-01-01

    The present study investigated the anti-oxidative and hepatoprotective effects of Glossogyne tenuifolia (GT) Cassini, against acetaminophen-induced acute liver injury in BALB/c mice. The extracts of GT by various solvents (hot water, 50% ethanol and 95% ethanol) were compared for their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, reducing power, total phenolic content, and total anti-oxidant capacity. The results showed that hot water (HW) extracts of GT contained high levels of phenolics and exerted an excellent anti-oxidative capacity; thus, these were used in the animal experiment. The male BALB/c mice were randomly divided into control group, acetaminophen (APAP) group, positive control group and two GT groups at low (GT-L) and high (GT-H) dosages. The results showed that mice treated with GT had significantly decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). GT-H increased glutathione levels and the ratios of reduced glutathione and oxidized glutathione (GSH/GSSG) in the liver, and inhibited serum and lipid peroxidation. This experiment was the first to determine phenolic compounds, chlorogenic acid and luteolin-7-glucoside in HW extract of GT. In conclusion, HW extract of GT may have potential anti-oxidant capacity and show hepatoprotective capacities in APAP-induced liver damaged mice.

  16. Hepatoprotective and anti-oxidant activities of Glossogyne tenuifolia against acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Tien, Yu-Hsiu; Chen, Bing-Huei; Wang Hsu, Guoo-Shyng; Lin, Wan-Teng; Huang, Jui-Hua; Lu, Yi-Fa

    2014-01-01

    The present study investigated the anti-oxidative and hepatoprotective effects of Glossogyne tenuifolia (GT) Cassini, against acetaminophen-induced acute liver injury in BALB/c mice. The extracts of GT by various solvents (hot water, 50% ethanol and 95% ethanol) were compared for their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, reducing power, total phenolic content, and total anti-oxidant capacity. The results showed that hot water (HW) extracts of GT contained high levels of phenolics and exerted an excellent anti-oxidative capacity; thus, these were used in the animal experiment. The male BALB/c mice were randomly divided into control group, acetaminophen (APAP) group, positive control group and two GT groups at low (GT-L) and high (GT-H) dosages. The results showed that mice treated with GT had significantly decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). GT-H increased glutathione levels and the ratios of reduced glutathione and oxidized glutathione (GSH/GSSG) in the liver, and inhibited serum and lipid peroxidation. This experiment was the first to determine phenolic compounds, chlorogenic acid and luteolin-7-glucoside in HW extract of GT. In conclusion, HW extract of GT may have potential anti-oxidant capacity and show hepatoprotective capacities in APAP-induced liver damaged mice. PMID:25384447

  17. Fatal combination of moclobemide overdose and whisky.

    PubMed

    Bleumink, G S; van Vliet, A C M; van der Tholen, A; Stricker, B H Ch

    2003-03-01

    The antidepressant moclobemide (Aurorix) is a reversible inhibitor of monoamine oxidase-A. Pure moclobemide overdose is considered to be relatively safe. Mixed drug overdoses including moclobemide are potentially lethal, especially when serotonergical drugs are involved. So far, only one fatality due to moclobemide mono-overdose has been reported. We report here on a fatality following the ingestion of a moclobemide overdose in combination with half a bottle of whisky. Although dietary restrictions during moclobemide therapy are not considered necessary, the combination of large quantities of moclobemide and tyramine-containing products seems to be lethal, probably because monoamine oxidase-A selectivity is overwhelmed after massive overdoses. Since there is no specific antidote and treatment is only symptomatic, the severity of an overdose with moclobemide must not be underestimated.

  18. Integrated proteomic and transcriptomic investigation of the acetaminophen toxicity in liver microfluidic biochip.

    PubMed

    Prot, Jean Matthieu; Briffaut, Anne-Sophie; Letourneur, Franck; Chafey, Philippe; Merlier, Franck; Grandvalet, Yves; Legallais, Cécile; Leclerc, Eric

    2011-01-01

    Microfluidic bioartificial organs allow the reproduction of in vivo-like properties such as cell culture in a 3D dynamical micro environment. In this work, we established a method and a protocol for performing a toxicogenomic analysis of HepG2/C3A cultivated in a microfluidic biochip. Transcriptomic and proteomic analyses have shown the induction of the NRF2 pathway and the related drug metabolism pathways when the HepG2/C3A cells were cultivated in the biochip. The induction of those pathways in the biochip enhanced the metabolism of the N-acetyl-p-aminophenol drug (acetaminophen-APAP) when compared to Petri cultures. Thus, we observed 50% growth inhibition of cell proliferation at 1 mM in the biochip, which appeared similar to human plasmatic toxic concentrations reported at 2 mM. The metabolic signature of APAP toxicity in the biochip showed similar biomarkers as those reported in vivo, such as the calcium homeostasis, lipid metabolism and reorganization of the cytoskeleton, at the transcriptome and proteome levels (which was not the case in Petri dishes). These results demonstrate a specific molecular signature for acetaminophen at transcriptomic and proteomic levels closed to situations found in vivo. Interestingly, a common component of the signature of the APAP molecule was identified in Petri and biochip cultures via the perturbations of the DNA replication and cell cycle. These findings provide an important insight into the use of microfluidic biochips as new tools in biomarker research in pharmaceutical drug studies and predictive toxicity investigations.

  19. MicroRNA-561 promotes acetaminophen-induced hepatotoxicity in HepG2 cells and primary human hepatocytes through downregulation of the nuclear receptor corepressor dosage-sensitive sex-reversal adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX-1).

    PubMed

    Li, Minghua; Yang, Yinxue; He, Zhi-Xu; Zhou, Zhi-Wei; Yang, Tianxin; Guo, Peixuan; Zhang, Xueji; Zhou, Shu-Feng

    2014-01-01

    One of the major mechanisms involved in acetaminophen (APAP)-induced hepatotoxicity is hepatocyte nuclear factor 4α (HNF4α)-mediated activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). In the present study, we investigated the role of miR-561 and its target gene DAX-1 encoding a corepressor of HNF4α in the process of APAP-induced hepatotoxicity. We used both human hepatocellular liver carcinoma cell line (HepG2) cells and primary human hepatocytes in this study and monitored the levels of reactive oxygen species, lactate dehydrogenase, and glutathione. Our bioinformatics study suggests an association between miR-561 and DAX-1, but not HNF4α. Treatment of HepG2 cells with APAP significantly reduced the expression of DAX-1 in a concentration-dependent manner. miR-561 was induced by APAP treatment in HepG2 cells. Transfection of HepG2 cells with an miR-561 mimic exacerbated APAP-induced hepatotoxicity. HNF4α is physically associated with DAX-1 in HepG2 cells. A decreased protein level of DAX-1 by APAP treatment was also enhanced by miR-561 mimic transfection in HepG2 cells and primary human hepatocytes. The basal and APAP-induced expression of PXR and CAR was enhanced by miR-561 mimic transfection; however, transfection of HepG2 cells or primary human hepatocytes with a miR-561 inhibitor or DAX-1 small interfering RNA reversed these effects. Additionally, the chromatin immunoprecipitation assay revealed that recruitment of DAX-1 onto the PXR promoter was inversely correlated with the recruitment of peroxisome proliferator-activated receptor-α coactivator-1α and HNF4α on APAP treatment. These results indicate that miR-561 worsens APAP-induced hepatotoxicity via inhibition of DAX-1 and consequent transactivation of nuclear receptors.

  20. Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway

    PubMed Central

    Jiang, Yi-ming; Wang, Ying; Tan, Hua-sen; Yu, Tao; Fan, Xiao-mei; Chen, Pan; Zeng, Hang; Huang, Min; Bi, Hui-chang

    2016-01-01

    Aim: The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect. Methods: Male C57BL/6 mice were treated with SolB (200 mg·kg−1·d−1, ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay. Results: SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5–20 μmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells. Conclusion: SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity. PMID:26806302

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

    PubMed

    Michaut, Anaïs; Le Guillou, Dounia; Moreau, Caroline; Bucher, Simon; McGill, Mitchell R; Martinais, Sophie; Gicquel, Thomas; Morel, Isabelle; Robin, Marie-Anne; Jaeschke, Hartmut; Fromenty, Bernard

    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 (2.5mM) or high (20mM) 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. PMID:26739624

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

    PubMed

    Michaut, Anaïs; Le Guillou, Dounia; Moreau, Caroline; Bucher, Simon; McGill, Mitchell R; Martinais, Sophie; Gicquel, Thomas; Morel, Isabelle; Robin, Marie-Anne; Jaeschke, Hartmut; Fromenty, Bernard

    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 (2.5mM) or high (20mM) 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.

  3. Distinct roles of NF-{kappa}B p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity

    SciTech Connect

    Dambach, Donna M.; Durham, Stephen K.; Laskin, Jeffrey D.; Laskin, Debra L. . E-mail: laskin@eohsi.rutgers.edu

    2006-03-01

    Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. In addition to inducing direct cellular damage, oxidants can activate transcription factors including NF-{kappa}B, which regulate the production of inflammatory mediators implicated in hepatotoxicity. Here, we investigated the role of APAP-induced oxidative stress and NF-{kappa}B in inflammatory mediator production. Treatment of mice with APAP (300 mg/kg, i.p.) resulted in centrilobular hepatic necrosis and increased serum aminotransferase levels. This was correlated with depletion of hepatic glutathione and CuZn superoxide dismutase (SOD). APAP administration also increased expression of the proinflammatory mediators, interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF{alpha}), macrophage chemotactic protein-1 (MCP-1), and KC/gro, and the anti-inflammatory cytokine, interleukin-10 (IL-10). Pretreatment of mice with the antioxidant, N-acetylcysteine (NAC) prevented APAP-induced depletion of glutathione and CuZnSOD, as well as hepatotoxicity. NAC also abrogated APAP-induced increases in TNF{alpha}, KC/gro, and IL-10, but augmented expression of the anti-inflammatory cytokines interleukin-4 (IL-4) and transforming growth factor-{beta} (TGF{beta}). No effects were observed on IL-1{beta} or MCP-1 expression. To determine if NF-{kappa}B plays a role in regulating mediator production, we used transgenic mice with a targeted disruption of the gene for NF-{kappa}B p50. As observed with NAC pretreatment, the loss of NF-{kappa}B p50 was associated with decreased ability of APAP to upregulate TNF{alpha}, KC/gro, and IL-10 expression and increased expression of IL-4 and TGF{beta}. However, in contrast to NAC pretreatment, the loss of p50 had no effect on APAP-induced hepatotoxicity. These data demonstrate that APAP-induced cytokine expression in the liver is influenced by oxidative stress and that this is dependent, in part, on NF-{kappa}B. However, NF-{kappa}B p50

  4. The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation

    SciTech Connect

    Du, Kuo; Williams, C. David; McGill, Mitchell R.; Xie, Yuchao; Farhood, Anwar; Vinken, Mathieu; Jaeschke, Hartmut

    2013-12-15

    Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the US. Although many aspects of the mechanism are known, recent publications suggest that gap junctions composed of connexin32 function as critical intercellular communication channels which transfer cytotoxic mediators into neighboring hepatocytes and aggravate liver injury. However, these studies did not consider off-target effects of reagents used in these experiments, especially the gap junction inhibitor 2-aminoethoxy-diphenyl-borate (2-APB). In order to assess the mechanisms of protection of 2-APB in vivo, male C56Bl/6 mice were treated with 400 mg/kg APAP to cause extensive liver injury. This injury was prevented when animals were co-treated with 20 mg/kg 2-APB and was attenuated when 2-APB was administered 1.5 h after APAP. However, the protection was completely lost when 2-APB was given 4–6 h after APAP. Measurement of protein adducts and c-jun-N-terminal kinase (JNK) activation indicated that 2-APB reduced both protein binding and JNK activation, which correlated with hepatoprotection. Although some of the protection was due to the solvent dimethyl sulfoxide (DMSO), in vitro experiments clearly demonstrated that 2-APB directly inhibits cytochrome P450 activities. In addition, JNK activation induced by phorone and tert-butylhydroperoxide in vivo was inhibited by 2-APB. The effects against APAP toxicity in vivo were reproduced in primary cultured hepatocytes without use of DMSO and in the absence of functional gap junctions. We conclude that the protective effect of 2-APB was caused by inhibition of metabolic activation of APAP and inhibition of the JNK signaling pathway and not by blocking connexin32-based gap junctions. - Highlights: • 2-APB protected against APAP-induced liver injury in mice in vivo and in vitro • 2-APB protected by inhibiting APAP metabolic activation and JNK signaling pathway • DMSO inhibited APAP metabolic activation as the solvent of 2-APB

  5. Secretory phospholipase A{sub 2}-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2

    SciTech Connect

    Bhave, Vishakha S.; Donthamsetty, Shashikiran; Latendresse, John R.; Cunningham, Michael L.; Mehendale, Harihara M.

    2011-03-15

    We have previously reported that among the other death proteins, hepatic secretory phospholipase A{sub 2} (sPLA{sub 2}) is a leading mediator of progression of liver injury initiated by CCl{sub 4} in rats. The aim of our present study was to test the hypothesis that increased hepatic sPLA{sub 2} released after acetaminophen (APAP) challenge mediates progression of liver injury in wild type (WT) and COX-2 knockout (KO) mice. COX-2 WT and KO mice were administered a normally non lethal dose (400 mg/kg) of acetaminophen. The COX-2 KO mice suffered 60% mortality compared to 100% survival of the WT mice, suggesting higher susceptibility of COX-2 KO mice to sPLA{sub 2}-mediated progression of acetaminophen hepatotoxicity. Liver injury was significantly higher at later time points in the KO mice compared to the WT mice indicating that the abatement of progression of injury requires the presence of COX-2. This difference in hepatotoxicity was not due to increased bioactivation of acetaminophen as indicated by unchanged cyp2E1 protein and covalently bound {sup 14}C-APAP in the livers of KO mice. Hepatic sPLA{sub 2} activity and plasma TNF-{alpha} were significantly higher after APAP administration in the KO mice. This was accompanied by a corresponding fall in hepatic PGE{sub 2} and lower compensatory liver regeneration and repair ({sup 3}H-thymidine incorporation) in the KO mice. These results suggest that hindered compensatory tissue repair and poor resolution of inflammation for want of beneficial prostaglandins render the liver very vulnerable to sPLA{sub 2}-mediated progression of liver injury. These findings are consistent with the destructive role of sPLA{sub 2} in the progression and expansion of tissue injury as a result of continued hydrolytic breakdown of plasma membrane phospholipids of perinecrotic hepatocytes unless mitigated by sufficient co-induction of COX-2.

  6. A case of Trientine Overdose.

    PubMed

    Hashim, Ahmed; Parnell, Nick

    2015-01-01

    Wilson disease is a rare genetic hepatic and neurological disorder of copper accumulation. Trientine is usually used as a second line in the management of patients with this condition. We present a case of a large overdose of Trientine (60 g) resulting in self-limiting dizziness and vomiting with no further clinical sequelae or significant biochemical abnormalities. This case shows that Trientine has a good safety profile and hence could be used as a first line treatment in patients with Wilson's disease who suffer from psychiatric complications and who might be at risk of self-harm.

  7. A case of Trientine Overdose

    PubMed Central

    Hashim, Ahmed; Parnell, Nick

    2015-01-01

    Wilson disease is a rare genetic hepatic and neurological disorder of copper accumulation. Trientine is usually used as a second line in the management of patients with this condition. We present a case of a large overdose of Trientine (60 g) resulting in self-limiting dizziness and vomiting with no further clinical sequelae or significant biochemical abnormalities. This case shows that Trientine has a good safety profile and hence could be used as a first line treatment in patients with Wilson's disease who suffer from psychiatric complications and who might be at risk of self-harm. PMID:26862278

  8. A case of Trientine Overdose.

    PubMed

    Hashim, Ahmed; Parnell, Nick

    2015-01-01

    Wilson disease is a rare genetic hepatic and neurological disorder of copper accumulation. Trientine is usually used as a second line in the management of patients with this condition. We present a case of a large overdose of Trientine (60 g) resulting in self-limiting dizziness and vomiting with no further clinical sequelae or significant biochemical abnormalities. This case shows that Trientine has a good safety profile and hence could be used as a first line treatment in patients with Wilson's disease who suffer from psychiatric complications and who might be at risk of self-harm. PMID:26862278

  9. Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes

    SciTech Connect

    Latchoumycandane, Calivarathan; Seah, Quee Ming; Tan, Rachel C.H.; Sattabongkot, Jetsumon; Beerheide, Walter; Boelsterli, Urs A. . E-mail: phcbua@nus.edu.sg

    2006-11-15

    Leflunomide, a disease-modifying anti-rheumatic drug, protects against T-cell-mediated liver injury by poorly understood mechanisms. The active metabolite of leflunomide, A77 1726 (teriflunomide) has been shown to inhibit stress-activated protein kinases (JNK pathway), which are key regulators of mitochondria-mediated cell death. Therefore, we hypothesized that leflunomide may protect from drugs that induce the mitochondrial permeability transition (mPT) by blocking the JNK signaling pathway. To this end, we exposed cultured immortalized human hepatocytes (HC-04) to the standard protoxicant drug acetaminophen (APAP), which induces CsA-sensitive mPT-mediated cell death. We determined the effects of leflunomide on the extent of APAP-induced hepatocyte injury and the upstream JNK-mediated mitochondrial signaling pathways. We found that leflunomide or A77 1726 concentration-dependently protected hepatocytes from APAP (1 mM)-induced mitochondrial permeabilization and lethal cell injury. This was not due to proximal inhibition of CYP-catalyzed APAP bioactivation to its thiol-reactive metabolite. Instead, we demonstrate that leflunomide (20 {mu}M) inhibited the APAP-induced early (3 h) activation (phosphorylation) of JNK1/2, thus inhibiting phosphorylation of the anti-apoptotic protein Bcl-2 and preventing P-Bcl-2-mediated induction of the mPT. This greatly attenuated mitochondrial cytochrome c release, which we used as a marker for mitochondrial permeabilization. The specific JNK2 inhibitor SP600125 similarly protected from APAP-induced cell death. In conclusion, these findings are consistent with our hypothesis that leflunomide protects from protoxicant-induced hepatocyte injury by inhibiting JNK signaling and preventing mPT induction.

  10. What heroin users tell us about overdose.

    PubMed

    Baca, Catherine T; Grant, Kenneth J

    2007-01-01

    This study describes overdose experiences of heroin users, both the overdoses they themselves experienced, as well as those that they witnessed. A structured interview was performed with 101 current heroin users in Albuquerque, New Mexico from January 7, 2002 to February 26, 2002. Heroin-related overdoses were found to be common in this sample of heroin users. Three or more persons were reported to be present during 80 of the 95 most recently witnessed overdoses. An ambulance was called in only 42 of the 95 witnessed overdoses. Seventy-five percent of the respondents who witnessed an overdose stated concern over police involvement was an important reason for delay or absence of a 911 call for help. One hundred of the 101 respondents reported willingness, if trained, to use rescue breathing and to inject naloxone to aid an overdose victim. New methods need to be found to reduce heroin overdose death. Scientific studies are needed on the efficacy of take-home naloxone.

  11. Intravenous acetaminophen use in pediatrics.

    PubMed

    Shastri, Nirav

    2015-06-01

    Acetaminophen is a commonly used pediatric medication that has recently been approved for intravenous use in the United States. The purpose of this article was to review the pharmacodynamics, indications, contraindications, and precautions for the use of intravenous acetaminophen in pediatrics.

