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Sample records for acetaminophen apap overdose

  1. Acetaminophen overdose

    MedlinePlus

    ... a variety of over-the-counter and prescription pain relievers. Tylenol is a brand name for acetaminophen. Other ... team. Related MedlinePlus Health Topics Medicines and Children Pain Relievers Browse the Encyclopedia A.D.A.M., Inc. ...

  2. Acetaminophen and codeine overdose

    MedlinePlus

    ... Concepts and Clinical Practice. 8th ed. Philadelphia, PA: Elsevier Saunders; 2014:chap 162. Doyon S. Opioids. In: Tintinalli ... FF, ed. Ferri's Clinical Advisor 2015. Philadelphia, PA: Elsevier; 2014:appendix VI. Hendrickson RG, McKeown NJ. Acetaminophen. ...

  3. 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

  4. 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. PMID:26931552

  5. 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

  6. N-acetylcysteine overdose after acetaminophen poisoning.

    PubMed

    Mahmoudi, Ghafar Ali; Astaraki, Peyman; Mohtashami, Azita Zafar; Ahadi, Maryam

    2015-01-01

    N-acetylcysteine (NAC) is used widely and effectively in oral and intravenous forms as a specific antidote for acetaminophen poisoning. Here we report a rare case of iatrogenic NAC overdose following an error in preparation of the solution, and describe its clinical symptoms. Laboratory results and are presented and examined. A 23-year-old alert female patient weighing 65 kg presented to the emergency ward with weakness, lethargy, extreme fatigue, nausea, and dizziness. She had normal arterial blood gas and vital signs. An excessive dosage of NAC over a short period of time can lead to hemolysis, thrombocytopenia, and acute renal failure in patients with normal glucose-6-phosphate dehydrogenase, and finally to death. Considering the similarity between some of the clinical symptoms of acetaminophen overdose and NAC overdose, it is vitally important for the administration phases and checking of the patient's symptoms to be carried out attentively and cautiously. PMID:25767408

  7. 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

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

    PubMed

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

    2014-09-01

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

  9. 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

  10. 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

  11. 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

  12. 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

  13. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils.

    PubMed

    Lawson, J A; Farhood, A; Hopper, R D; Bajt, M L; Jaeschke, H

    2000-04-01

    Acetaminophen overdose induces severe liver injury and hepatic failure. There is evidence that inflammatory cells may be involved in the pathophysiology. Thus, the aim of this investigation was to characterize the neutrophilic inflammatory response after treatment of C3Heb/FeJ mice with 300 mg/kg acetaminophen. A time course study showed that neutrophils accumulate in the liver parallel to or slightly after the development of liver injury. The number of neutrophils in the liver was substantial (209 +/- 64 PMN/50 high-power fields at 12 h) compared to baseline levels (7 +/- 1). Serum levels of TNF-alpha and the C-X-C chemokines KC and MIP-2 increased by 28-, 14-, and 295-fold, respectively, over levels found in controls during the injury process. In addition, mRNA expression of MIP-2 and KC were upregulated in livers of acetaminophen-treated animals as determined by ribonuclease protection assay. However, none of these mediators were generated in large enough quantities to account for neutrophil sequestration in the liver. There was no upregulation of Mac-1 (CD11b/ CD18) or shedding of L-selectin on circulating neutrophils. Moreover, an anti-CD18 antibody had no protective effect against acetaminophen overdose during the first 24 h. These results indicate that there is a local inflammatory response after acetaminophen overdose, including a substantial accumulation of neutrophils in the liver. Because of the critical importance of beta2 integrins for neutrophil cytotoxicity, these results suggest that neutrophils do not contribute to the initiation or progression of AAP-induced liver. The inflammation observed after acetaminophen overdose may be characteristic for a response sufficient to recruit neutrophils for the purpose of removing necrotic cells but is not severe enough to cause additional damage. PMID:10774834