  12. A Massive Overdose of Dalfampridine

    PubMed Central

    Fil, Laura J.; Sud, Payal; Sattler, Steven

    2015-01-01

    Multiple sclerosis (MS) is an immune mediated inflammatory disease that attacks myelinated axons in the central nervous system. Dalfampridine (4-aminopyridine) was approved by the Food and Drug Administration in January 2010 for treatment of MS. Our patient was a 34-year-old male with a history of MS, who was brought to the emergency department after being found unresponsive. His current medications were valacyclovir, temazepam, dalfampridine (4-AP) and a tysabri intravenous (IV) infusion. Fifteen minutes after arrival the patient seized. The seizures were refractory to benzodiazepines, barbiturates and phenytoin. The 4-AP level was 530ng/mL (25ng/mL and 49ng/mL). The patient stopped seizing on hospital day 3 and was discharged 14 days later with normal mental status and neurologic exam. 4-AP is a potassium channel blocker that blocks the potassium ion current of repolarization following an action potential. The blockade of the potassium channel at the level of the membrane widens the action potential and enhances the release of acetylcholine, thus increasing post-synaptic action potentials. The treatment of patients with 4-AP overdose is supportive. Animal data suggest that patients with toxic levels of 4-AP may respond to phenytoin. Our case illustrates the highest recorded level of 4-AP in an overdose. Our patient appeared to be refractory to a combination of high doses of anticonvulsants and only improved with time. PMID:26759675

  13. Acetaminophen Induced Hepatotoxicity in Wistar Rats--A Proteomic Approach.

    PubMed

    Ilavenil, Soundharrajan; Al-Dhabi, Naif Abdullah; Srigopalram, Srisesharam; Ock Kim, Young; Agastian, Paul; Baru, Rajasekhar; Choi, Ki Choon; Valan Arasu, Mariadhas

    2016-01-01

    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. PMID:26828476

  14. Acetaminophen Induced Hepatotoxicity in Wistar Rats--A Proteomic Approach.

    PubMed

    Ilavenil, Soundharrajan; Al-Dhabi, Naif Abdullah; Srigopalram, Srisesharam; Ock Kim, Young; Agastian, Paul; Baru, Rajasekhar; Choi, Ki Choon; Valan Arasu, Mariadhas

    2016-01-28

    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.

  15. Overdose

    MedlinePlus

    ... poisoning, although the effects can be the same. Poisoning occurs when someone or something (such as the environment) exposes you to dangerous chemicals, plants, or other harmful substances without your knowledge.

  16. All APAPs Are Not Equivalent for the Treatment of Sleep Disordered Breathing: A Bench Evaluation of Eleven Commercially Available Devices

    PubMed Central

    Zhu, Kaixian; Roisman, Gabriel; Aouf, Sami; Escourrou, Pierre

    2015-01-01

    Study Objectives: This study challenged on a bench-test the efficacy of auto-titrating positive airway pressure (APAP) devices for obstructive sleep disordered breathing treatment and evaluated the accuracy of the device reports. Methods: Our bench consisted of an active lung simulator and a Starling resistor. Eleven commercially available APAP devices were evaluated on their reactions to single-type SDB sequences (obstructive apnea and hypopnea, central apnea, and snoring), and to a long general breathing scenario (5.75 h) simulating various SDB during four sleep cycles and to a short scenario (95 min) simulating one sleep cycle. Results: In the single-type sequence of 30-minute repetitive obstructive apneas, only 5 devices normalized the airflow (> 70% of baseline breathing amplitude). Similarly, normalized breathing was recorded with 8 devices only for a 20-min obstructive hypopnea sequence. Five devices increased the pressure in response to snoring. Only 4 devices maintained a constant minimum pressure when subjected to repeated central apneas with an open upper airway. In the long general breathing scenario, the pressure responses and the treatment efficacy differed among devices: only 5 devices obtained a residual obstructive AHI < 5/h. During the short general breathing scenario, only 2 devices reached the same treatment efficacy (p < 0.001), and 3 devices underestimated the AHI by > 10% (p < 0.001). The long scenario led to more consistent device reports. Conclusion: Large differences between APAP devices in the treatment efficacy and the accuracy of report were evidenced in the current study. Citation: Zhu K, Roisman G, Aouf S, Escourrou P. All APAPs are not equivalent for the treatment of sleep disordered breathing: a bench evaluation of eleven commercially available devices. J Clin Sleep Med 2015;11(7):725–734. PMID:25766708

  17. Pediatric cinnarizine overdose and toxicokinetics.

    PubMed

    Turner, Dan; Lurie, Yael; Finkelstein, Yoram; Schmid, Tal; Gopher, Asher; Kleid, David; Bentur, Yedidia

    2006-05-01

    Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel-blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t(1/2) = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the

  18. Fatal overdoses associated with quetiapine.

    PubMed

    Langman, Loralie J; Kaliciak, Henry A; Carlyle, Sheila

    2004-09-01

    Quetiapine (Seroquel) is an atypical antipsychotic drug belonging to a new chemical class, the benzothiazepine derivatives. We present three cases from the Provincial Toxicology Center of British Columbia, Canada in which suicidal overdose deaths were associated with quetiapine. The blood specimens were initially subjected to a thorough qualitative analysis. Basic drugs were screened for by liquid-liquid extraction followed by gas chromatography-nitrogen-phosphorus (GC-NPD) and gas chromatography-mass spectrometry-electron impact detection utilizing both in-house and commercial search libraries. Acidic and neutral drugs were screened for by liquid-liquid extraction followed by high-performance liquid chromatography-diode-array detection. Volatiles were assayed by gas chromatography-flame-ionization detection. Quetiapine was assayed in biological specimens by basic extraction with n-butyl chloride and derivatized with 50 microL of MTBSTFA and separation by GC-NPD. Linearity was observed up to 2.0 mg/L. Samples with concentrations exceeding the linearity were diluted. These cases were chosen for study because they were all deaths as a result of suicidal ingestion of drugs in which quetiapine was considered a significant factor. The concentrations of quetiapine in these cases are 6-16 times greater than the upper reported therapeutic range (0.1-1.0 mg/L). In case #1, the concentrations of quetiapine found were 7.20 mg/L (19 micromol/L) in blood and 0.93 mg/L (2.4 micromol/L) in vitreous fluid. In case #2, the concentrations of quetiapine found were 16 mg/L in blood (42 micromol/L), 120 mg/kg (310 micromol/kg) in liver, and 1.8 mg/L (4.6 micromol/L) in vitreous fluid. In case #3, the concentrations of quetiapine found in femoral blood was 5.90 mg/L (15 micromol/L). In all cases, drugs in addition to quetiapine were detected, but in cases #1 and #2, the cause of death was considered to be a quetiapine overdose and the other drugs were not considered to be contributory

  19. Late Brain Recovery Processes after Drug Overdose

    PubMed Central

    Haider, Ijaz; Oswald, Ian

    1970-01-01

    Though recovery of consciousness after drug overdose may occur within a day or two, the drug itself may not finally leave the brain for another one to three weeks, and at this late time a withdrawal syndrome can occur, with insomnia, restlessness, raised paradoxical (R.E.M.) sleep, epileptic phenomena, and even delirium. It is proposed that a high degree of drug-tolerance and dependence can be rapidly acquired after overdose. Abnormal sleep features of 10 patients resolved only slowly over a period of up to two months after overdose. The data support the view that R.E.M. sleep is concerned with processes of brain repair. PMID:4317051

  20. Lidocaine overdose: another preventable case?

    PubMed

    Gonzalez del Rey, J; Wason, S; Druckenbrod, R W

    1994-12-01

    Physicians who prescribe viscous lidocaine preparations should be aware of the adverse effects and the high risk for overdose in pediatric patients. Owing to altered pharmacokinetics (increased absorption, decreased clearance, and prolonged half-life), doses that are innocuous for adults may present a significant potential toxic hazard in children. Lidocaine should not be used to treat painful mouth lesions in children until further safety data are available. Benzocaine may be considered as a safe alternative to lidocaine. Its low incidence of side effects makes it a safer choice for infants and children. If no other choices are appropriate, then very specific instructions should be given to parents. The amount, frequency, maximum daily dose, and mode of administration should be clearly communicated (eg, cotton pledget to individual lesions, one-half dropper to each cheek every four hours, or 20 minutes before meals). They should never be prescribed on a "PRN" basis.

  1. Trimebutine: abuse, addiction and overdose.

    PubMed

    2013-10-01

    Trimebutine, an antispasmodic drug, is used to relieve pain associated with irritable bowel syndrome, despite a lack of proven efficacy. Trimebutine has been shown to act on peripheral opioid receptors. Cases of trimebutine abuse and addiction have been reported in young adults, especially with the injectable form. Cases of serious accidental or intentional trimebutine overdose have been reported in infants and young adults, leading to neurological disorders (loss of consciousness, coma, drowsiness and convulsions) and cardiac disorders (bradycardia, ventricular tachycardia, arterial hypertension). Time to symptom onset was less than 3 hours after trimebutine intake. In practice, trimebutine is by no means a harmless drug, contrary to the impression given by the limited safety data available. Patients with pain due to irritable bowel syndrome should be informed of the adverse effects of trimebutine, and the harm-benefit balance should be reassessed in patients already taking this drug. PMID:24298588

  2. High-Throughput Cytotoxicity Testing System of Acetaminophen Using a Microfluidic Device (MFD) in HepG2 Cells.

    PubMed

    Ju, Seon Min; Jang, Hyun-Jun; Kim, Kyu-Bong; Kim, Jeongyun

    2015-01-01

    A lab-on-a-chip (LOC) is a microfluidic device (MFD) that integrates several lab functions into a single chip of only millimeters in size. LOC provides several advantages, such as low fluidic volumes consumption, faster analysis, compactness, and massive parallelization. These properties enable a microfluidic-based high-throughput drug screening (HTDS) system to acquire cell-based abundant cytotoxicity results depending on linear gradient concentration of drug with only few hundreds of microliters of the drug. Therefore, a microfluidic device was developed containing an array of eight separate microchambers for cultivating HepG2 cells to be exposed to eight different concentrations of acetaminophen (APAP) through a diffusive-mixing-based concentration gradient generator. Every chamber array with eight different concentrations (0, 5.7, 11.4, 17.1, 22.8, 28.5, 34.2, or 40 mM) APAP had four replicating cell culture chambers. Consequently, 32 experimental results were acquired with a single microfluidic device experiment. The microfluidic high-throughput cytotoxicity device (μHTCD) and 96-well culture system showed comparable cytotoxicity results with increasing APAP concentration of 0 to 40 mM. The HTDS system yields progressive concentration-dependent cytotoxicity results using minimal reagent and time. Data suggest that the HTDS system may be applicable as alternative method for cytotoxicity screening for new drugs in diverse cell types. PMID:26241707

  3. Moringa oleifera hydroethanolic extracts effectively alleviate acetaminophen-induced hepatotoxicity in experimental rats through their antioxidant nature.

    PubMed

    Fakurazi, Sharida; Sharifudin, Syazana Akmal; Arulselvan, Palanisamy

    2012-01-01

    The aim of the study was to investigate the in vitro antioxidant properties Moringa oleifera Lam. (MO) extracts and its curative role in acetaminophen (APAP)-induced toxic liver injury in rats caused by oxidative damage. The total phenolic content and antioxidant properties of hydroethanolic extracts of different MO edible parts were investigated by employing an established in vitro biological assay. In the antihepatotoxic study, either flowers or leaves extract (200 mg/kg or 400 mg/kg, i.p) were administered an hour after APAP administration, respectively. N-Acetylcysteine was used as the positive control against APAP-induced hepatotoxicity. The levels of liver markers such as alanine aminotransferase (ALT) and the levels of oxidative damage markers including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) protein adduct, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were analysed and compared between experimental groups. Among MO edible parts the flower extracts contain the highest total phenolic content and antioxidant capacity, followed by leaves extract. The oxidative marker MDA, as well as 4-HNE protein adduct levels were elevated and GSH, SOD and CAT were significantly decreased in groups treated with hepatotoxin. The biochemical liver tissue oxidative markers measured in the rats treated with MO flowers and leaves hydroethanolic extracts showed a significant (p < 0.05) reduction in the severity of the liver damage. The results of this study strongly indicate the therapeutic properties of MO hydroethanolic extracts against acute liver injury and thereby scientifically support its traditional use. PMID:22781444

  4. Moringa oleifera hydroethanolic extracts effectively alleviate acetaminophen-induced hepatotoxicity in experimental rats through their antioxidant nature.

    PubMed

    Fakurazi, Sharida; Sharifudin, Syazana Akmal; Arulselvan, Palanisamy

    2012-07-10

    The aim of the study was to investigate the in vitro antioxidant properties Moringa oleifera Lam. (MO) extracts and its curative role in acetaminophen (APAP)-induced toxic liver injury in rats caused by oxidative damage. The total phenolic content and antioxidant properties of hydroethanolic extracts of different MO edible parts were investigated by employing an established in vitro biological assay. In the antihepatotoxic study, either flowers or leaves extract (200 mg/kg or 400 mg/kg, i.p) were administered an hour after APAP administration, respectively. N-Acetylcysteine was used as the positive control against APAP-induced hepatotoxicity. The levels of liver markers such as alanine aminotransferase (ALT) and the levels of oxidative damage markers including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) protein adduct, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were analysed and compared between experimental groups. Among MO edible parts the flower extracts contain the highest total phenolic content and antioxidant capacity, followed by leaves extract. The oxidative marker MDA, as well as 4-HNE protein adduct levels were elevated and GSH, SOD and CAT were significantly decreased in groups treated with hepatotoxin. The biochemical liver tissue oxidative markers measured in the rats treated with MO flowers and leaves hydroethanolic extracts showed a significant (p < 0.05) reduction in the severity of the liver damage. The results of this study strongly indicate the therapeutic properties of MO hydroethanolic extracts against acute liver injury and thereby scientifically support its traditional use.

  5. Flavokawains A and B in Kava, Not Dihydromethysticin, Potentiate Acetaminophen-Induced Hepatotoxicity in C57BL/6 Mice

    PubMed Central

    2015-01-01

    Anxiolytic kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer kava product and limits its beneficial applications. In this study we evaluated the toxicity of kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstrate the hepatotoxic risk of kava and its chalcone-based FKA and FKB in vivo and suggest that herb–drug interaction may account for the rare hepatotoxicity associated with anxiolytic kava usage in humans. PMID:25185080

  6. Injection drug users trained by overdose prevention programs: Responses to witnessed overdoses

    PubMed Central

    Lankenau, Stephen E.; Wagner, Karla D.; Silva, Karol; Kecojevic, Aleksander; Iverson, Ellen; McNeely, Miles; Kral, Alex H.

    2012-01-01

    In response to the growing public health problem of drug overdose, community-based organizations have initiated overdose prevention programs (OPP), which distribute naloxone, an opioid antagonist, and teach overdose response techniques. Injection drug users (IDUs) have been targeted for this intervention due to their high risk for drug overdose. Limited research attention has focused on factors that may inhibit or prevent IDUs who have been trained by OPPs to undertake recommended response techniques when responding to a drug overdose. IDUs (n=30) trained by two OPPs in Los Angeles were interviewed in 2010–11 about responses to their most recently witnessed drug overdose using an instrument containing both open and closed-ended questions. Among the 30 witnessed overdose events, the victim recovered in 29 cases while the outcome was unknown in one case. Participants responded to overdoses using a variety of techniques taught by OPP. Injecting the victim with naloxone was the most common recommended response while other recommended responses included stimulating the victim with knuckles, calling 911, and giving rescue breathing. Barriers preventing participants from employing recommended response techniques in certain circumstances included prior successes using folk remedies to revive a victim, concerns over attracting police to the scene, and issues surrounding access to or use of naloxone. Practical solutions, such as developing booster sessions to augment OPP, are encouraged to increase the likelihood that trained participants respond to a drug overdose with the full range of recommended techniques. PMID:22847602

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

    SciTech Connect

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

    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.

  8. Opioids: The Prescription Drug & Heroin Overdose Epidemic

    MedlinePlus

    ... Resources Law Enforcement Resources Opioids: The Prescription Drug & Heroin Overdose Epidemic Opioids are natural or synthetic chemicals ... in your brain or body. Common opioids include heroin and prescription drugs such as oxycodone, hydrocodone, and ...

  9. Acute liver failure following cleft palate repair: a case of therapeutic acetaminophen toxicity.

    PubMed

    Iorio, Matthew L; Cheerharan, Meera; Kaufman, Stuart S; Reece-Stremtan, Sarah; Boyajian, Michael

    2013-11-01

    Background : Acetaminophen is a widely used analgesic and antipyretic agent in the pediatric population. While the hepatotoxic effects of the drug have been well recognized in cases of acute overdose and chronic supratherapeutic doses, the toxic effects of acetaminophen are rarely documented in cases where therapeutic guidelines are followed. Case : An 8-month-old boy underwent cleft palate repair and placement of bilateral myringotomy tubes. His anesthetic course was uneventful, consisting of maintenance with desflurane and fentanyl. He received acetaminophen for routine postoperative pain management and was tolerating liquids and discharged home on postoperative day 1. On day 3, the child was profoundly lethargic with multiple episodes of emesis and was taken to the emergency department. He suffered a 45-second tonic-clonic seizure in transport to the regional children's medical center, and initial laboratory results demonstrated acute hepatitis with AST 24,424 U/L, ALT 12,885 U/L, total bilirubin 3.1 mg/dL, and a serum acetaminophen level of 83 μg/mL. Aggressive supportive measures including blood products and periprocedural fresh frozen plasma, piperacillin/tazobactam, and intravenous infusions of N-acetylcysteine, sodium phenylacetate and sodium benzoate, carnitine, and citrulline were administered. His metabolic acidosis and acute hepatitis began to correct by day 4, and he was discharged home without further surgical intervention on day 15. Conclusion : Although acetaminophen is an effective and commonly used analgesic in pediatric practice, hepatotoxicity is a potentially devastating complication. This report challenges the appropriateness of existing guidelines for acetaminophen administration and emphasizes the importance of close follow-up and hydration after even relatively minor surgery.

  10. Fulminate Hepatic Failure in a 5 Year Old Female after Inappropriate Acetaminophen Treatment

    PubMed Central

    Kasmi, Irena; Sallabanda, Sashenka; Kasmi, Gentian

    2015-01-01

    BACKGROUND: Acetaminophen is a drug widely used in children because of its safety and efficacy. Although the risk of its toxicity is lower in children such reactions occur in pediatric patients from intentional overdoses and less frequently attributable to unintended inappropriate dosing. The aim of reporting this case is to attract the attention to the risk of the acetaminophen toxicity when administered in high doses. CASE PRESENTATION: We report here a 5 year old girl who developed fulminate liver failure with renal impairment and acute pancreatitis, as a result of acetaminophen toxicity caused from unintentional repeated supratherapeutic ingestion, with a total administered dose of 4800 mg in three consecutive days, 1600 mg/day, approximately 90 mg/kg/day. The blood level of acetaminophen after 10 hours of the last administered dose was 32 mg/l. The patient presented with high fever, jaundice, lethargic, agitating with abdominal pain accompanied by encephalopathy. The liver function test revealed with high level of alanine aminotransferase 5794 UI/l and aspartate aminotransferase 6000 UI/l. Early initiation of oral N-acetylcysteine (NAC) after biochemical evidence of liver toxicity was beneficial with rapid improvement of liver enzymes, hepatic function and encephalopathy. During the course of the illness the child developed acute pancreatitis with hyperamylasemia 255 UI/L and hyperlypasemia 514 UI/L. Patient totally recovered within 29 days. 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. PMID:27275268

  11. Pharmacokinetics of acetaminophen in children.

    PubMed

    Peterson, R G; Rumack, B H

    1978-11-01

    Acetaminophen absorption may occur at a somewhat greater rate in children if the syrup form is utilized. The overall plasma elimination of acetaminophen is somewhat slow in the neonate, but is comparable to that of adults in both children and adolescents, as judged by half-life determinations. This would suggest that the frequency of acetaminophen administration in children should be similar to the schedule recommended for adults and that a dosing interval of four hours should not result in drug accumulation. The question of a toxic quantity of acetaminophen for young children must remain open until adequate metabolic or retrospective toxicologic data become known. Since the volumes of distribution appear to be the same in both adults and children, the same dose should apply in both groups; currently, 10 mg/kg is considered to be both safe and effective for antipyresis. PMID:364399

  12. Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity.