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

    PubMed Central

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

    2014-01-01

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

  15. 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

  16. 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

  17. Role of Bile Acids in Liver Injury and Regeneration following Acetaminophen Overdose

    PubMed Central

    Bhushan, Bharat; Borude, Prachi; Edwards, Genea; Walesky, Chad; Cleveland, Joshua; Li, Feng; Ma, Xiaochao; Apte, Udayan

    2014-01-01

    Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)–induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)–containing diet for bile acid depletion, or a 0.2% cholic acid (CA)–containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet–fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury. PMID:24007882

  18. Role of bile acids in liver injury and regeneration following acetaminophen overdose.

    PubMed

    Bhushan, Bharat; Borude, Prachi; Edwards, Genea; Walesky, Chad; Cleveland, Joshua; Li, Feng; Ma, Xiaochao; Apte, Udayan

    2013-11-01

    Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)-induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)-containing diet for bile acid depletion, or a 0.2% cholic acid (CA)-containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet-fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury. PMID:24007882

  19. [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

  20. 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

  1. Plasminogen Activator Inhibitor-1 Limits Liver Injury and Facilitates Regeneration after Acetaminophen Overdose

    PubMed Central

    Bajt, Mary Lynn; Yan, Hui-Min; Farhood, Anwar; Jaeschke, Hartmut

    2008-01-01

    Deficiency in plasminogen activator inhibitor-1 (PAI-1) gene expression is known to promote growth factor activation and regeneration in a number of hepatotoxicity models. To evaluate if PAI-1 has similar effects in acetaminophen (APAP) hepatotoxicity, wild-type (WT) and PAI-1 gene knockout mice (PAI-KO) were treated with 200 mg/kg APAP and liver injury and its repair were assessed. In WT animals, plasma alanine aminotransferase (ALT) activities increased during the first 12 h and then returned to baseline within 48 h. The area of necrosis increased in parallel to the ALT values, peaked between 12 and 24 h and was completely resolved by 96 h. The regenerative response of cells outside the necrotic area, as indicated by proliferating cell nuclear antigen protein and cyclin D1 gene expression, was observed within 24 h, peaked at 48 h and then declined but remained elevated until 96 h. Liver injury in response to APAP was similar in PAI-KO as in WT animals during the first 12 h. However, plasma ALT values and the area of necrosis further increased during the following 12 h with development of massive intrahepatic hemorrhage. Approximately, 50% of the PAI-KO animals did not survive. Although liver injury of the surviving animals was repaired, the regeneration process was delayed until 48 h. A potential reason for this delay may have been due to the more severe injury and/or the increased expression of the cell cycle inhibitor p21. Our data indicate that PAI activation limits liver injury and mortality during APAP hepatotoxicity by preventing excessive hemorrhage and thereby facilitating tissue repair. PMID:18469330

  2. Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose.

    PubMed

    Bajt, Mary Lynn; Yan, Hui-Min; Farhood, Anwar; Jaeschke, Hartmut

    2008-08-01

    Deficiency in plasminogen activator inhibitor-1 (PAI-1) gene expression is known to promote growth factor activation and regeneration in a number of hepatotoxicity models. To evaluate if PAI-1 has similar effects in acetaminophen (APAP) hepatotoxicity, wild-type (WT) and PAI-1 gene knockout mice (PAI-KO) were treated with 200 mg/kg APAP and liver injury and its repair were assessed. In WT animals, plasma alanine aminotransferase (ALT) activities increased during the first 12 h and then returned to baseline within 48 h. The area of necrosis increased in parallel to the ALT values, peaked between 12 and 24 h and was completely resolved by 96 h. The regenerative response of cells outside the necrotic area, as indicated by proliferating cell nuclear antigen protein and cyclin D(1) gene expression, was observed within 24 h, peaked at 48 h and then declined but remained elevated until 96 h. Liver injury in response to APAP was similar in PAI-KO as in WT animals during the first 12 h. However, plasma ALT values and the area of necrosis further increased during the following 12 h with development of massive intrahepatic hemorrhage. Approximately, 50% of the PAI-KO animals did not survive. Although liver injury of the surviving animals was repaired, the regeneration process was delayed until 48 h. A potential reason for this delay may have been due to the more severe injury and/or the increased expression of the cell cycle inhibitor p21. Our data indicate that PAI activation limits liver injury and mortality during APAP hepatotoxicity by preventing excessive hemorrhage and thereby facilitating tissue repair. PMID:18469330