    PubMed Central

    Roberts, D. W.; Bucci, T. J.; Benson, R. W.; Warbritton, A. R.; McRae, T. A.; Pumford, N. R.; Hinson, J. A.

    1991-01-01

    Acetaminophen overdose causes severe hepatotoxicity in humans and laboratory animals, presumably by metabolism to N-acetyl-p-benzoquinone imine: and binding to cysteine groups as 3-(cystein-S-yl)acetaminophen-protein adduct. Antiserum specific for the adduct was used immunohistochemically to demonstrate the formation, distribution, and concentration of this specific adduct in livers of treated mice and was correlated with cell injury as a function of dose and time. Within the liver lobule, immunohistochemically demonstrable adduct occurred in a temporally progressive, central-to-peripheral pattern. There was concordance between immunohistochemical staining and quantification of the adduct in hepatic 10,000g supernate, using a quantitative particle concentration fluorescence immunoassay. Findings include: 1) immunochemically detectable adduct before the appearance of centrilobular necrosis, 2) distinctive lobular zones of adduct localization with subsequent depletion during the progression of toxicity, 3) drug-protein binding in hepatocytes at subhepatotoxic doses and before depletion of total hepatic glutathione, 4) immunohistochemical evidence of drug binding in the nucleus, and 5) adduct in metabolically active and dividing hepatocytes and in macrophagelike cells in the regenerating liver. Images Figure 2 Figure 4 PMID:1992763

  13. Nitric oxide releasing acetaminophen (nitroacetaminophen).

    PubMed

    Moore, P K; Marshall, M

    2003-05-01

    The nitric oxide releasing derivative of acetaminophen (nitroacetaminophen) exhibits potent anti-inflammatory and anti-nociceptive activity in a variety of animal models. On a mol for mol basis nitroacetaminophen is some 3-20 times more potent than acetaminophen. Nitroacetaminophen exhibits little or no hepatotoxicity following administration in rat or mouse and indeed protects against the hepatotoxic activity of acetaminophen. Nitroacetaminophen does not affect blood pressure or heart rate of anaesthetised rats but has similar potency to acetaminophen as an anti-pyretic agent. The enhanced anti-inflammatory and anti-nociceptive activity of nitroacetaminophen and the reduced hepatotoxicity in these animal models is likely to be secondary to the slow release of nitric oxide from the molecule. As yet the precise molecular mechanism(s) underlying these actions of nitroacetaminophen are not clear. Evidence for inhibition of cytokine-directed formation of pro-inflammatory molecule production (e.g. COX-2, iNOS) by an effect on the NF-kappaB transduction system and/or nitrosylation (and thence inhibition) of caspase enzyme activity has been reported. Data described in this review indicate that the profile of pharmacological activity of nitroacetaminophen and acetaminophen are markedly different. The possibility that nitroacetaminophen could be an attractive alternative to acetaminophen in the clinic is discussed. PMID:12846444

  14. Investigation of acetaminophen toxicity in HepG2/C3a microscale cultures using a system biology model of glutathione depletion.

    PubMed

    Leclerc, Eric; Hamon, Jeremy; Claude, Isabelle; Jellali, Rachid; Naudot, Marie; Bois, Frederic

    2015-06-01

    We have integrated in vitro and in silico information to investigate acetaminophen (APAP) and its metabolite N-acetyl-p-benzoquinone imine (NAPQI) toxicity in liver biochip. In previous works, we observed higher cytotoxicity of HepG2/C3a cultivated in biochips when exposed to 1 mM of APAP for 72 h as compared to Petri cultures. We complete our investigation with the present in silico approach to extend the mechanistic interpretation of the intracellular kinetics of the toxicity process. For that purpose, we propose a mathematical model based on the coupling of a drug pharmacokinetic model (PK) with a systemic biology model (SB) describing the reactive oxygen species (ROS) production by NAPQI and the subsequent glutathione (GSH) depletion. The SB model was parameterized using (i) transcriptomic data, (ii) qualitative results of time lapses ROS fluorescent curves for both control and 1-mM APAP-treated experiments, and (iii) additional GSH literature data. The PK model was parameterized (i) using the in vitro kinetic data (at 160 μM, 1 mM, 10 mM), (ii) using the parameters resulting from a physiologically based pharmacokinetic (PBPK) literature model for APAP, and (iii) by literature data describing NAPQI formation. The PK-SB model predicted a ROS increase and GSH depletion due to the NAPQI formation. The transition from a detoxification phase and NAPQI and ROS accumulation was predicted for a NAPQI concentration ranging between 0.025 and 0.25 μM in the cytosol. In parallel, we performed a dose response analysis in biochips that shows a reduction of the final hepatic cell number appeared in agreement with the time and doses associated with the switch of the NAPQI detoxification/accumulation. As a result, we were able to correlate in vitro extracellular APAP exposures with an intracellular in silico ROS accumulation using an integration of a coupled mathematical and experimental liver on chip approach.

  15. Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems.

    PubMed

    Rodrigues, Robim M; Heymans, Anja; De Boe, Veerle; Sachinidis, Agapios; Chaudhari, Umesh; Govaere, Olivier; Roskams, Tania; Vanhaecke, Tamara; Rogiers, Vera; De Kock, Joery

    2016-01-01

    Primary human hepatocytes (hHEP), human HepaRG and HepG2 cell lines are the most used human liver-based in vitro models for hepatotoxicity testing, including screening of drug-induced liver injury (DILI)-inducing compounds. hHEP are the reference hepatic in vitro system, but their availability is limited and the cells available for toxicology studies are often of poor quality. Hepatic cell lines on the other hand are highly proliferative and represent an inexhaustible hepatic cell source. However, these hepatoma-derived cells do not represent the population diversity and display reduced hepatic metabolism. Alternatively, stem cell-derived hepatic cells, which can be produced in high numbers and can differentiate into multiple cell lineages, are also being evaluated as a cell source for in vitro hepatotoxicity studies. Human skin-derived precursors (hSKP) are post-natal stem cells that, after conversion towards hepatic cells (hSKP-HPC), respond to hepatotoxic compounds in a comparable way as hHEP. In the current study, four different human hepatic cell systems (hSKP-HPC, hHEP, HepaRG and HepG2) are evaluated for their capacity to predict hepatic toxicity. Their hepatotoxic response to acetaminophen (APAP) exposure is compared to data obtained from patients suffering from APAP-induced acute liver failure (ALF). The results indicate that hHEP, HepaRG and hSKP-HPC identify comparable APAP-induced hepatotoxic functions and that HepG2 cells show the slightest hepatotoxic response. Pathway analyses further points out that HepaRG cells show the highest predicted activation of the functional genes related to 'damage of liver', followed by hSKP-HPC and hHEP cells that generated similar results. HepG2 did not show any activation of this function. PMID:26497421

  16. Know Concentration Before Giving Acetaminophen to Infants

    MedlinePlus

    ... urging consumers to carefully read the labels of liquid acetaminophen marketed for infants to avoid giving the ... less concentrated version for all children. Until now, liquid acetaminophen marketed for infants has only been available ...

  17. Toxicity Thresholds for Diclofenac, Acetaminophen and Ibuprofen in the Water Flea Daphnia magna.

    PubMed

    Du, Juan; Mei, Cheng-Fang; Ying, Guang-Guo; Xu, Mei-Ying

    2016-07-01

    Non-steroid anti-inflammatory drugs (NSAIDs) have been frequently detected in aquatic ecosystem and posed a huge risk to non-target organisms. The aim of this study was to evaluate the toxic effects of three typical NSAIDs, diclofenac (DFC), acetaminophen (APAP) and ibuprofen (IBP), toward the water flea Daphnia magna. All three NSAIDs showed remarkable time-dependent and concentration-dependent effects on D. magna, with DFC the highest and APAP the lowest toxic. Survival, growth and reproduction data of D. magna from all bioassays were used to determine the LC10 and LC50 (10 % lethal and median lethal concentrations) values of NSAIDs, as well as the EC10 and EC50 (10 % effect and median effect concentrations) values. Concentrations for the lethal and sublethal toxicity endpoints were mainly in the low ppm-range, of which reproduction was the most sensitive one, indicating that non-target organisms might be adversely affected by relevant ambient low-level concentrations of NSAIDs after long-time exposures. PMID:27098253

  18. Solid dispersion of acetaminophen and poly(ethylene oxide) prepared by hot-melt mixing.

    PubMed

    Yang, Min; Wang, Peng; Huang, Chien-Yueh; Ku, M Sherry; Liu, Huiju; Gogos, Costas

    2010-08-16

    In this study, a model drug, acetaminophen (APAP), was melt mixed with poly(ethylene oxide) (PEO) using a Brabender mixer. APAP was found to recrystallize upon cooling to room temperature for all the drug loadings investigated. Higher drug loading leads to faster recrystallization rate. However, the morphology of the recrystallized drug crystals is identical in samples with different drug loadings and does not change with the storage time. To adjust the drug's dissolution rate, nanoclay Cloisite 15A and 30B were added into the binary mixture. The presence of either of the nanoclay dramatically accelerates the drug's recrystallization rate and slows down the drug's releasing rate. The drop of the releasing rate is mainly due to the decrease of wettability, as supported by the contact angle data. Data analysis of the dissolution results suggests that the addition of nanoclays changes the drug's release mechanism from erosion dominant to diffusion dominant. This study suggests that nanoclays may be utilized to tailor the drug's releasing rate and to improve the dosage form's stability by dramatically shortening the lengthy recrystallization process. PMID:20435110

  19. Solid dispersion of acetaminophen and poly(ethylene oxide) prepared by hot-melt mixing.

    PubMed

    Yang, Min; Wang, Peng; Huang, Chien-Yueh; Ku, M Sherry; Liu, Huiju; Gogos, Costas

    2010-08-16

    In this study, a model drug, acetaminophen (APAP), was melt mixed with poly(ethylene oxide) (PEO) using a Brabender mixer. APAP was found to recrystallize upon cooling to room temperature for all the drug loadings investigated. Higher drug loading leads to faster recrystallization rate. However, the morphology of the recrystallized drug crystals is identical in samples with different drug loadings and does not change with the storage time. To adjust the drug's dissolution rate, nanoclay Cloisite 15A and 30B were added into the binary mixture. The presence of either of the nanoclay dramatically accelerates the drug's recrystallization rate and slows down the drug's releasing rate. The drop of the releasing rate is mainly due to the decrease of wettability, as supported by the contact angle data. Data analysis of the dissolution results suggests that the addition of nanoclays changes the drug's release mechanism from erosion dominant to diffusion dominant. This study suggests that nanoclays may be utilized to tailor the drug's releasing rate and to improve the dosage form's stability by dramatically shortening the lengthy recrystallization process.

  20. Unique mechanism of facile polymorphic conversion of acetaminophen in aqueous medium.

    PubMed

    Gao, Yi; Olsen, Kenneth W

    2014-09-01

    Rapid polymorphic conversion of acetaminophen (APAP) in solution, from metastable orthorhombic Form II to the stable monoclinic Form I, is well-known. The mechanism is believed to be solution-mediated phase transformation (SMPT), but with little experimental evidence. The present study was undertaken to understand this phenomenon from both thermodynamic and kinetic perspectives. Reliable apparent solubility of Form II was measured, for the first time, in 0.15 M aqueous NaCl solution at 37 °C. The solubility ratio of Form II over Form I, 1.27 ± 0.04, is quite low, which translates to a relatively low thermodynamic driving force for the conversion. Further solution crystallization experiments at supersaturation levels equal to or much greater than Form II solubility did not result in any crystallization in 10 days. Therefore, fast conversion is not possible through SMPT. To explore alternative mechanisms, molecular dynamics (MD) simulations were conducted to investigate the molecular level dissolution behavior and the solid state differences between the two polymorphs. The MD simulations reveal very different behavior. Form II exhibits a much higher rate of H-bond breakage, leading to the accumulation of a large number of disordered APAP molecules on the crystal surface. This thick disordered molecular layer provides a high local acetaminophen concentration which could be responsible for the fast crystallization of Form I. This was further supported by the observations made, using polarized light microscopy and powder X-ray diffractometry, when monitoring Form II crystals coming into contact with NaCl solution. We thus concluded that the hydrated surface layer is the "catalyst" for the facile phase conversion. This new mechanism, termed as SurFPT (surface-facilitated phase transformation), is much more effective in promoting polymorphic transformation than the well-known SMPT.

  1. Magnetic beads as an extraction medium for simultaneous quantification of acetaminophen and structurally related compounds in human serum.

    PubMed

    Bylda, Caroline; Velichkova, Vanya; Bolle, Jens; Thiele, Roland; Kobold, Uwe; Volmer, Dietrich A

    2015-06-01

    This paper describes a sample preparation method that complements a previously published liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for acetaminophen and eight structurally-related compounds in human serum (C. Bylda, R. Thiele, U. Kobold, D.A. Volmer. Drug Test. Anal. 2014, 6, 451). The analytes (acetaminophen [APAP] + metabolites acetaminophen-glucuronide [APG], -cysteine [APC], -mercapturate [APM] and -cysteine [APC], structurally similar analogues phenacetin and p-phenetidine, as well as tricyclic antidepressants imipramine and amitryptiline) were extracted from serum using magnetized hyper-crosslinked polystyrene particles. The sample preparation protocol was developed by means of a design of experiments (DoE) statistical approach. Using three representative compounds from the analyte panel with different polarities (high, medium, and low), two screening designs were used to identify factors that exhibited significant impact on recovery of the analytes. These parameters were then optimized to permit extraction of the complete target panel exhibiting a broad range of chemical polarities. Liquid chromatographic separations were achieved by gradient elution using a pentafluorphenyl column with subsequent detection by electrospray ionization-triple quadrupole mass spectrometry in multiple reaction monitoring (MRM) mode. The method was linear over the range 0.1-100 µg/mL for APAP, APG, p-phenetidine and phenacetin, 0.03-50 µg/mL for APS, and 0.01-10 µg/mL for APM, APC, imipramine and amitriptyline, with R(2)  > 0.99. The assay exhibited good precision with CVs ranging from 2 to 9% for all analytes; the accuracy was assessed by comparing two LC-MS/MS methods using a set of 68 patient samples.

  2. Improving Heart rate variability in sleep apnea patients: differences in treatment with auto-titrating positive airway pressure (APAP) versus conventional CPAP.

    PubMed

    Karasulu, Levent; Epöztürk, Pinar Ozkan; Sökücü, Sinem Nedime; Dalar, Levent; Altin, Sedat

    2010-08-01

    The effect of positive airway pressure treatments in different modalities on the cardiovascular consequences of the disease in sleep apnea patients is still unclear. We aimed to compare auto-titrating positive airway pressure (APAP) and conventional continuous positive airway pressure (CPAP) in terms of improving heart rate variability (HRV) in obstructive sleep apnea patients. This was a prospective study done in a tertiary research hospital. All patients underwent a manual CPAP titration procedure to determine the optimal pressure that abolishes abnormal respiratory events. Then patients underwent two treatment nights, one under APAP mode and one under conventional CPAP mode with a 1-week interval. Forty newly diagnosed obstructive sleep apnea patients were enrolled in the study. We compared heart rate variability analysis parameters between the APAP night and the CPAP night. This final analysis included the data of 28 patients (M/F: 22/6; mean age = 46 +/- 10 years). Sleep characteristics were comparable between the two treatment nights, whereas all-night time domains of HRV analysis such as HF, nuLF, and LF/HF were different between APAP and CPAP nights (2.93 +/- 0.31 vs. 3.01 +/- 0.31; P = 0.041; 0.75 +/- 0.13 vs. 0.71 +/- 0.14; P = 0.027; and 4.37 +/- 3.24 vs. 3.56 +/- 2.07; P = 0.023, respectively). HRV analysis for individual sleep stages showed that Stage 2 LF, nuLF, nuHF, LF/HF parameters entirely improved under CPAP treatment whereas APAP treatment resulted in nonsignificant changes. These results suggest that despite comparable improvement in abnormal respiratory events with APAP or CPAP treatments, CPAP may be superior to APAP in terms of correcting cardiovascular alterations in sleep apnea patients.

  3. Drug Monitoring Programs Do Curb Overdose Deaths: Study

    MedlinePlus

    ... html Drug Monitoring Programs Do Curb Overdose Deaths: Study Opioid epidemic demands such measures, researcher says To ... deaths from prescription painkillers called opioids, a new study finds. In an effort to curb overdose deaths ...

  4. The treatment of acetaminophen poisoning

    SciTech Connect

    Prescott, L.F.; Critchley, J.A.

    1983-01-01

    Acetaminophen has become a very popular over-the-counter analgesic in some countries and as a result it is used increasingly as an agent for self-poisoning. Without treatment only a minority of patients develop severe liver damage and 1 to 2% die in hepatic failure. Until Mitchell and his colleagues discovered the biochemical mechanisms of toxicity in 1973 there was no effective treatment. They showed that the metabolic activation of acetaminophen resulted in the formation of a reactive arylating intermediate, and that hepatic reduced glutathione played an essential protective role by preferential conjugation and inactivation of the metabolite. Early treatment with sulphydryl compounds and glutathione precursors has been dramatically effective in preventing liver damage, renal failure, and death following acetaminophen overdosage. It seems likely that these agents act primarily by stimulating glutathione synthesis. Inhibition of the metabolic activation of acetaminophen is another potential therapeutic approach that has not yet been put to the test clinically. The clinical management of acetaminophen poisoning has been transformed and it is particularly gratifying to have effective treatment based on a well established biochemical mechanism of toxicity. It is likely that effective treatment will be developed for toxicity caused through similar mechanisms by other agents.

  5. Intravenous paracetamol (acetaminophen).

    PubMed

    Duggan, Sean T; Scott, Lesley J

    2009-01-01

    Intravenous paracetamol (rINN)/intravenous acetaminophen (USAN) is an analgesic and antipyretic agent, recommended worldwide as a first-line agent for the treatment of pain and fever in adults and children. In double-blind clinical trials, single or multiple doses of intravenous paracetamol 1 g generally provided significantly better analgesic efficacy than placebo treatment (as determined by primary efficacy endpoints) in adult patients who had undergone dental, orthopaedic or gynaecological surgery. Furthermore, where evaluated, intravenous paracetamol 1 g generally showed similar analgesic efficacy to a bioequivalent dose of propacetamol, and a reduced need for opioid rescue medication. In paediatric surgical patients, recommended doses of intravenous paracetamol 15 mg/kg were not significantly different from propacetamol 30 mg/kg for the treatment of pain, and showed equivocal analgesic efficacy compared with intramuscular pethidine 1 mg/kg in several randomized, active comparator-controlled studies. In a randomized, noninferiority study in paediatric patients with an infection-induced fever, intravenous paracetamol 15 mg/kg treatment was shown to be no less effective than propacetamol 30 mg/kg in terms of antipyretic efficacy. Intravenous paracetamol was well tolerated in clinical trials, having a tolerability profile similar to placebo. Additionally, adverse reactions emerging from the use of the intravenous formulation of paracetamol are extremely rare (<1/10 000). [table: see text]. PMID:19192939

  6. Wide complex tachycardia after bupropion overdose.

    PubMed

    Franco, Vanessa

    2015-10-01

    Here we describe a wide complex tachycardia after bupropion overdose that was responsive to sodium bicarbonate. This rhythm was likely secondary to bupropion-induced sodium channel blockade and corrected QT interval (QTc) prolongation. It is critical for the emergency medicine physician to recognize that a wide complex rhythm in a patient with bupropion overdose may be secondary to sodium channel toxicity and prolonged QTc as this rhythm may be responsive to sodium bicarbonate. Identifying this rhythm as purely ventricular tachycardia can lead to the administration of medications such as amiodarone that may further prolong QTc and contribute to sodium channel blockade, exacerbating bupropion-induced cardiotoxicity.

  7. Acetaminophen injection: a review of clinical information.

    PubMed

    Jones, Virginia M

    2011-01-01

    Acetaminophen injection is an antipyretic and analgesic agent recently marketed in the United States as Ofirmev. Five published trials directly compare acetaminophen injection to drugs available in the United States. For management of pain in adults, acetaminophen injection was at least as effective as morphine injection in renal colic, oral ibuprofen after cesarean delivery, and oral acetaminophen after coronary artery bypass surgery. In children (3 to 16 years old), single-dose acetaminophen injection was similar to meperidine intramuscular (i.m.) for pain after tonsillectomy; readiness for discharge from the recovery room was shorter with acetaminophen injection (median 15 minutes) compared with meperidine i.m. (median 25 minutes), P = .005. In children (2 to 5 years old) postoperative adenotonsillectomy or adenoidectomy, the time to rescue analgesia was superior with high-dose acetaminophen rectal suppository (median 10 hours) compared with acetaminophen injection (median 7 hours), P = .01. One published trial demonstrated acetaminophen injection is noninferior to propacetamol injection for fever related to infection in pediatric patients. Dosing adjustments are not required when switching between oral and injectable acetaminophen formulations in adult and adolescent patients. Acetaminophen injection represents another agent for multimodal pain management. PMID:21936636

  8. Personal social network factors associated with overdose prevention training participation.

    PubMed

    Wagner, Karla D; Iverson, Ellen; Wong, Carolyn F; Bloom, Jennifer Jackson; McNeeley, Miles; Davidson, Peter J; McCarty, Christopher; Kral, Alex H; Lankenau, Stephen E

    2013-01-01

    We investigated social network factors associated with participation in overdose prevention training among injection drug users (IDUs). From 2008 to 2010, 106 IDUs who had witnessed an overdose in the past year from two syringe exchange programs in Los Angeles provided data on overdose prevention training status (trained vs. untrained), social networks, history of overdose, and demographics. In multivariate logistic regression, naming at least one network member who had been trained in overdose prevention was significantly associated with being trained (Adjusted Odds Ratio 3.25, 95% Confidence Interval 1.09, 9.68). Using social network approaches may help increase training participation. Limitations are noted.

  9. Personal Social Network Factors Associated with Overdose Prevention Training Participation

    PubMed Central

    Iverson, Ellen; Wong, Carolyn F.; Jackson-Bloom, Jennifer; McNeeley, Miles; Davidson, Peter J.; McCarty, Christopher; Kral, Alex H.; Lankenau, Stephen E.

    2013-01-01

    We investigated social network factors associated with participation in overdose prevention training among injection drug users (IDUs). From 2008-2010, 106 IDUs who had witnessed an overdose in the past year from two syringe exchange programs in Los Angeles provided data on: overdose prevention training status (trained vs. untrained), social networks, history of overdose, and demographics. In multivariate logistic regression, naming at least one network member who had been trained in overdose prevention was significantly associated with being trained (Adjusted Odds Ratio 3.25, 95% Confidence Interval 1.09, 9.68). Using social network approaches may help increase training participation. Limitations are noted. PMID:22988840

  10. Metabolomics analysis of the toxicity pathways of triphenyl phosphate in HepaRG cells and comparison to oxidative stress mechanisms caused by acetaminophen.

    PubMed

    Van den Eede, Nele; Cuykx, Matthias; Rodrigues, Robim M; Laukens, Kris; Neels, Hugo; Covaci, Adrian; Vanhaecke, Tamara

    2015-12-01

    Since the publication of REACH guidelines, the need for in vitro tools for toxicity testing has increased. We present here the development of a hepatotoxicity testing tool using human HepaRG cell cultures and metabolomics. HepaRG cells were exposed to either 4mM acetaminophen (APAP) as reference toxicant for oxidative stress or 50 μM triphenyl phosphate (TPHP) as toxicant with unknown toxicity pathways (TPs). After 72 h exposure, cells were subjected to quenching and liquid-liquid extraction which resulted in a polar and an apolar fraction. Analysis of fractions was performed by ultrahigh performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-QTOF-MS). Significantly up or down regulated metabolites were selected by univariate statistics prior to identification. In order to obtain robust and specific TP biomarkers, the experiment was also repeated using a different culture medium composition to assess which metabolites show consistent changes. Potential biomarkers belonging to different TPs were found for APAP and TPHP. For APAP, the biomarkers were related to a decrease in unsaturated phospholipids, and for TPHP to an accumulation of phosphoglycerolipids and increase of palmitoyl lysophosphatidylcholine. This first proof-of-concept opens new perspectives for the analysis of other (reference) toxicants with different TPs and it can be used to expand the in vitro tool for hepatotoxicity screening of various compounds. PMID:26318275

  11. Metabolomics analysis of the toxicity pathways of triphenyl phosphate in HepaRG cells and comparison to oxidative stress mechanisms caused by acetaminophen.

    PubMed

    Van den Eede, Nele; Cuykx, Matthias; Rodrigues, Robim M; Laukens, Kris; Neels, Hugo; Covaci, Adrian; Vanhaecke, Tamara

    2015-12-01

    Since the publication of REACH guidelines, the need for in vitro tools for toxicity testing has increased. We present here the development of a hepatotoxicity testing tool using human HepaRG cell cultures and metabolomics. HepaRG cells were exposed to either 4mM acetaminophen (APAP) as reference toxicant for oxidative stress or 50 μM triphenyl phosphate (TPHP) as toxicant with unknown toxicity pathways (TPs). After 72 h exposure, cells were subjected to quenching and liquid-liquid extraction which resulted in a polar and an apolar fraction. Analysis of fractions was performed by ultrahigh performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-QTOF-MS). Significantly up or down regulated metabolites were selected by univariate statistics prior to identification. In order to obtain robust and specific TP biomarkers, the experiment was also repeated using a different culture medium composition to assess which metabolites show consistent changes. Potential biomarkers belonging to different TPs were found for APAP and TPHP. For APAP, the biomarkers were related to a decrease in unsaturated phospholipids, and for TPHP to an accumulation of phosphoglycerolipids and increase of palmitoyl lysophosphatidylcholine. This first proof-of-concept opens new perspectives for the analysis of other (reference) toxicants with different TPs and it can be used to expand the in vitro tool for hepatotoxicity screening of various compounds.

  12. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen

    PubMed Central

    Zhao, Yanli; Harmatz, Jerold S; Epstein, Carol R; Nakagawa, Yukako; Kurosaki, Chie; Nakamura, Tetsuro; Kadota, Takumi; Giesing, Dennis; Court, Michael H; Greenblatt, David J

    2015-01-01

    Aims The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo. Methods The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers. Results Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control. Conclusion Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance. PMID:25808818

  13. Overdose experiences among injection drug users in Bangkok, Thailand

    PubMed Central

    2010-01-01

    Background Although previous studies have identified high levels of drug-related harm in Thailand, little is known about illicit drug overdose experiences among Thai drug users. We sought to investigate non-fatal overdose experiences and responses to overdose among a community-recruited sample of injection drug users (IDU) in Bangkok, Thailand. Methods Data for these analyses came from IDU participating in the Mit Sampan Community Research Project. The primary outcome of interest was a self-reported history of non-fatal overdose. We calculated the prevalence of past overdose and estimated its relationship with individual, drug-using, social, and structural factors using multivariate logistic regression. We also assessed the prevalence of ever witnessing an overdose and patterns of response to overdose. Results These analyses included 252 individuals; their median age was 36.5 years (IQR: 29.0 - 44.0) and 66 (26.2%) were female. A history of non-fatal overdose was reported by 75 (29.8%) participants. In a multivariate model, reporting a history of overdose was independently associated with a history of incarceration (Adjusted Odds Ratio [AOR] = 3.83, 95% Confidence Interval [CI]: 1.52 - 9.65, p = 0.004) and reporting use of drugs in combination (AOR = 2.48, 95% CI: 1.16 - 5.33, p = 0.019). A majority (67.9%) reported a history of witnessing an overdose; most reported responding to the most recent overdose using first aid (79.5%). Conclusions Experiencing and witnessing an overdose were common in this sample of Thai IDU. These findings support the need for increased provision of evidence-based responses to overdose including peer-based overdose interventions. PMID:20465842

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

    PubMed

    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. PMID:27235652

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

    PubMed

    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.

  16. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

    SciTech Connect

    Cover, Cathleen; Liu Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P.; Bajt, Mary Lynn; Jaeschke, Hartmut . E-mail: jaeschke@email.arizona.edu

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.

  17. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats

    PubMed Central

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-01-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5–2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content. PMID:27043622

  18. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats.

    PubMed

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-01-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5-2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content. PMID:27043622

  19. Nrf2-mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKCδ-GSK3β pathway.

    PubMed

    Kay, Hee Yeon; Kim, Young Woo; Ryu, Da Hye; Sung, Sang Hyun; Hwang, Se Jin; Kim, Sang Geon

    2011-08-01

    BACKGROUND AND PURPOSE Sauchinone, an antioxidant lignan, protects hepatocytes from iron-induced toxicity. This study investigated the protective effects of sauchinone against acetaminophen (APAP)-induced toxicity in the liver and the role of nuclear factor erythroid-2-related factor-2 (Nrf2) in this effect. EXPERIMENTAL APPROACH Blood biochemistry and histopathology were assessed in mice treated with APAP or APAP + sauchinone. The levels of mRNA and protein were measured using real-time PCR assays and immunoblottings. KEY RESULTS Sauchinone ameliorated liver injury caused by a high dose of APAP. This effect was prevented by a deficiency of Nrf2. Sauchinone treatment induced modifier subunit of glutamate-cysteine ligase, NAD(P)H:quinone oxidoreductase-1 (NQO1) and heat shock protein 32 in the liver, which was abolished by Nrf2 deficiency. In a hepatocyte model, sauchinone activated Nrf2, as evidenced by the increased nuclear accumulation of Nrf2, the induction of NQO1-antioxidant response element reporter gene, and glutamate-cysteine ligase and NQO1 protein induction, which contributed to the restoration of hepatic glutathione content. Consistently, treatment of sauchinone enhanced Nrf2 phosphorylation with a reciprocal decrease in its interaction with Kelch-like ECH-associated protein-1. Intriguingly, sauchinone activated protein kinase C-δ (PKCδ), which led to Nrf2 phosphorylation. In addition, it increased the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β), derepressing Nrf2 activity, which was supported by the reversal of sauchinone's activation of Nrf2 by an activated mutant of GSK3β. Moreover, phosphorylation of GSK3β by sauchinone depended on PKCδ activation. CONCLUSION AND IMPLICATIONS Our results demonstrate that sauchinone protects the liver from APAP-induced toxicity by activating Nrf2, and this effect is mediated by PKCδ activation, which induces inhibitory phosphorylation of GSK3β.

  20. Curie surface of the alkaline provinces of Goiás (GAP) and Alto Paranaíba (APAP), central Brazil

    NASA Astrophysics Data System (ADS)

    Moraes Rocha, Loiane Gomes de; Pires, Augusto César Bittencourt; Carmelo, Adriana Chatack; Oksum, Erdinc

    2015-05-01

    The study area includes the most important carbonatite and kimberlite complexes in Brazil, located in the Brazilian states of Goiás and Minas Gerais. The central portion of this area involves the Azimuth 125° lineament (Az 125°) that consists of an extensive set of faults (oriented in the NW-SE direction) that served as a conduit for magma ascent. This lineament is the main structural feature associated with these complexes. The Goiás (GAP) and Alto Paranaíba (APAP) Alkaline Provinces occur along the Az 125° and include highly economically valuable mineralizations. In this study, we aim to map the depth to the curie isotherm (or Curie Point Depths: CPD) of the study area (mainly the Gap and APAP regions) based on spectral analysis of aeromagnetic data. The CPD estimations were achieved from a spectral approach known as the centroid method, providing the relationship between the spectra of magnetic anomalies and the depths of the magnetic source of a 2-D magnetic data. The CPD estimates from approximately 500 overlapping blocks vary from 7 km to 40 km deep. The shallower depths are related to the GAP and APAP regions, and the deeper ones are related to the São Franciscana Plate. The Curie depths related to the Az 125° are between 30 km and 15.7 km deep. According to the results, the GAP and APAP intrusive bodies have shallower roots the major faults of the Az 125°.

  1. Detection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors

    PubMed Central

    Kaur, Gurnit; Leslie, Elaine M.; Tillman, Holly; Lee, William M.; Swanlund, Diane P.; Karvellas, Constantine J.

    2015-01-01

    Background/Aim Acetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant. Methods Serum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004–2011). Results Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 μmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all). Conclusion OA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production. PMID:26407170

  2. 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.

    PubMed

    Truong, Van-Long; Ko, Se-Yeon; Jun, Mira; Jeong, Woo-Sik

    2016-01-01

    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. PMID:27428996

  3. 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

    PubMed Central

    Truong, Van-Long; Ko, Se-Yeon; Jun, Mira; Jeong, Woo-Sik

    2016-01-01

    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. PMID:27428996

  4. Use of a systems model of drug-induced liver injury (DILIsym(®)) to elucidate the mechanistic differences between acetaminophen and its less-toxic isomer, AMAP, in mice.

    PubMed

    Howell, Brett A; Siler, Scott Q; Watkins, Paul B

    2014-04-21

    Acetaminophen (APAP) has been used as a probe drug to investigate drug-induced liver injury (DILI). In mice, 3'-hydroxyacetanilide (AMAP), a less-toxic isomer of APAP, has also been studied as a negative control. Various mechanisms for the divergence in toxicological response between the two isomers have been proposed. This work utilized a mechanistic, mathematical model of DILI to test the plausibility of four mechanistic hypotheses. Simulation results were compared to an array of measured endpoints in mice treated with APAP or AMAP. The four hypotheses included: (1) quantitative differences in drug metabolism profiles as a result of different affinities for the relevant enzymes; (2) differences in the amount of reactive metabolites produced due to cytochrome P450 (CYP450) inhibition by the AMAP reactive metabolites; (3) differences in the rate of conjugation between the reactive metabolites and proteins; (4) differences in the downstream effects or potencies of the reactive metabolites on vital components within hepatocytes. The simulations did not support hypotheses 3 or 4 as the most likely hypotheses underlying the difference in hepatoxic potential of APAP and AMAP. Rather, the simulations supported hypotheses 1 and 2 (less reactive metabolite produced per mole of AMAP relative to APAP). Within the simulations, the difference in reactive metabolite formation was equally likely to have occurred from differential affinities for the relevant drug metabolism enzymes or from direct CYP450 inhibition by the AMAP reactive metabolite. The demonstrated method of using simulation tools to probe the importance of possible contributors to toxicological observations is generally applicable across species.

  5. Fatality following a suicidal overdose with varenicline.

    PubMed

    Stove, Christophe P; De Letter, Els A; Piette, Michel H; Lambert, Willy E

    2013-01-01

    The smoking cessation agent varenicline acts as a partial agonist on α(4)β(2) nicotinic acetylcholine receptors. Although debated, several reports have linked varenicline therapy to an increased risk of suicidal thoughts and/or suicide. In addition, several non-fatal overdose cases have been reported. In this report, we utilised a sample preparation procedure suitable for postmortem samples and gas chromatography coupled to mass spectrometry to analyse samples obtained from a suicidal case in which ingestion of an overdose of varenicline had occurred. Extremely high concentrations of varenicline (>250 ng/ml) were detected in the blood of the deceased, in addition to high concentrations in urine and vitreous humour. To the best of our knowledge, similar high concentrations have not been reported yet. Although, with respect to the mechanism of death in this case, confounding factors were concomitant ethanol consumption and, importantly, potentially fatal hypothermia, this is the first report of a fatality associated with the ingestion of an overdose of varenicline.

  6. Toxicity of 50-nm polystyrene particles co-administered to mice with acetaminophen, 5-aminosalicylic acid or tetracycline.

    PubMed

    Isoda, K; Nozawa, T; Tezuka, M; Ishida, I

    2014-09-01

    We investigated whether nano-sized polystyrene particles affect drug-induced toxicity. The particles, which are widely used industrially, had diameters of 50 (NPP50), 200 (NPP200) or 1000 (NPP1000) nm. The toxic chemicals tested were acetaminophen (APAP), 5-aminosalicylic acid (5-ASA), tetracycline (TC), and sodium valproate (VPA). All treatments in the absence of the nanoparticles were non-lethal and did not result in severe toxicity. However, when mice were injected with APAP, 5-ASA or TC together with polystyrene particles, synergistic, enhanced toxicity was observed in mice injected with NPP50. These synergic effects were not observed in mice co-injected with NPP200 or NPP1000. On the other hand, co-administration of VPA and NPP50, NPP200 or NPP1000 did not elevate toxicity. The results show that NPP50 differs in hepatotoxicity depending on the drug co-administered. These findings suggest that further evaluation of the interactions between polystyrene nanoparticles and drugs is a critical prerequisite to the pharmaceutical application of nanotechnology.

  7. [Tramadol/acetaminophen combination tablets].

    PubMed

    Yokotsuka, Shoko; Kato, Jitsu

    2013-07-01

    Tramadol/acetaminophen fixed-dose combination tablets (Tramse) combine tramadol, a centrally acting week opioid analgesic, with low-dose acetaminophen. The action of tramadol may be described as a weak agonist at the mu-opioid receptor, inhibition of serotonin reuptake, and inhibition of noradrenaline reuptake. The second component in these tablets, acetaminophen mainly appears to act through central mechanism. Chronic pain may be broadly classified into nociceptive, neuropathic and mixed. Tramset may exert additive or synergic benefits in treating the multiple mechanism of pain. Clinical studies have revealed its efficacy and safety for a variety of pain condition such as chronic low back pain, rheumatoid arthritis, fibromyalgia and painful diabetic peripheral neuropathy. It is expected that Tramset is going to induce pain relief and to improve disturbance of daily life in patients with intractable chronic pain. However overuse of Tramset may induce severe adverse effects such as addiction, abuse and hepatotoxicity. Therefore clinician should continuously assess pain intensity, activity of daily life, mode of its consumption, and adverse effects after prescription. PMID:23905401

  8. Risk factors for opioid overdose and awareness of overdose risk among veterans prescribed chronic opioids for addiction or pain

    PubMed Central

    Wilder, Christine M.; Miller, Shannon C.; Tiffany, Elizabeth; Winhusen, Theresa; Winstanley, Erin L.; Stein, Michael D.