  3. 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

  4. 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

  5. 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

  6. 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

  7. Novel protective mechanisms for S-adenosyl-L-methionine against acetaminophen hepatotoxicity: improvement of key antioxidant enzymatic function.

    PubMed

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

    2012-08-01

    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

  8. 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. PMID:24080264

  9. 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

  10. 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

  11. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis?

    PubMed

    Gujral, Jaspreet S; Knight, Tamara R; Farhood, Anwar; Bajt, Mary Lynn; Jaeschke, Hartmut

    2002-06-01

    Acetaminophen (AAP) overdose can cause severe liver injury and liver failure in experimental animals and humans. Recently, several authors proposed that apoptosis might be a major mechanism of cell death after AAP treatment. To address this controversial issue, we evaluated a detailed time course of liver injury after AAP (300 mg/kg) in fasted C3Heb/FeJ mice. Apoptotic hepatocytes were quantified in H&E-stained liver sections using morphologic criteria (cell shrinkage, chromatin condensation and margination, and apoptotic bodies). The number of apoptotic hepatocytes remained at baseline (0.2 +/- 0.1 cells/10 high-power fields [HPF]) up to 2 h after AAP administration. However, between 3 and 24 h, apoptotic cell death increased significantly, e.g., 6.3 +/- 0.8 cells/10 HPF at 6 h. Despite the increase in the number of hepatocytes meeting the morphological criteria of apoptosis, this cell fraction remained well below 1% of all parenchymal cells. No evidence for caspase-3 processing or increase in enzyme activity was detected at any time. These results were compared to the overall percent of necrotic cells in liver sections. Confluent areas of centrilobular necrosis were estimated to involve 40-60% of all hepatocytes between 3 and 24 h after AAP administration. These numbers correlated with the increase in plasma alanine aminotransferase activities, which reached a peak level of 5900 +/- 1350 U/l at 24 h. A similar result was obtained with higher doses of AAP and with the use of fed animals. Thus, oncotic necrosis and not apoptosis is the principal mechanism of liver-cell death after AAP overdose in vivo. PMID:12011492

  12. 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%.

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

    PubMed

    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(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. PMID:24440789

  14. Neutrophil Activation During Acetaminophen Hepatotoxicity and Repair in Mice and Humans

    PubMed Central

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

    2014-01-01

    Following acetaminophen (APAP) overdose there is an inflammatory response triggered by release of cellular contents from necrotic hepatocytes into 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 is 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: >800U/L) had serial blood draws during the injury and recovery phases for determination of neutrophil activation. Neutrophils in the peripheral blood of mice showed 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, gp91phox-/- 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 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. PMID:24440789

  15. 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

  16. ROLE OF CASPASE-1 AND INTERLEUKIN-1β IN ACETAMINOPHEN-INDUCED HEPATIC INFLAMMATION AND LIVER INJURY

    PubMed Central

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

    2010-01-01

    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-1β signaling has been implicated in the potentiating of APAP-induced liver injury. To test if IL-1β 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-1β during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1β gene transcription but prevented the increase in IL-1β plasma levels. However, APAP-induced liver injury and neutrophil infiltration was 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-1β to increase injury, mice were given pharmacological doses of IL-1β 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-1β formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1β, 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. PMID:20637792

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

    PubMed

    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-1beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1beta 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-1beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1beta gene transcription but prevented the increase in IL-1beta 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-1beta to increase injury, mice were given pharmacological doses of IL-1beta 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-1beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1beta, 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. PMID:20637792

  18. 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.