    2016-01-01

    Background Rising overdose fatalities among US veterans suggest veterans taking prescription opioids may be at risk for overdose. However, it is unclear whether veterans prescribed chronic opioids are aware of this risk. Objectives The objective of this study was to identify risk factors and determine awareness of risk for opioid overdose in veterans treated with opioids for chronic pain, using veterans treated with methadone or buprenorphine for opioid use disorder as a high-risk comparator group. Methods Ninety veterans on chronic opioid medication for either opioid use disorder or pain management completed a questionnaire assessing risk factors, knowledge, and self-estimate of risk for overdose. Results Nearly all veterans in both groups had multiple overdose risk factors although individuals in the pain management group had on average a significantly lower total number of risk factors than did individuals in the opioid use disorder group (5.9 v. 8.5, p<0.0001). On average, participants treated for pain management scored slightly but significantly lower on knowledge of opioid overdose risk factors (12.1 v. 13.5, p<0.01). About 70% of participants, regardless of group, believed their overdose risk was below that of the average American adult. There was no significant relationship between self-estimate of overdose risk and either number or knowledge of opioid overdose risk factors. Discussion Our results suggest that veterans in both groups underestimated their risk for opioid overdose. Expansion of overdose education to include individuals on chronic opioids for pain management and a shift in educational approaches to overdose prevention may be indicated. PMID:26566771

  9. 21 CFR 862.3030 - Acetaminophen test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Acetaminophen test system. 862.3030 Section 862....3030 Acetaminophen test system. (a) Identification. An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained...

  10. 21 CFR 862.3030 - Acetaminophen test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Acetaminophen test system. 862.3030 Section 862....3030 Acetaminophen test system. (a) Identification. An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained...

  11. 21 CFR 862.3030 - Acetaminophen test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Acetaminophen test system. 862.3030 Section 862....3030 Acetaminophen test system. (a) Identification. An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained...

  12. 21 CFR 862.3030 - Acetaminophen test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Acetaminophen test system. 862.3030 Section 862....3030 Acetaminophen test system. (a) Identification. An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained...

  13. 21 CFR 862.3030 - Acetaminophen test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Acetaminophen test system. 862.3030 Section 862....3030 Acetaminophen test system. (a) Identification. An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained...

  14. Brief Opioid Overdose Knowledge (BOOK): A Questionnaire to Assess Overdose Knowledge in Individuals Who Use Illicit or Prescribed Opioids

    PubMed Central

    Dunn, Kelly E.; Barrett, Frederick S.; Yepez-Laubach, Claudia; Meyer, Andrew C.; Hruska, Bryce J.; Sigmon, Stacey C.; Fingerhood, Michael; Bigelow, George E.

    2016-01-01

    Background: Opioid overdose is a public health crisis. This study describes efforts to develop and validate the Brief Opioid Overdose Knowledge (BOOK) questionnaire to assess patient knowledge gaps related to opioid overdose risks. Methods: Two samples of illicit opioid users and a third sample of patients receiving an opioid for the treatment of chronic pain (total N = 848) completed self-report items pertaining to opioid overdose risks. Results: A 3-factor scale was established, representing Opioid Knowledge (4 items), Opioid Overdose Knowledge (4 items), and Opioid Overdose Response Knowledge (4 items). The scale had strong internal and face validity. Patients with chronic pain performed worse than illicit drug users in almost all items assessed, highlighting the need to increase knowledge of opioid overdose risk to this population. Conclusions: This study sought to develop a brief, internally valid method for quickly assessing deficits in opioid overdose risk areas within users of illicit and prescribed opioids, to provide an efficient metric for assessing and comparing educational interventions, facilitate conversations between physicians and patients about overdose risks, and help formally identify knowledge deficits in other patient populations. PMID:27504923

  15. Increases in heroin overdose deaths - 28 States, 2010 to 2012.

    PubMed

    Rudd, Rose A; Paulozzi, Len J; Bauer, Michael J; Burleson, Richard W; Carlson, Rick E; Dao, Dan; Davis, James W; Dudek, Jennifer; Eichler, Beth Ann; Fernandes, Jessie C; Fondario, Anna; Gabella, Barbara; Hume, Beth; Huntamer, Theron; Kariisa, Mbabazi; Largo, Thomas W; Miles, JoAnne; Newmyer, Ashley; Nitcheva, Daniela; Perez, Beatriz E; Proescholdbell, Scott K; Sabel, Jennifer C; Skiba, Jessica; Slavova, Svetla; Stone, Kathy; Tharp, John M; Wendling, Tracy; Wright, Dagan; Zehner, Anne M

    2014-10-01

    Nationally, death rates from prescription opioid pain reliever (OPR) overdoses quadrupled during 1999-2010, whereas rates from heroin overdoses increased by <50%. Individual states and cities have reported substantial increases in deaths from heroin overdose since 2010. CDC analyzed recent mortality data from 28 states to determine the scope of the heroin overdose death increase and to determine whether increases were associated with changes in OPR overdose death rates since 2010. This report summarizes the results of that analysis, which found that, from 2010 to 2012, the death rate from heroin overdose for the 28 states increased from 1.0 to 2.1 per 100,000, whereas the death rate from OPR overdose declined from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. OPR overdose mortality declined significantly among males, persons aged <45 years, persons in the South, and non-Hispanic whites. Five states had increases in the OPR death rate, seven states had decreases, and 16 states had no change. Of the 18 states with statistically reliable heroin overdose death rates (i.e., rates based on at least 20 deaths), 15 states reported increases. Decreases in OPR death rates were not associated with increases in heroin death rates. The findings indicate a need for intensified prevention efforts aimed at reducing overdose deaths from all types of opioids while recognizing the demographic differences between the heroin and OPR-using populations. Efforts to prevent expansion of the number of OPR users who might use heroin when it is available should continue.

  16. Heroin Addicts Reporting Previous Heroin Overdoses Also Report Suicide Attempts

    ERIC Educational Resources Information Center

    Bradvik, Louise; Frank, Arne; Hulenvik, Per; Medvedeo, Alvaro; Berglund, Mats

    2007-01-01

    Nonfatal heroin overdoses and suicide attempts are both common among heroin addicts, but there is limited knowledge about the association between them. The sample in the present study consisted of 149 regular heroin users in Malmo, Sweden. Out of these 98 had taken an unintentional heroin overdose at some time and 51 had made at least one attempt…

  17. Extracorporeal circulation in the management of massive propranolol overdose.

    PubMed

    McVey, F K; Corke, C F

    1991-09-01

    A case of refractory hypotension following propranolol overdose is reported. Management included isoprenaline, glucagon and extracorporeal circulatory support using femoral vein-femoral artery bypass. The unreliability of neurological observations, especially unreactive pupils, in the presence of drug overdose is reiterated. PMID:1928675

  18. “I Felt Like a Superhero”: The Experience of Responding to Drug Overdose Among Individuals Trained in Overdose Prevention

    PubMed Central

    Wagner, Karla D.; Davidson, Peter J.; Iverson, Ellen; Washburn, Rachel; Burke, Emily; Kral, Alex H.; McNeeley, Miles; Bloom, Jennifer Jackson; Lankenau, Stephen E.

    2013-01-01

    Background Overdose prevention programs (OPPs) train people who inject drugs and other community members to prevent, recognise and respond to opioid overdose. However, little is known about the experience of taking up the role of an “overdose responder” for the participants. Methods We present findings from qualitative interviews with 30 participants from two OPPs in Los Angeles, CA, USA from 2010–2011 who had responded to at least one overdose since being trained in overdose prevention and response. Results Being trained by an OPP and responding to overdoses had both positive and negative effects for trained “responders”. Positive effects include an increased sense of control and confidence, feelings of heroism and pride, and a recognition and appreciation of one’s expertise. Negative effects include a sense of burden, regret, fear, and anger, which sometimes led to cutting social ties, but might also be mitigated by the increased empowerment associated with the positive effects. Conclusion Findings suggest that becoming an overdose responder can involve taking up a new social role that has positive effects, but also confers some stress that may require additional support. OPPs should provide flexible opportunities for social support to individuals making the transition to this new and critical social role. Equipping individuals with the skills, technology, and support they need to respond to drug overdose has the potential to confer both individual and community-wide benefits. PMID:23932166

  19. The Social Side Effects of Acetaminophen

    NASA Astrophysics Data System (ADS)

    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

  20. Acetaminophen toxicity with concomitant use of carbamazepine.

    PubMed

    Jickling, Glen; Heino, Angela; Ahmed, S Nizam

    2009-12-01

    Acetaminophen is a widely used analgesic that can cause acute liver failure when consumed above a maximum daily dose. Certain patients may be at increased risk of hepatocellular damage even at conventional therapeutic doses. We report a case of a 34-year-old man on carbamazepine for complex partial seizures who developed acute liver and renal failure on less than 2.5 grams a day of acetaminophen. This raises caution that patients on carbamazepine should avoid chronic use of acetaminophen, and if required use at lower doses with vigilant monitoring for signs of liver damage.

  1. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury

    PubMed Central

    Grespan, Renata; Aguiar, Rafael Pazinatto; Giubilei, Frederico Nunes; Fuso, Rafael Rocco; Damião, Marcio José; Silva, Expedito Leite; Mikcha, Jane Graton; Hernandes, Luzmarina; Bersani Amado, Ciomar; Cuman, Roberto Kenji Nakamura

    2014-01-01

    Acute liver damage caused by acetaminophen overdose is a significant clinical problem and could benefit from new therapeutic strategies. Objective. This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO), which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects. The hepatoprotective activity of TEO was determined by assessing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in mice. Their livers were then used to determine myeloperoxidase (MPO) enzyme activity and subjected to histological analysis. In vitro antioxidant activity was evaluated by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•)-scavenging effects of TEO and TEO-induced lipid peroxidation. TEO reduced the levels of the serum marker enzymes AST, ALT, and ALP and MPO activity. The histopathological analysis indicated that TEO prevented acetaminophen-induced necrosis. The essential oil also exhibited antioxidant activity, reflected by its DPPH radical-scavenging effects and in the lipid peroxidation assay. These results suggest that TEO has hepatoprotective effects on acetaminophen-induced hepatic damage in mice. PMID:24639884

  2. Development of an Incarceration-Specific Overdose Prevention Video: "Staying Alive on the Outside"

    ERIC Educational Resources Information Center

    Green, Traci C.; Bowman, Sarah E.; Ray, Madeline; McKenzie, Michelle; Lord, Sarah E.; Rich, Josiah D.

    2015-01-01

    Objectives: The first 2 weeks following release from prison are associated with extraordinary risk of fatal drug overdose. However, bystanders can reverse opioid overdoses using rescue breathing and naloxone, an overdose antidote. We reviewed overdose prevention and naloxone administration training videos for incarceration specific and behaviour…

  3. Gene interaction network analysis suggests differences between high and low doses of acetaminophen

    SciTech Connect

    Toyoshiba, Hiroyoshi . E-mail: toyoshiba.hiroyoshi@nies.go.jp; Sone, Hideko; Yamanaka, Takeharu; Parham, Frederick M.; Irwin, Richard D.; Boorman, Gary A.; Portier, Christopher J.

    2006-09-15

    Bayesian networks for quantifying linkages between genes were applied to detect differences in gene expression interaction networks between multiple doses of acetaminophen at multiple time points. Seventeen (17) genes were selected from the gene expression profiles from livers of rats orally exposed to 50, 150 and 1500 mg/kg acetaminophen (APAP) at 6, 24 and 48 h after exposure using a variety of statistical and bioinformatics approaches. The selected genes are related to three biological categories: apoptosis, oxidative stress and other. Gene interaction networks between all 17 genes were identified for the nine dose-time observation points by the TAO-Gen algorithm. Using k-means clustering analysis, the estimated nine networks could be clustered into two consensus networks, the first consisting of the low and middle dose groups, and the second consisting of the high dose. The analysis suggests that the networks could be segregated by doses and were consistent in structure over time of observation within grouped doses. The consensus networks were quantified to calculate the probability distribution for the strength of the linkage between genes connected in the networks. The quantifying analysis showed that, at lower doses, the genes related to the oxidative stress signaling pathway did not interact with the apoptosis-related genes. In contrast, the high-dose network demonstrated significant interactions between the oxidative stress genes and the apoptosis genes and also demonstrated a different network between genes in the oxidative stress pathway. The approaches shown here could provide predictive information to understand high- versus low-dose mechanisms of toxicity.

  4. Management of calcium channel antagonist overdose.

    PubMed

    Salhanick, Steven D; Shannon, Michael W

    2003-01-01

    Calcium channel antagonists are used primarily for the treatment of hypertension and tachyarrhythmias. Overdose of calcium channel antagonists can be lethal. Calcium channel antagonists act at the L-type calcium channels primarily in cardiac and vascular smooth muscle preventing calcium influx into cells with resultant decreases in vascular tone and cardiac inotropy and chronotropy. The L-type calcium channel is a complex structure and is thus affected by a large number of structurally diverse antagonists. In the setting of overdose, patients may experience vasodilatation and bradycardia leading to a shock state. Patients may also be hyperglycaemic and acidotic due to the blockade of L-type calcium channels in the pancreatic islet cells that affect insulin secretion. Aggressive therapy is warranted in the setting of toxicity. Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products is indicated. Specific antidotes include calcium salts, glucagon and insulin. Calcium salts may be given in bolus doses or may be employed as a continuous infusion. Care should be exercised to avoid the administration of calcium in the setting of concomitant digoxin toxicity. Insulin administration has been used effectively to increase cardiac inotropy and survival. The likely mechanism involves a shift to carbohydrate metabolism in the setting of decreased availability of carbohydrates due to decreased insulin secretion secondary to blockade of calcium channels in pancreatic islet cells. Glucose should be administered as well to maintain euglycaemia. Supportive care including the use of phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump or extracorporeal bypass is frequently indicated if antidotal therapy is not effective. Careful evaluation of asymptomatic patients, including and electrocardiogram and a period of observation, is indicated. Patients ingesting a nonsustained

  5. Did acetaminophen provoke the autism epidemic?

    PubMed

    Good, Peter

    2009-12-01

    Schultz et al (2008) raised the question whether regression into autism is triggered, not by the measles-mumps-rubella (MMR) vaccine, but by acetaminophen (Tylenol) given for its fever and pain. Considerable evidence supports this contention, most notably the exponential rise in the incidence of autism since 1980, when acetaminophen began to replace aspirin for infants and young children. The impetus for this shift - a Centers for Disease Control and Prevention warning that aspirin was associated with Reye's syndrome - has since been compellingly debunked. If aspirin is not to be feared as a cause of Reyes syndrome, and acetaminophen is to be feared as a cause of autism, can the autism epidemic be reversed by replacing acetaminophen with aspirin or other remedies?

  6. Herb-induced cardiotoxicity from accidental aconitine overdose.

    PubMed

    Sheth, Sujata; Tan, Elaine Ching Ching; Tan, Hock Heng; Tay, Leslie

    2015-07-01

    Patients who overdose on aconite can present with life-threatening ventricular arrhythmia. Aconite must be prepared and used with caution to avoid cardiotoxic effects that can be fatal. We herein describe a case of a patient who had an accidental aconite overdose but survived with no lasting effects. The patient had prepared Chinese herbal medication to treat his pain, which resulted in an accidental overdose of aconite with cardiotoxic and neurotoxic effects. The patient had ventricular tachycardia, bidirectional ventricular tachycardia and ventricular fibrillation. Following treatment with anti-arrhythmic medications, defibrillation and cardiopulmonary resuscitation, he made an uneventful recovery, with no further cardiac arrhythmias reported. PMID:26243980

  7. Fatal overdose of iron tablets in adults.

    PubMed

    Abhilash, Kundavaram P P; Arul, J Jonathan; Bala, Divya

    2013-09-01

    Acute iron toxicity is usually seen in children with accidental ingestion of iron-containing syrups. However, the literature on acute iron toxicity with suicidal intent in adults is scant. We report, the first instance of two adults with fatal ingestion of a single drug overdose with iron tablets from India. Two young adults developed severe gastro-intestinal bleeding and fulminant hepatic failure 48 h after deliberate consumption of large doses of iron tablets. Serum iron levels measured 36 h after ingestion were normal presumably due to the redistribution of iron to the intracellular compartment. Despite aggressive supportive management in medical intensive care unit of a tertiary care hospital, the patients succumbed to the toxic doses of iron.

  8. Fatal overdose of iron tablets in adults.

    PubMed

    Abhilash, Kundavaram P P; Arul, J Jonathan; Bala, Divya

    2013-09-01

    Acute iron toxicity is usually seen in children with accidental ingestion of iron-containing syrups. However, the literature on acute iron toxicity with suicidal intent in adults is scant. We report, the first instance of two adults with fatal ingestion of a single drug overdose with iron tablets from India. Two young adults developed severe gastro-intestinal bleeding and fulminant hepatic failure 48 h after deliberate consumption of large doses of iron tablets. Serum iron levels measured 36 h after ingestion were normal presumably due to the redistribution of iron to the intracellular compartment. Despite aggressive supportive management in medical intensive care unit of a tertiary care hospital, the patients succumbed to the toxic doses of iron. PMID:24339645

  9. Hydroxyapatite crystallization in the presence of acetaminophen

    NASA Astrophysics Data System (ADS)

    Mangood, A.; Malkaj, P.; Dalas, E.

    2006-05-01

    The effect of acetaminophen; a widely used analgesic and fever reducing medicine; in supersaturated solutions of calcium phosphate was investigated under plethostatic conditions, at 37 °C, 0.15 M NaCl, pH 7.40. The rates of crystal growth measured in the presence of acetaminophen 1.654×10 -4 mol dm -3 to 6.616×10 -4 mol dm -3 were reduced by 43% to 79%, respectively. The inhibition effect on the crystal growth rate may be explained through adsorption onto the active growth sites. Kinetic analysis suggested Langmuir-type adsorption of acetaminophen on the HAP surface with a affinity value of 2.4×10 -4 dm 3 mol -1, for the substrate in the concentration range investigated. The electrophoretic mobility measurements showed that in the presence of acetaminophen the charge of the acetaminophen covered HAP particles was shifted to more negative values as compared to bare HAP. In the presence of acetaminophen no changes observed in the HAP overgrown morphology or in the apparent order of crystallization.

  10. Bioactivation and toxicity of acetaminophen in a rat hepatocyte micropatterned coculture system.

    PubMed

    Ukairo, Okechukwu; McVay, Michael; Krzyzewski, Stacy; Aoyama, Simon; Rose, Kelly; Andersen, Melvin E; Khetani, Salman R; Lecluyse, Edward L

    2013-10-01

    We have recently shown that primary rat hepatocytes organized in micropatterned cocultures with murine embryonic fibroblasts (HepatoPac™) maintain high levels of liver functions for at least 4 weeks. In this study, rat HepatoPac was assessed for its utility to study chemical bioactivation and associated hepatocellular toxicity. Treatment of HepatoPac cultures with acetaminophen (APAP) over a range of concentrations (0-15 mM) was initiated at 1, 2, 3, or 4 weeks followed by the assessment of morphological and functional endpoints. Consistent and reproducible concentration-dependent effects on hepatocyte structure, viability, and basic functions were observed over the 4-week period, and were exacerbated by depleting glutathione using buthionine sulfoximine or inducing CYP3A using dexamethasone, presumably due to increased reactive metabolite-induced stress and adduct formation. In conclusion, the results from this study demonstrate that rat HepatoPac represents a structurally and functionally stable hepatic model system to assess the long-term effects of bioactivated compounds.

  11. Methadone-induced rigid-chest syndrome after substantial overdose.

    PubMed

    Lynch, Robert E; Hack, Richard A

    2010-07-01

    We report here the case of an infant who developed life-threatening rigid-chest syndrome after receiving an accidental overdose of methadone. The child responded to narcotic reversal. Pediatric physicians should be aware of this possible complication.

  12. Alcohol Overdose: The Dangers of Drinking Too Much

    MedlinePlus

    ... The Dangers of Drinking Too Much Print version Alcohol Overdose: The Dangers of Drinking Too Much Celebrating ... excess. And the results can be deadly. Identifying Alcohol Poisoning Critical Signs and Symptoms of Alcohol Poisoning ...

  13. Acetaminophen During Pregnancy May Up Risk of ADHD in Kids

    MedlinePlus

    ... html Acetaminophen During Pregnancy May Up Risk of ADHD in Kids But only association found, and researchers ... their child will develop behavioral problems such as attention-deficit/hyperactivity disorder (ADHD), a new study suggests. Acetaminophen is generally ...

  14. The B-RafV600E inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury

    PubMed Central

    Li, J-X; Feng, J-M; Wang, Y; Li, X-H; Chen, X-X; Su, Y; Shen, Y-Y; Chen, Y; Xiong, B; Yang, C-H; Ding, J; Miao, Z-H

    2014-01-01

    Receptor-interacting protein (RIP)3 is a critical regulator of necroptosis and has been demonstrated to be associated with various diseases, suggesting that its inhibitors are promising in the clinic. However, there have been few RIP3 inhibitors reported as yet. B-RafV600E inhibitors are an important anticancer drug class for metastatic melanoma therapy. In this study, we found that 6 B-Raf inhibitors could inhibit RIP3 enzymatic activity in vitro. Among them, dabrafenib showed the most potent inhibition on RIP3, which was achieved by its ATP-competitive binding to the enzyme. Dabrafenib displayed highly selective inhibition on RIP3 over RIP1, RIP2 and RIP5. Moreover, only dabrafenib rescued cells from RIP3-mediated necroptosis induced by the necroptosis-induced combinations, that is, tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand or Fas ligand plus Smac mimetic and the caspase inhibitor z-VAD. Dabrafenib decreased the RIP3-mediated Ser358 phosphorylation of mixed lineage kinase domain-like protein (MLKL) and disrupted the interaction between RIP3 and MLKL. Notably, RIP3 inhibition of dabrafenib appeared to be independent of its B-Raf inhibition. Dabrafenib was further revealed to prevent acetaminophen-induced necrosis in normal human hepatocytes, which is considered to be mediated by RIP3. In acetaminophen-overdosed mouse models, dabrafenib was found to apparently ease the acetaminophen-caused liver damage. The results indicate that the anticancer B-RafV600E inhibitor dabrafenib is a RIP3 inhibitor, which could serve as a sharp tool for probing the RIP3 biology and as a potential preventive or therapeutic agent for RIP3-involved necroptosis-related diseases such as acetaminophen-induced liver damage. PMID:24901049

  15. Dipyridamole and paracetamol overdose resulting in multi-organ failure.

    PubMed

    Cullis, P S; Watson, D; Cameron, A; McKee, R F

    2013-08-01

    Dipyridamole intoxication is rare and few reports exist amongst the current literature. A case of dipyridamole and paracetamol overdose is described in a previously healthy 58-year-old woman, which resulted in multi-organ failure requiring dialysis, inotropic support, ventilation and extensive surgical intervention for small bowel ischaemia. This case highlights the dangers of an unusually large overdose of a commonly prescribed drug, and reviews current knowledge of dipyridamole intoxication.

  16. Law enforcement attitudes toward overdose prevention and response

    PubMed Central

    Green, Traci C.; Zaller, Nickolas; Palacios, Wilson R.; Bowman, Sarah E.; Ray, Madeline; Heimer, Robert; Case, Patricia

    2014-01-01

    Background Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. Methods We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose “outbreaks.” Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. Results Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers’ feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. Conclusion Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety. PMID:24051061

  17. Two cases of oral aspirin overdose.

    PubMed

    Kato, Hideaki; Yoshimoto, Kanji; Ikegaya, Hiroshi

    2010-07-01

    A 30-year-old woman and a 27-year-old man were found in a parked car after the man had telephoned his father to tell him of their suicide attempt. In spite of emergent hospitalization and intensive care, the woman died. Due to the possibility of his assisting her suicide, medicolegal autopsy and toxicological analysis were performed. On forensic autopsy, no external injuries or pathological findings were detected. The man recovered after 5 days of hospitalization. In spite of a negative toxicological screening test, the police investigation revealed that they may have taken 120 tablets (330 mg/tablet; 39,600 mg total dose) of aspirin (acetylsalicylic acid) orally; therefore, we analyzed the concentrations of acetylsalicylic acid and two kinds of metabolite in specimens obtained at autopsy and on emergent hospitalization using high performance liquid chromatography. Acetylsalicylic acid and/or the two metabolites were found in the woman's specimens. These substances were also present in the man's specimens. It is still unclear why the man survived in spite of what appeared to be a fatal aspirin overdose. It was very straightforward to diagnose aspirin poisoning in these cases; however, we have to be aware of poisoning by drugs which are not included in simple drug screening examinations. PMID:20569957

  18. Safety of rapid intravenous of infusion acetaminophen

    PubMed Central

    2013-01-01

    Intravenous acetaminophen, Ofirmev®, is approved for management of mild to moderate pain, management of moderate to severe pain with adjunctive opioids, and reduction of fever. The product is supplied as a 100 mL glass vial. As stated in the prescribing information, it is recommended to be infused over 15 minutes. This recommendation is related to the formulation propacetamol, the prodrug to acetaminophen, approved in Europe, which caused pain on infusion, and data from the clinical development of acetaminophen. The objective of this retrospective chart review study was to show the lack of side effects of rapidly infusing intravenous acetaminophen. Charts of American Society of Anesthesiology (ASA) Class I–III ambulatory surgical patients who received only acetaminophen in the preoperative setting were reviewed for any infusion-related side effects. Using standard binomial proportion analyses and employing SAS/JMP software, all vital signs were analyzed for statistically significant changes between pre- and postinfusion values. One hundred charts were reviewed. Only one patient had pain on infusion, which lasted 10 seconds. No reported side effects or erythema was seen at the injection site. No infusions had to be slowed or discontinued. The median infusion time was 3:41 minutes. Of the vital signs monitored, only the systolic (P < 0.0001) and diastolic (P < 0.0099) blood pressures had statistically significant changes from pre- to postinfusion; however, they were of no clinical relevance. Acetaminophen can be administered as a rapid infusion with no significant infusion-related side effects or complications. PMID:23814378

  19. Safety of rapid intravenous of infusion acetaminophen.

    PubMed

    Needleman, Steven M

    2013-07-01

    Intravenous acetaminophen, Ofirmev®, is approved for management of mild to moderate pain, management of moderate to severe pain with adjunctive opioids, and reduction of fever. The product is supplied as a 100 mL glass vial. As stated in the prescribing information, it is recommended to be infused over 15 minutes. This recommendation is related to the formulation propacetamol, the prodrug to acetaminophen, approved in Europe, which caused pain on infusion, and data from the clinical development of acetaminophen. The objective of this retrospective chart review study was to show the lack of side effects of rapidly infusing intravenous acetaminophen. Charts of American Society of Anesthesiology (ASA) Class I-III ambulatory surgical patients who received only acetaminophen in the preoperative setting were reviewed for any infusion-related side effects. Using standard binomial proportion analyses and employing SAS/JMP software, all vital signs were analyzed for statistically significant changes between pre- and postinfusion values. One hundred charts were reviewed. Only one patient had pain on infusion, which lasted 10 seconds. No reported side effects or erythema was seen at the injection site. No infusions had to be slowed or discontinued. The median infusion time was 3:41 minutes. Of the vital signs monitored, only the systolic (P < 0.0001) and diastolic (P < 0.0099) blood pressures had statistically significant changes from pre- to postinfusion; however, they were of no clinical relevance. Acetaminophen can be administered as a rapid infusion with no significant infusion-related side effects or complications. PMID:23814378

  20. Reducing Fatal Opioid Overdose: Prevention, Treatment and Harm Reduction Strategies

    PubMed Central

    Hawk, Kathryn F.; Vaca, Federico E.; D’Onofrio, Gail

    2015-01-01

    The opioid overdose epidemic is a major threat to the public’s health, resulting in the development and implementation of a variety of strategies to reduce fatal overdose [1-3]. Many strategies are focused on primary prevention and increased access to effective treatment, although the past decade has seen an exponential increase in harm reduction initiatives. To maximize identification of opportunities for intervention, initiatives focusing on prevention, access to effective treatment, and harm reduction are examined independently, although considerable overlap exists. Particular attention is given to harm reduction approaches, as increased public and political will have facilitated widespread implementation of several initiatives, including increased distribution of naloxone and policy changes designed to increase bystander assistance during a witnessed overdose [4-7]. PMID:26339206

  1. Life-threatening overdose with lamotrigine, citalopram, and chlorpheniramine.

    PubMed

    Venkatraman, N; O'Neil, D; Hall, A P

    2008-01-01

    Lamotrigine is a commonly used agent for seizure control in epilepsy. There are limited data on the adverse effects of lamotrigine in overdose. We report a number of serious side-effects associated with a large overdose of lamotrigine. A 23-year-old female presented to the emergency department after taking an intentional overdose of 9.2 g of lamotrigine, 56 mg of chlorpheniramine, and 220 mg of citalopram. On admission, she had a reduced level of consciousness and electrocardiographic abnormalities; a widened QRS and a prolonged corrected QT (QTc) interval. Prompt treatment with early intubation, along with the use of magnesium for cardioprotection and administration of sodium bicarbonate may have aided in a quick recovery with a short intensive care stay and good outcome.

  2. Effects of Acetaminophen on Left Atrial Contractility

    PubMed Central

    Chang, Jun-Hei; Cheng, Pao-Yun; Hsu, Chih-Hsueng; Chen, Yao-Chang; Hong, Po-Da

    2016-01-01

    Background It has been observed that acetaminophen shows cardioprotective efficacy in mammals. In this study, we investigated the electromechanical effects of acetaminophen on the left atrium (LA). Methods Conventional microelectrodes were used to record the action potentials (AP) in rabbit LA preparations. The action potential duration (APD) at repolarization levels of 90%, 50% and 20% of the AP amplitude (APD90, APD50, and APD20, respectively), resting membrane potential, and contractile force were measured during 2 Hz electrical stimulation before and after sequential acetaminophen administration to the LA. Results Acetaminophen (0.1, 0.3, 1, and 3 mM) reduced APD20 from 9.4 ± 1.2 to 8.0 ± 1.1 (p < 0.05), 7.1 ± 0.8 (p < 0.05), 7.8 ± 1.1, and 6.8 ± 1.2 ms (p < 0.05), respectively, and APD50 from 20.2 ± 1.9 to 17.4 ± 2.0, 15.6 ± 1.8 (p < 0.05), 15.8 ± 2.2 (p < 0.05), and 14.1 ± 2.4 ms (p < 0.05), respectively, in a concentration-dependent manner. APD90 was reduced from 72.0 ± 3.6 to 64.7 ± 4.2, 61.9 ± 4.3, 60.5 ± 3.7, and 53.4 ± 4.4 ms (p < 0.05), respectively. Acetaminophen increased LA contractility from 45 ± 9 to 52 ± 10 (p < 0.05), 55 ± 9 (p < 0.01), 58 ± 9 (p < 0.01), and 60 ± 9 mg (p < 0.01), respectively, in a concentration-dependent manner. In the presence of the NOS inhibitor L-NAME or PKG-I inhibitor DT-2, additional acetaminophen treatment did not significantly increase LA contractility. Conclusions Acetaminophen modulated the electromechanical characteristics of LA by inhibiting the NOS and PKG I pathway, and then contributed to the positive inotropic effect. PMID:27471362

  3. The management of lomustine overdose in malignant glioma patients

    PubMed Central

    Wirsching, Hans-Georg; Tritschler, Isabel; Palla, Antonella; Renner, Christoph; Weller, Michael; Tabatabai, Ghazaleh

    2014-01-01

    Lomustine is an oral alkylating drug commonly used for brain tumor patients. Recently, the lomustine-containing PCV polychemotherapy regime (procarbazine, CCNU/lomustine, and vincristine) in combination with radiotherapy has become the standard of care for anaplastic oligodendroglioma with 1p/19q codeletion and high-risk low-grade glioma. Here, we review the literature of all reported cases of lomustine overdose, highlight complications by exemplifying a case of inadvertent lomustine overdose, and outline the management of this potential complication of outpatient PCV therapy. PMID:26034630

  4. Successful use of haemodialysis to treat phenobarbital overdose.

    PubMed

    Hoyland, Kimberley; Hoy, Michael; Austin, Richard; Wildman, Martyn

    2013-01-01

    A 50-year-old woman presented with coma caused by a phenobarbital overdose, requiring intubation and admission to critical care. She was an international visitor and had been prescribed the drug for night-sedation. Phenobarbital is a long-acting barbiturate, which in an overdose can cause central nervous system depression, respiratory failure and haemodynamic instability; these patients can remain obtunded for many days. After initial supportive therapy, she was dialysed to help in the elimination of the drug. Haemodialysis resulted in a markedly reduced plasma level of phenobarbital, which decreased the length of intubation and stay in the critical care unit and aided full recovery. PMID:24265338

  5. Successful use of haemodialysis to treat phenobarbital overdose

    PubMed Central

    Hoyland, Kimberley; Hoy, Michael; Austin, Richard; Wildman, Martyn

    2013-01-01

    A 50-year-old woman presented with coma caused by a phenobarbital overdose, requiring intubation and admission to critical care. She was an international visitor and had been prescribed the drug for night-sedation. Phenobarbital is a long-acting barbiturate, which in an overdose can cause central nervous system depression, respiratory failure and haemodynamic instability; these patients can remain obtunded for many days. After initial supportive therapy, she was dialysed to help in the elimination of the drug. Haemodialysis resulted in a markedly reduced plasma level of phenobarbital, which decreased the length of intubation and stay in the critical care unit and aided full recovery. PMID:24265338

  6. Preventing and Responding to Alcohol Overdose on the College Campus.

    ERIC Educational Resources Information Center

    Rapaport, Ross J.

    Rapid ingestion of alcohol is common and unfortunately an all too frequent cause of alcohol-related death among young people. Drinking a lot of alcohol over a short amount of time may result in an alcohol overdose. This situation is a medical emergency and requires sound decision making. The information the campus community needs to know includes…

  7. Young Adult's Immediate Reaction to a Personal Alcohol Overdose

    ERIC Educational Resources Information Center

    Reis, Janet; Harned, Ilene; Riley, William

    2004-01-01

    Following an emergency medical transport for alcohol overdose, first-year college students were asked to complete a survey assessing their reactions to the transport experience, their assessment of why they required this emergency response, and plans for future personal alcohol consumption. Transported students who responded to a baseline survey…

  8. Risk Factors Associated with Overdose among Bahraini Youth.

    ERIC Educational Resources Information Center

    Al Ansari, Ahmed M.; Hamadeh, Randah R.; Matar, Ali M.; Marhoon, Huda; Buzaboon, Bana Y.; Raees, Ahmed G.

    2001-01-01

    Study aimed to identify risk factors, such as family pathology and psychosocial stress, of overdose suicide attempts among Bahraini youth. Stresses from living in a non-intact family; interpersonal relationships mainly with the opposite sex; unemployment; and school performance emerged as main risk factors. Previously identified factors, such as…

  9. Acetaminophen Attenuates House Dust Mite-Induced Allergic Airway Disease in Mice.

    PubMed

    Smith, Gregory J; Thrall, Roger S; Cloutier, Michelle M; Manautou, Jose E; Morris, John B

    2016-09-01

    Epidemiologic evidence suggests that N-acetyl-para-aminophenol (APAP) may play a role in the pathogenesis of asthma, likely through pro-oxidant mechanisms. However, no studies have investigated the direct effects of APAP on the development of allergic inflammation. To determine the likelihood of a causal relationship between APAP and asthma pathogenesis, we explored the effects of APAP on inflammatory responses in a murine house dust mite (HDM) model of allergic airway disease. We hypothesized that APAP would enhance the development of HDM-induced allergic inflammation. The HDM model consisted of once daily intranasal instillations for up to 2 weeks with APAP or vehicle administration 1 hour prior to HDM during either week 1 or 2. Primary assessment of inflammation included bronchoalveolar lavage (BAL), cytokine expression in lung tissue, and histopathology. Contrary to our hypothesis, the effects of HDM treatment were substantially diminished in APAP-treated groups compared with controls. APAP-treated groups had markedly reduced airway inflammation: including decreased inflammatory cells in the BAL fluid, lower cytokine expression in lung tissue, and less perivascular and peribronchiolar immune cell infiltration. The anti-inflammatory effect of APAP was not abrogated by an inhibitor of cytochrome P450 (P450) metabolism, suggesting that the effect was due to the parent compound or a non-P450 generated metabolite. Taken together, our studies do not support the biologic plausibility of the APAP hypothesis that APAP use may contribute to the causation of asthma. Importantly, we suggest the mechanism by which APAP modulates airway inflammation may provide novel therapeutic targets for asthma. PMID:27402277

  10. Patients Who Attend the Emergency Department Following Medication Overdose: Self-Reported Mental Health History and Intended Outcomes of Overdose

    ERIC Educational Resources Information Center

    Buykx, Penny; Ritter, Alison; Loxley, Wendy; Dietze, Paul

    2012-01-01

    Medication overdose is a common method of non-fatal self-harm. Previous studies have established which mental health disorders are commonly associated with the behaviour (affective, substance use, anxiety and personality disorders) and which medications are most frequently implicated (benzodiazepines, antidepressants, antipsychotics and non-opioid…

  11. Optimization in development of acetaminophen syrup formulation.

    PubMed

    Worakul, Nimit; Wongpoowarak, Wibul; Boonme, Prapaporn

    2002-03-01

    Formulation of acetaminophen syrup could be developed by an optimization technique to reduce the time and cost of study. Cosolvents were used in the formulation because of the low solubility of acetaminophen in water. They were composed of polyethylene glycol 4000, propylene glycol, sorbitol solution, and glycerin. Their effects on the solubility of acetaminophen and the pH of formulations were investigated. Effects on taste and price were calculated based on their properties. Simulation study of the effect of cosolvents upon the formulation scores was performed, using an algorithm based upon a simulated annealing concept to achieve the global optima and heuristic optimization concept to accelerate convergence. The program written as a Visual Basic module within Microsoft Access 97 was used to simulate and assess the optimal cosolvent amounts to achieve the most desirable formulations automatically according to the specified criteria. Formulators could customize the optimal formulation according to their needs and cost constraints by redefining the desirable outcomes in the source code of the program. PMID:12026227

  12. Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

    PubMed Central

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

    2012-01-01

    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 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. PMID

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

    PubMed

    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.

  14. Worldwide Prevalence and Trends in Unintentional Drug Overdose: A Systematic Review of the Literature

    PubMed Central

    Sampson, Laura; Cerdá, Magdalena; Galea, Sandro

    2015-01-01

    Background. Drug overdose is an important, yet an inadequately understood, public health problem. Global attention to unintentional drug overdose has been limited by comparison with the scope of the problem. There has been a substantial increase in drug overdose incidence and prevalence in several countries worldwide over the past decade, contributing to both increased costs and mortality. Objectives. The aim of this study was to systematically synthesize the peer-reviewed literature to document the global epidemiological profile of unintentional drug overdoses and the prevalence, time trends, mortality rates, and correlates of drug overdoses. We searched different combinations of Medical Subject Headings (MeSH) terms in PubMed for articles published from 1980 until July 2013, and we organized these results in tabular spreadsheets and compared them. We restricted the search to English-language articles that deal with unintentional overdose, focusing on 1 or more of the following key constructs: prevalence, time trends, mortality rates, and correlates. The term “overdose” as a MeSH major topic yielded 1076 publications. In addition, we searched the following combinations of nonmajor MeSH terms: “street drugs” and “overdose” yielded 180, “death” and “overdose” yielded 114, and “poisoning” and “drug users” yielded 17. There was some overlap among the searches. Based on the search and inclusion and exclusion criteria, we selected a total of 169 relevant articles for this article based on a close review of abstracts. Results. We found wide variability in lifetime prevalence of experiencing a nonfatal overdose or witnessing an overdose, and in mortality rates attributable to overdose. Lifetime prevalence of witnessed overdose among drug users (n = 17 samples) ranged from 50% to 96%, with a mean of 73.3%, a median of 70%, and a standard deviation of 14.1%. Lifetime prevalence of drug users personally experiencing a nonfatal overdose (n

  15. Social and structural aspects of the overdose risk environment in St. Petersburg, Russia

    PubMed Central

    Grau, Lauretta E.; Blinnikova, Ksenia N.; Torban, Mikhail; Krupitsky, Evgeny; Ilyuk, Ruslan; Kozlov, Andrei; Heimer, Robert

    2009-01-01

    Background While overdose is a common cause of mortality among opioid injectors worldwide, little information exists on opioid overdoses or how context may influence overdose risk in Russia. This study sought to uncover social and structural aspects contributing to fatal overdose risk in St. Petersburg and assess prevention intervention feasibility. Methods Twenty-one key informant interviews were conducted with drug users, treatment providers, toxicologists, police, and ambulance staff. Thematic coding of interview content was conducted to elucidate elements of the overdose risk environment. Results Several factors within St. Petersburg’s environment were identified as shaping illicit drug users’ risk behaviors and contributing to conditions of suboptimal response to overdose in the community. Most drug users live and experience overdoses at home, where family and home environment may mediate or moderate risk behaviors. The overdose risk environment is also worsened by inefficient emergency response infrastructure, insufficient cardiopulmonary or naloxone training resources, and the preponderance of abstinence-based treatment approaches to the exclusion of other treatment modalities. However, attitudes of drug users and law enforcement officials generally support overdose prevention intervention feasibility. Modifiable aspects of the risk environment suggest community-based and structural interventions, including overdose response training for drug users and professionals that encompasses naloxone distribution to the users and equipping more ambulances with naloxone. Conclusion Local social and structural elements influence risk environments for overdose. Interventions at the community and structural levels to prevent and respond to opioid overdoses are needed for and integral to reducing overdose mortality in St. Petersburg. PMID:18774283

  16. Pre-exposure to a novel nutritional mixture containing a series of phytochemicals prevents acetaminophen-induced programmed and unprogrammed cell deaths by enhancing BCL-XL expression and minimizing oxidative stress in the liver.

    PubMed

    Ray, Sidhartha D; Patel, Nirav; Shah, Nilank; Nagori, Akila; Naqvi, Anne; Stohs, Sidney J

    2006-12-01

    From a disease-prevention perspective, recent progress in phytochemical and nutraceutical research clearly suggests (benefits outweigh the risk pattern). Although powerful antioxidant properties have been the most acclaimed mechanism of action for these entities, the individual antioxidants studied in clinical trials do not appear to have consistent preventative effects. The actions of the antioxidant nutrients alone do not explain the observed health benefits of diets rich in fruits and vegetables for chronic diseases. Therefore, we proposed that the additive and synergistic effects of phytochemicals in fruits and vegetables are responsible for these potent antioxidant and anticancer activities, and that the benefit of a diet rich in fruits and vegetables is attributed to the complex mixture of phytochemicals present in plants [1]. Surprisingly, however, no studies have attempted to evaluate the combined antitoxic potential of a phytochemical-nutraceutical mixture (PNM) in in vivo models. Therefore, this study, for the first time, was designed to investigate whether pre-exposure to a unique PNM has the ability to impede mechanistic events involved in acetaminophen (APAP)-induced hepatotoxicity. Besides several vitamins and minerals in balanced proportions (approximately US RDA), the PNM used in this investigation contained several well-known phytochemicals such as citrus flavonoids, red wine polyphenols, Garcinia, Gymnema, Ginkgo, Ephedra sinica, Camellia sinensis, Silybum, Guarana, Eluthero, Allium sativum and Ocimum basilicum extracts. To evaluate PNM's antitoxic potential, groups of animals ICR mice, 3 months old) received either a control diet or PNM containing diets (1X and 10X) for 4 weeks. On day-28, animals were divided into two subgroups. Half the animals were administered normal saline and the other half received 400mg/kg ip injections of APAP. All the animals were sacrificed 24h after APAP exposure. Serum and tissue (liver and kidneys) samples were

  17. Double-peaked Acetaminophen Concentration Secondary to Intestinal Trauma.

    PubMed

    Alyahya, B; Tamur, S; Aljenedil, S; Larocuque, A; Holody, E; Gosselin, S

    2016-01-01

    BackgroundReduced gastrointestinal motility can alter the toxicokinetics of acetaminophen poisoning. We report a case of altered acetaminophen toxicokinetics due to delayed gastrointestinal absorption, likely secondary to intestinal trauma/surgery.  Case ReportA 37-year-old woman ingested an unknown amount of acetaminophen and ethanol then stabbed herself in the abdomen. The initial acetaminophen was 1,285.9 μmol/L and the time of ingestion was not known. Intravenous acetylcysteine protocol was started. She developed an ileus post-surgery for the stab wounds. At 31 hours post-presentation, the acetaminophen returned undetectable, and the transaminases were normal. After the resolution of the ileus, repeated acetaminophen peaked at 363.3 μmol/L 52 hours post-admission. At 76 hours post-admission, the acetaminophen was undetectable, and transaminases and coagulation parameters were normal. ConclusionsReduction in gastrointestinal motility secondary to trauma and/or surgery must be considered when determining when to initiate or discontinue treatment as well as how long to monitor acetaminophen concentrations. PMID:27463118

  18. Acetaminophen hepatotoxicity: studies on the mechanism of cysteamine protection

    SciTech Connect

    Miller, M.G.; Jollow, D.J.

    1986-03-30

    Inhibition of the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite was investigated as a possible mechanism for cysteamine protection against acetaminophen hepatotoxicity. Studies in isolated hamster hepatocytes indicated that cysteamine competitively inhibited the cytochrome P-450 enzyme system as represented by formation of the acetaminophen-glutathione conjugate. However, cysteamine was not a potent inhibitor of glutathione conjugate formation (Ki = 1.17 mM). Cysteamine also weakly inhibited the glucuronidation of acetaminophen (Ki = 2.44 mM). In vivo studies were in agreement with the results obtained in isolated hepatocytes; cysteamine moderately inhibited both glucuronidation and the cytochrome P-450-dependent formation of acetaminophen mercapturate. The overall elimination rate constant (beta) for acetaminophen was correspondingly decreased. Since cysteamine decreased both beta and the apparent rate constant for mercapturate formation (K'MA), the proportion of the dose of acetaminophen which is converted to the toxic metabolite (K'MA/beta) was not significantly decreased in the presence of cysteamine. Apparently, cysteamine does inhibit the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite, but this effect is not sufficient to explain antidotal protection.

  19. Electronic Spectra of the Jet-Cooled Acetaminophen

    NASA Astrophysics Data System (ADS)

    Lee, Seung Jun; Min, Ahreum; Kim, Yusic; Choi, Myong Yong; Chang, Jinyoung; Lee, Sang Hak; Kim, Seong Keun

    2010-06-01

    Resonant two-photon ionization (R2PI), laser induced fluorescence (LIF) and UV-UV double resonance spectra of the jet-cooled acetaminophen, widely used as a pain reliever and fever reducer, were obtained in the gas phase. Conformational characterizations for acetaminophen will be presented with an aid of spectroscopic techniques and DFT B3LYP calculations.

  20. Acetaminophen prevents oxidative burst and delays apoptosis in human neutrophils.

    PubMed

    Freitas, Marisa; Costa, Vera M; Ribeiro, Daniela; Couto, Diana; Porto, Graça; Carvalho, Félix; Fernandes, Eduarda

    2013-05-23

    Acetaminophen is a frequently prescribed over-the-counter drug to reduce fever and pain in the event of inflammatory process. As neutrophils are relevant cells in inflammatory processes, the putative interaction of acetaminophen with these cells, if present, would be of paramount importance. The present study was undertaken to evaluate the effect of acetaminophen in human neutrophils' oxidative burst and lifespan in vitro. The obtained results demonstrate that acetaminophen efficiently modulates neutrophils' oxidative burst in phorbol myristate acetate-activated neutrophils, in a concentration-dependent manner, at in vivo relevant concentrations. It was clearly demonstrated that acetaminophen is a strong scavenger of HOCl and H2O2, which probably contributed to the effect observed in neutrophils. Acetaminophen also induced the depletion of glutathione in stimulated neutrophils, suggesting its transformation into a reactive intermediate. Obtained results further revealed that acetaminophen affects programmed cell death of human neutrophils, resulting in a delay of previously stimulated neutrophils-mediated apoptosis. Overall, our data suggested that acetaminophen has considerable potential to be included in anti-inflammatory therapeutic strategies, by preventing biological damage induced by an excessive production of reactive species generated in activated neutrophils and by extending the lifespan of neutrophils, favoring the elimination of pathogens, thus contributing to tissue healing and resolution of inflammation. PMID:23518321

  1. Decrease of plasma and urinary oxidative metabolites of acetaminophen after consumption of watercress by human volunteers.

    PubMed

    Chen, L; Mohr, S N; Yang, C S

    1996-12-01

    To investigate the effect of the consumption of watercress (Nasturtium officinale R. Br.), a cruciferous vegetable, on acetaminophen metabolism, the pharmacokinetics of acetaminophen and its metabolites were studied in a crossover trial of human volunteers. A single oral dose of acetaminophen (1 gm) was given 10 hours after ingestion of watercress homogenates (50 gm). In comparison with acetaminophen only, the ingestion of watercress resulted in a significant reduction in the area under the plasma cysteine acetaminophen (Cys-acetaminophen) concentration-time curve and in the peak plasma Cys-acetaminophen concentration by 28% +/- 3% and by 21% +/- 4% (mean +/- SE; n = 7; p < 0.005), respectively. Correspondingly, the Cys-acetaminophen formation rate constant and Cys-acetaminophen formation fraction were decreased by 55% +/- 9% and 52% +/- 7% (p < 0.01), respectively. Consistent with the results obtained from the plasma, the total urinary excretion of Cys-acetaminophen in 24 hours was also reduced. A decrease of mercapturate acetaminophen, a Cys-acetaminophen metabolite, was also shown in the plasma and urine samples. However, the plasma pharmacokinetic processes and the urinary excretions of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were not altered significantly by the watercress treatment. These results suggest that the consumption of watercress causes a decrease in the levels of oxidative metabolites of acetaminophen, probably due to inhibition of oxidative metabolism of this drug.

  2. Police officers' and paramedics' experiences with overdose and their knowledge and opinions of Washington State's drug overdose-naloxone-Good Samaritan law.

    PubMed

    Banta-Green, Caleb J; Beletsky, Leo; Schoeppe, Jennifer A; Coffin, Phillip O; Kuszler, Patricia C

    2013-12-01

    Opioid overdoses are an important public health concern. Concerns about police involvement at overdose events may decrease calls to 911 for emergency medical care thereby increasing the chances than an overdose becomes fatal. To address this concern, Washington State passed a law that provides immunity from drug possession charges and facilitates the availability of take-home-naloxone (the opioid overdose antidote) to bystanders in 2010. To examine the knowledge and opinions regarding opioid overdoses and this new law, police (n = 251) and paramedics (n = 28) in Seattle, WA were surveyed. The majority of police (64 %) and paramedics (89 %) had been at an opioid overdose in the prior year. Few officers (16 %) or paramedics (7 %) were aware of the new law. While arrests at overdose scenes were rare, drugs or paraphernalia were confiscated at 25 % of the most recent overdoses police responded to. Three quarters of officers felt it was important they were at the scene of an overdose to protect medical personnel, and a minority, 34 %, indicated it was important they were present for the purpose of enforcing laws. Police opinions about the immunity and naloxone provisions of the law were split, and we present a summary of the reasons for their opinions. The results of this survey were utilized in public health efforts by the police department which developed a roll call training video shown to all patrol officers. Knowledge of the law was low, and opinions of it were mixed; however, police were concerned about the issue of opioid overdose and willing to implement agency-wide training.

  3. Hepatic histological alterations and biochemical changes induced by sildenafil overdoses.

    PubMed

    Jarrar, Bashir Mahmoud; Almansour, Mansour Ibrahim

    2015-11-01

    Sildenafil is used for the treatment of erectile dysfunction and is helping millions of men around the world to achieve and maintain a long lasting erection. Fifty healthy male rabbits (Oryctolagus cuniculus) were used in the present study and exposed daily to sildenafil (0, 1, 3, 6, 9 mg/kg) for 5 days per week for 7 weeks to investigate the biochemical changes and alterations in the hepatic tissues induced by this drug overdosing. In comparison with respective control rabbits, sildenafil overdoses elevated significantly (p-value<0.05, ANOVA test) alanine aminotransferase (ALT), aspartate aminotransferase (AST), testosterone, follicular stimulating hormone and total protein, while creatinine and urea were lowered with no significant alteration was observed in uric acid and luteinizing hormone concentration. Also sildenafil provoked hepatocytes nuclear alterations, necrosis, hydropic degeneration, bile duct hyperplasia, Kupffer cells hyperplasia, inflammatory cells infiltration, hepatic vessels congestion and evident partial depletion of glycogen content. The results show that subchronic exposure to sildenafil overdoses exhibits significant biochemical and alterations in the hepatic tissues that might affect the functions of the liver and other vital organs. PMID:26639481

  4. Clinical course and outcome in class IC antiarrhythmic overdose.

    PubMed

    Köppel, C; Oberdisse, U; Heinemeyer, G

    1990-01-01

    120 cases of class IC antiarrhythmic overdose, including propafenone, flecainide, ajmaline and prajmaline overdose, were evaluated with respect to clinical course, therapy and outcome. Whereas drug overdose in general has an overall mortality of less than 1%, intoxication with antiarrhythmic drugs of class IC was associated with a mean mortality of 22.5%. Nausea, which occurred within the first 30 minutes after ingestion, was the earliest symptom. Spontaneous vomiting probably led to self-detoxication in about half the patients. Cardiac symptoms including bradycardia and, less frequently, tachyrhythmia occurred after about 30 minutes to 2 hours. Therapeutic measures included administration of activated charcoal, gastric lavage and a saline laxative, catecholamines, and in some patients, hypertonic sodium bicarbonate, insertion of a transvenous pacemaker and hemoperfusion. Fatal outcome was mainly due to cardiac conduction disturbances progressing to electromechanical dissociation or asystolia. Resuscitation, which had to be performed in 29 patients, was successful in only two of them. No correlation was found between fatal outcome, the type of antiarrhythmic, and ingested dose. Since a specific treatment is not available and resuscitive procedures including sodium bicarbonate and insertion of a pacemaker are of limited therapeutic value, early diagnosis and primary detoxification are most important for prevention of fatal outcome. PMID:2176700

  5. Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo

    SciTech Connect

    Lin, Ming-Chung; Chen, Chia-Ling; Yang, Tsan-Tzu; Choi, Pui-Ching; Hsing, Chung-Hsi; Lin, Chiou-Feng

    2012-12-01

    An overdose and a prolonged treatment of propofol may cause cellular cytotoxicity in multiple organs and tissues such as brain, heart, kidney, skeletal muscle, and immune cells; however, the underlying mechanism remains undocumented, particularly in vascular endothelial cells. Our previous studies showed that the activation of glycogen synthase kinase (GSK)-3 is pro-apoptotic in phagocytes during overdose of propofol treatment. Regarding the intravascular administration of propofol, we therefore hypothesized that propofol overdose also induces endothelial cytotoxicity via GSK-3. Propofol overdose (100 μg/ml) inhibited growth in human arterial and microvascular endothelial cells. After treatment, most of the endothelial cells experienced caspase-independent necrosis-like cell death. The activation of cathepsin D following lysosomal membrane permeabilization (LMP) determined necrosis-like cell death. Furthermore, propofol overdose also induced caspase-dependent apoptosis, at least in part. Caspase-3 was activated and acted downstream of mitochondrial transmembrane potential (MTP) loss; however, lysosomal cathepsins were not required for endothelial cell apoptosis. Notably, activation of GSK-3 was essential for propofol overdose-induced mitochondrial damage and apoptosis, but not necrosis-like cell death. Intraperitoneal administration of a propofol overdose in BALB/c mice caused an increase in peritoneal vascular permeability. These results demonstrate the cytotoxic effects of propofol overdose, including cathepsin D-regulated necrosis-like cell death and GSK-3-regulated mitochondrial apoptosis, on endothelial cells in vitro and the endothelial barrier dysfunction by propofol in vivo. Highlights: ► Propofol overdose causes apoptosis and necrosis in endothelial cells. ► Propofol overdose triggers lysosomal dysfunction independent of autophagy. ► Glycogen synthase kinase-3 facilitates propofol overdose-induced apoptosis. ► Propofol overdose causes an increase

  6. Intravenous use of illicit buprenorphine/naloxone to reverse an acute heroin overdose.

    PubMed

    Yokell, Michael A; Zaller, Nickolas D; Green, Traci C; McKenzie, Michelle; Rich, Josiah D

    2012-01-01

    A case of heroin overdose reversed through the intravenous (IV) administration of a crushed sublingual tablet of buprenorphine/naloxone (Suboxone) by a lay responder is described. Although the sublingual administration of buprenorphine/naloxone to reverse an overdose has been reported elsewhere, this is the first report of IV administration. Healthcare professionals should be aware that injection drug users may respond to an opioid overdose by injecting buprenorphine/naloxone and should consequently counsel all opioid-using patients on the proper response to an overdose. Physicians should also consider prescribing naloxone to at-risk patients. The work of community-based naloxone distribution programs should be expanded. PMID:22479887

  7. Opioid Overdose Prevention Programs Providing Naloxone to Laypersons - United States, 2014.

    PubMed

    Wheeler, Eliza; Jones, T Stephen; Gilbert, Michael K; Davidson, Peter J

    2015-06-19

    Drug overdose deaths in the United States have more than doubled since 1999. During 2013, 43,982 drug overdose deaths (unintentional, intentional [suicide or homicide], or undetermined intent) were reported. Among these, 16,235 (37%) were associated with prescription opioid analgesics (e.g., oxycodone and hydrocodone) and 8,257 (19%) with heroin. For many years, community-based programs have offered opioid overdose prevention services to laypersons who might witness an overdose, including persons who use drugs, their families and friends, and service providers. Since 1996, an increasing number of programs provide laypersons with training and kits containing the opioid antagonist naloxone hydrochloride (naloxone) to reverse the potentially fatal respiratory depression caused by heroin and other opioids. In July 2014, the Harm Reduction Coalition (HRC), a national advocacy and capacity-building organization, surveyed 140 managers of organizations in the United States known to provide naloxone kits to laypersons. Managers at 136 organizations completed the survey, reporting on the amount of naloxone distributed, overdose reversals by bystanders, and other program data for 644 sites that were providing naloxone kits to laypersons as of June 2014. From 1996 through June 2014, surveyed organizations provided naloxone kits to 152,283 laypersons and received reports of 26,463 overdose reversals. Providing opioid overdose training and naloxone kits to laypersons who might witness an opioid overdose can help reduce opioid overdose mortality. PMID:26086633

  8. Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

    SciTech Connect

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-05-15

    Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1{sup -/-} mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1{sup -/-} mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1beta, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1{sup -/-} mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1{sup -/-} mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

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

    SciTech Connect

    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

    2013-01-15

    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.

  10. Rationale for Use of Intravenous Acetaminophen in Special Operations Medicine.

    PubMed

    Vokoun, Edward Scott

    2015-01-01

    Use of intravenous acetaminophen has increased recently as an opioid-sparing strategy for patients undergoing major surgery. Its characteristics and efficacy suggest that it would a useful adjunct in combat trauma medicine. This article reviews those characteristics, which include rapid onset, high peak plasma concentration, and favorable side-effect profile. Also discussed is the hepatotoxicity risk of acetaminophen in a combat trauma patient. It concludes that intravenous acetaminophen should be considered as an addition to the US Special Operations Command Tactical Trauma Protocols and supplied to medics for use in field care.

  11. Mechanisms of Acetaminophen-Induced Liver Necrosis

    PubMed Central

    Roberts, Dean W.; James, Laura P.

    2010-01-01

    Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function. PMID:20020268

  12. High risk and little knowledge: Overdose experiences and knowledge among young adult nonmedical prescription opioid users

    PubMed Central

    Frank, David; Mateu-Gelabert, Pedro; Guarino, Honoria; Bennett, Alex; Wendel, Travis; Jessell, Lauren; Teper, Anastasia

    2014-01-01

    Background Opioid-involved overdoses in the United States have dramatically increased in the last 15 years, largely due to a rise in prescription opioid (PO) use. Yet few studies have examined the overdose knowledge and experience of nonmedical PO users. Methods In depth, semi-structured, audio-recorded interviews were conducted with 46 New York City young adults (ages 18–32) who reported using POs nonmedically within the past 30 days. Verbatim interview transcripts were coded for key themes in an analytic process informed by grounded theory. Results Despite significant experience with overdose (including overdose deaths), either personally or within opioid-using networks, participants were relatively uninformed about overdose awareness, avoidance and response strategies, in particular the use of naloxone. Overdose experiences typically occurred when multiple pharmaceuticals were used (often in combination with alcohol) or after participants had transitioned to heroin injection. Participants tended to see themselves as distinct from traditional heroin users, and were often outside of the networks reached by traditional opioid safety/overdose prevention services. Consequently, they were unlikely to utilize harm reduction services, such as syringe exchange programs (SEPs), that address drug users' health and safety. Conclusions These findings suggest that many young adult nonmedical PO users are at high risk of both fatal and non-fatal overdose. There is a pressing need to develop innovative outreach strategies and overdose prevention programs to better reach and serve young PO users and their network contacts. Prevention efforts addressing risk for accidental overdose, including opioid safety/overdose reversal education and naloxone distribution, should be tailored for and targeted to this vulnerable group. PMID:25151334

  13. Self-cutting versus intentional overdose: psychological risk factors.

    PubMed

    Larkin, C; Di Blasi, Z; Arensman, E

    2013-08-01

    Individuals who present to emergency departments with self-harm are at elevated risk of further self-harm and suicide, and these risks are yet higher among patients who self-cut. Repetitive self-injury has previously been explained using a behaviourist approach focussing on operant conditioning, but we propose that the increased risk of self-harm repetition among those who present with self-cutting is at least partly mediated by pre-existing psychological risk factors. Several studies show that those who present with self-cutting differ from intentional overdose patients on demographic, psychiatric and social factors, but, based on findings from community-based studies, we hypothesise that there may be additional psychological differences that may also be associated with increased repetition risk. We conducted a small-scale cohort study of 29 self-harm patients presenting to A&E and compared theoretically-derived psychological variables between 8 self-cutting and 21 overdose patients. Those presenting with self-cutting scored significantly higher on hopelessness and lower on non-reactivity to inner experience and generally had a more vulnerable profile than those presenting with overdose. These findings support our hypothesis that the association between self-cutting and prospective repetition is at least partly due to pre-existing psychological vulnerabilities that increase both the likelihood of engaging in self-cutting as a method of self-harm and the likelihood of subsequent repetition of self-harm. Existing evidence suggests that self-cutting is a risk factor for repetition of self-harm, and it is possible that reducing and preventing repetition among these patients can be achieved by implementing psychological interventions to reduce hopelessness and increase tolerance of emotional distress.

  14. We use Continuous Renal Replacement Therapy for Overdoses and Intoxications.

    PubMed

    Cabrera, Valerie Jorge; Shirali, Anushree C

    2016-07-01

    Extracorporeal modalities for the removal of drugs and toxins are indicated for the treatment of overdoses and intoxications. Well-established modalities include hemodialysis (HD), high-flux HD (HfD), and charcoal hemoperfusion (HP). Recently, there have been increasing reports on the use of continuous renal replacement therapy (CRRT), such as continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemofiltration (CVVH) or CVVH combined with dialysis (CVVHDF). In the present article, we will discuss the various factors that determine the clearance of drugs and toxins and accordingly, we will propose that with few exceptions, CRRT does not have a role in the routine management of intoxications.

  15. The aftermath of Angie's overdose: is soap (opera) damaging to your health?

    PubMed Central

    Platt, S

    1987-01-01

    In a study designed to evaluate the behavioural impact of a fictional parasuicide--namely, Angie's overdose on the popular television soap opera EastEnders--information about cases of deliberate overdose treated in accident and emergency departments in 63 hospitals throughout Britain was obtained for the week after the televised overdose (experimental period) and the week before the overdose (control period). After adjusting for trends in the equivalent weeks in a control year (1985) the increase in the cases of parasuicide treated by hospitals during the experimental week was not found to be significant. A significant increase (31%) was found among people aged greater than or less than 45, but this is not thought to be reliable. The increase among women alone (21%) was significant with a one tailed test. Contrary to expectations there was a positive association between trends in overdose and distance from London--that is, the further the distance of the region from London the greater the increase in cases of overdose during the experimental period--and a negative association between trends in overdose and viewing figures--that is, the higher the viewing figure the less the impact on the incidence of overdoses. These findings do not lend support to the claim that there was a strong imitation effect after this televised parasuicide. PMID:3107671

  16. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol

    SciTech Connect

    Tee, L.B.; Boobis, A.R.; Huggett, A.C.; Davies, D.S.

    1986-04-01

    The toxicity of acetaminophen in freshly isolated hamster hepatocytes was investigated. Cells exposed to 2.5 mM acetaminophen for 90 min, followed by washing to completely remove unbound acetaminophen, and resuspension in fresh buffer, showed a dramatic decrease in viability over the ensuing 4.5 hr by which time only 4% of the cells could still exclude trypan blue. During the initial 90-min incubation, there was a substantial depletion of glutathione, to 19% of control values, covalent binding of (/sup 14/C)acetaminophen to cellular proteins, and evidence of morphological changes consistent with some disturbance of the plasma membrane. During subsequent incubation of these cells, covalent binding did not change nor did lipid peroxidation, despite the decrease in viability that occurred. Subsequent incubation of cells exposed to acetaminophen for 90 min in buffer containing 1.5 mM dithiothreitol (DTT), a disulfide-reducing agent, largely prevented the decrease in cell viability and reversed the morphological changes that occurred during the first 90-min incubation. However, there was no change in lipid peroxidation, glutathione content, or covalent binding. It is concluded that acetaminophen interacted with some critical target in the cell, and that this left unchecked, led eventually to the death of the cell. DTT prevented and reversed this effect. The toxicity of acetaminophen, and its reversal by DTT, appear independent of either covalent binding of acetaminophen or lipid peroxidation. In addition, the effect of DTT was independent of the concentration of glutathione, most probably acting by directly reducing oxidized SH-groups in critical enzymes, possibly membrane-bound ATP-dependent Ca2+ translocases.

  17. Awareness and Attitudes Toward Intranasal Naloxone Rescue for Opioid Overdose Prevention.

    PubMed

    Kirane, Harshal; Ketteringham, Michael; Bereket, Sewit; Dima, Richie; Basta, Ann; Mendoza, Sonia; Hansen, Helena

    2016-10-01

    Opioid overdose prevention is a pressing public health concern and intranasal naloxone rescue kits are a useful tool in preventing fatal overdose. We evaluated the attitudes, knowledge, and experiences of patients and providers related to overdose and naloxone rescue. Over a six month period, patients and providers within a large community hospital in Staten Island were recruited to complete tailored questionnaires for their respective groupings. 100 patients and 101 providers completed questionnaires between August, 2014 and January, 2015. Patient participants were primarily Caucasian males with a mean age of 37.7 years, of which 65% accurately identified naloxone for opioid overdose, but only 21% knew more specific clinical features. 68% of patients had previously witnessed a drug overdose. Notably, 58% of patients anticipated their behavior would change if provided access to an intranasal naloxone rescue kit, of which 83% predicted an increase in opioid use. Prior overdose was significantly correlated with anticipating no change in subsequent opioid use pattern (p=0.02). 99% of patients reported that their rapport with their health-care provider would be enhanced if offered an intranasal naloxone rescue kit. As for providers, 24% had completed naloxone rescue kit training, and 96% were able to properly identify its clinical application. 50% of providers felt naloxone access would decrease the likelihood of an overdose occurring, and 58% felt it would not contribute to high-risk behavior. Among providers, completion of naloxone training was correlated with increased awareness of where to access kits for patients (p<0.001). This study suggests that patients and providers have distinct beliefs and attitudes toward overdose prevention. Patient-Provider discussion of overdose prevention enhances patients' rapport with providers. However, access to an intranasal naloxone rescue kit may make some patients more vulnerable to high-risk behavior. Future research efforts

  18. Effect of acetaminophen on sulfamethazine acetylation in male volunteers.

    PubMed

    Tahir, I M; Iqbal, T; Saleem, S; Mehboob, H; Akhter, N; Riaz, M

    2016-03-01

    The effect of acetaminophen on sulfamethazine N-acetylation by human N-acetyltrasferase-2 (NAT2) was studied in 19 (n=19) healthy male volunteers in two different phases. In the first phase of the study the volunteers were given an oral dose of sulfamethazine 500 mg alone and blood and urine samples were collected. After the 10-day washout period the same selected volunteers were again administered sulfamethazine 500 mg along with 1000 mg acetaminophen. The acetylation of sulfamethazine by human NAT2 in both phases with and without acetaminophen was determined by HPLC to establish their respective phenotypes. In conclusion obtained statistics of present study revealed that acetaminophen significantly (P<0.0001) decreased sulfamethazine acetylation in plasma of both slow and fast acetylator male volunteers. A highly significant (P<0.0001) decrease in plasma-free and total sulfamethazine concentration was also observed when acetaminophen was co-administered. Urine acetylation status in both phases of the study was found not to be in complete concordance with that of plasma. Acetaminophen significantly (P<0.0001) increased the acetyl, free and total sulfamethazine concentration in urine of both slow and fast acetylators. Urine acetylation analysis has not been found to be a suitable approach for phenotypic studies.

  19. Opioid overdose with gluteal compartment syndrome and acute peripheral neuropathy

    PubMed Central

    Adrish, Muhammad; Duncalf, Richard; Diaz-Fuentes, Gilda; Venkatram, Sindhaghatta

    2014-01-01

    Patient: Male, 42 Final Diagnosis: Gluteal compartment syndrome • acute peripheral nauropathy Symptoms: — Medication: — Clinical Procedure: — Specialty: Critical Care Medicine Objective: Management of emergency care Background: Heroin addiction is common, with an estimated 3.7 million Americans reporting to have used it at some point in their lives. Complications of opiate overdose include infection, rhabdomyolysis, respiratory depression and central or peripheral nervous system neurological complications. Conclusions: We present a 42-year-old male admitted after heroin use with heroin-related peripheral nervous system complication preceded by an acute gluteal compartment syndrome and severe rhabdomyolysis. Case Report: Early diagnosis and surgical intervention of the compartment syndrome can lead to full recovery while any delay in management can be devastating and can lead to permanent disability. The presence of peripheral nervous system injuries may portend a poor prognosis and can also lead to long term disability. Careful neurological evaluation for signs and symptoms of peripheral nervous system injuries is of paramount importance, as these may be absent at presentation in patients with opioid overdose. There is a potential risk of delaying a necessary treatment like fasciotomy in these patients by falsely attributing clinical symptoms to a preexisting neuropathy. Early EMG and nerve conduction studies should be considered when the etiology of underlying neurological weakness is unclear. PMID:24459539

  20. Characterization of methadone overdose: clinical considerations and the scientific evidence.

    PubMed

    Wolff, Kim

    2002-08-01

    Overdosing with methadone is a growing phenomenon in Britain and other countries due to the increase in prescription and the availability of this compound. Little is known of the circumstances surrounding methadone death due to some extent to the difficulty of defining drug-related death and also the difficulty of collecting clinical and biographical data in a predominantly illegal and marginal milieu. However, the evidence points to highest risk at night (to this end manifestations of its toxicity often go unrecognized) in those whose usual tolerance has been reduced and occurring some considerable time after ingestion. Further investigations are needed to elucidate fully the mechanism and spectrum of methadone overdose. Death from methadone is eminently preventable more so because of the long-term nature of the clinical sequelae. Indeed the key issue with methadone that sets it apart from other opioids is its potential for delayed toxicity. Consequently steps should be taken to disseminate the salient facts to all those who come into contact with the drug.

  1. Ocfentanil overdose fatality in the recreational drug scene.

    PubMed

    Coopman, Vera; Cordonnier, Jan; De Leeuw, Marc; Cirimele, Vincent

    2016-09-01

    This paper describes the first reported death involving ocfentanil, a potent synthetic opioid and structure analogue of fentanyl abused as a new psychoactive substance in the recreational drug scene. A 17-year-old man with a history of illegal substance abuse was found dead in his home after snorting a brown powder purchased over the internet with bitcoins. Acetaminophen, caffeine and ocfentanil were identified in the powder by gas chromatography mass spectrometry and reversed-phase liquid chromatography with diode array detector. Quantitation of ocfentanil in biological samples was performed using a target analysis based on liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry. In the femoral blood taken at the external body examination, the following concentrations were measured: ocfentanil 15.3μg/L, acetaminophen 45mg/L and caffeine 0.23mg/L. Tissues sampled at autopsy were analyzed to study the distribution of ocfentanil. The comprehensive systematic toxicological analysis on the post-mortem blood and tissue samples was negative for other compounds. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of death was an acute intoxication with ocfentanil. The manner of death was assumed to be accidental after snorting the powder. PMID:27471990

  2. Ocfentanil overdose fatality in the recreational drug scene.

    PubMed

    Coopman, Vera; Cordonnier, Jan; De Leeuw, Marc; Cirimele, Vincent

    2016-09-01

    This paper describes the first reported death involving ocfentanil, a potent synthetic opioid and structure analogue of fentanyl abused as a new psychoactive substance in the recreational drug scene. A 17-year-old man with a history of illegal substance abuse was found dead in his home after snorting a brown powder purchased over the internet with bitcoins. Acetaminophen, caffeine and ocfentanil were identified in the powder by gas chromatography mass spectrometry and reversed-phase liquid chromatography with diode array detector. Quantitation of ocfentanil in biological samples was performed using a target analysis based on liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry. In the femoral blood taken at the external body examination, the following concentrations were measured: ocfentanil 15.3μg/L, acetaminophen 45mg/L and caffeine 0.23mg/L. Tissues sampled at autopsy were analyzed to study the distribution of ocfentanil. The comprehensive systematic toxicological analysis on the post-mortem blood and tissue samples was negative for other compounds. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of death was an acute intoxication with ocfentanil. The manner of death was assumed to be accidental after snorting the powder.

  3. Responding to opioid overdose in Rhode Island: where the medical community has gone and where we need to go.

    PubMed

    Green, Traci C; Bratberg, Jef; Dauria, Emily F; Rich, Josiah D

    2014-10-01

    The number of opioid overdose events in Rhode Island has increased dramatically/catastrophically in the last decade; Rhode Island now has one of the highest per capita overdose death rates in the country. Healthcare professionals have an important role to play in the reduction of unintentional opioid overdose events. This article explores the medical community's response to the local opioid overdose epidemic and proposes strategies to create a more collaborative and comprehensive response. We emphasize the need for improvements in preventing, identifying and treating opioid addiction, providing overdose education and ensuring access to the rescue medicine naloxone.

  4. Opioid Prescribing and Potential Overdose Errors Among Children 0 to 36 Months Old

    PubMed Central

    Basco, William T.; Ebeling, Myla; Garner, Sandra S.; Hulsey, Thomas C.; Simpson, Kit

    2015-01-01

    Objective To estimate the frequency of potential overdoses among outpatient opioid-containing prescriptions. Method Using 11 years of outpatient Medicaid prescription data, we compared opioid dose dispensed (observed) versus expected dose to estimate overdose error frequencies. A potential overdose was defined as any preparation dispensed that was >110% of expected based on imputed, 97th percentile weights. Results There were 59 536 study drug prescriptions to children 0 to 36 months old. Overall, 2.7% of the prescriptions contained potential overdose quantities, and the average excess amount dispensed was 48% above expected. Younger ages were associated with higher frequencies of potential overdose. For example, 8.9% of opioid prescriptions among infants 0 to 2 months contained potential overdose quantities, compared with 5.7% among infants 3 to 5 months old, 3.6% among infants 6 to 11 months old, and 2.3% among children >12 months (P < .0001). Conclusions Opioid prescriptions for infants and children routinely contained potential overdose quantities. PMID:25971461

  5. Two cases of intranasal naloxone self-administration in opioid overdose

    PubMed Central

    Green, Traci C.; Ray, Madeline; Bowman, Sarah E.; McKenzie, Michelle; Rich, Josiah D.

    2013-01-01

    Background Overdose is a leading cause of death for former prisoners, exacting its greatest toll during the first 2 weeks post-release. Protective effects have been observed with training individuals at high risk of overdose and prescribing them naloxone, an opioid antagonist that reverses the effects of the opioid-induced respiratory depression that causes death. Cases We report two people with opiate use histories who self-administered intranasal naloxone to treat their own heroin overdoses following release from prison. Patient A is a 34-year-old male, who reported having experienced an overdose on heroin the day after he was released from incarceration. Patient B is a 29-year-old female, who reported an