  19. 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

  20. Acute renal dysfunction in acetaminophen poisoning.

    PubMed

    Mour, Girish; Feinfeld, Donald A; Caraccio, Thomas; McGuigan, Michael

    2005-01-01

    Although acetaminophen (APAP)-associated liver injury is well recognized, there are few reports describing APAP nephrotoxicity, and most of them are single cases. It has also been suggested that N-acetylcysteine (NAC), used to treat the hepatotoxicity, may be harmful to the kidneys. To examine this contention and to determine whether renal involvement in APAP poisoning is at all common, we analyzed the incidence and outcome of acute renal dysfunction in patients hospitalized for APAP overdose reported to our regional poison center over a year. Eleven APAP-poisoned patients had elevated liver function tests; nine of them had azotemia. Those with higher AST levels tended to be younger and to have lower APAP levels on admission. Two patients with acute renal injury died after admission. The other seven patients with renal dysfunction recovered in 2 to 7 days. Six of these received NAC; their mean serum creatinine fell from 3.2 +/- 2.0 versus 1.7 +/- 0.9 mg/dL (p < 0.05). We conclude that acute renal failure is not uncommon in APAP poisoning and appears to be unrelated to the degree of liver injury. NAC therapy did not seem to worsen nephrotoxicity. PMID:16060123

  1. 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

  2. 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

  3. Carnosic acid protects against acetaminophen-induced hepatotoxicity by potentiating Nrf2-mediated antioxidant capacity in mice

    PubMed Central

    Guo, Qi; Shen, Zhiyang; Yu, Hongxia; Lu, Gaofeng; Yu, Yong; Liu, Xia

    2016-01-01

    Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure. The study aimed to investigate the protective effect of carnosic acid (CA) on APAP-induced acute hepatotoxicity and its underlying mechanism in mice. To induce hepatotoxicity, APAP solution (400 mg/kg) was administered into mice by intraperitoneal injection. Histological analysis revealed that CA treatment significantly ameliorated APAP-induced hepatic necrosis. The levels of both alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum were reduced by CA treatment. Moreover, CA treatment significantly inhibited APAP-induced hepatocytes necrosis and lactate dehydrogenase (LDH) releasing. Western blot analysis showed that CA abrogated APAP-induced cleaved caspase-3, Bax and phosphorylated JNK protein expression. Further results showed that CA treatment markedly inhibited APAP-induced pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and MCP-1 mRNA expression and the levels of phosphorylated IκBα and p65 protein in the liver. In addition, CA treatment reduced APAP- induced hepatic malondialdehyde (MDA) contents and reactive oxygen species (ROS) accumulation. Conversely, hepatic glutathione (GSH) level was increased by administration of CA in APAP-treated mice. Mechanistically, CA facilitated Nrf2 translocation into nuclear through blocking the interaction between Nrf2 and Keap1, which, in turn, upregulated anti-oxidant genes mRNA expression. Taken together, our results indicate that CA facilitates Nrf2 nuclear translocation, causing induction of Nrf2-dependent genes, which contributes to protection from acetaminophen hepatotoxicity. PMID:26807019

  4. 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

  5. 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

  6. 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.

  7. ROLE OF THE NALP3 INFLAMMASOME IN ACETAMINOPHEN-INDUCED STERILE INFLAMMATION AND LIVER INJURY

    PubMed Central

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

    2011-01-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this investigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (Caspase-1, ASC and NALP3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose. PMID:21396389

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

    PubMed

    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-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300mg/kg APAP for 24h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose. PMID:21396389

  9. 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.

  10. 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

  11. 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. PMID:25835736

  12. 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

  13. 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

  14. New Therapeutic Approach: Diphenyl Diselenide Reduces Mitochondrial Dysfunction in Acetaminophen-Induced Acute Liver Failure

    PubMed Central

    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

  15. 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

  16. Acetaminophen-induced microvascular injury in the rat liver: protection with misoprostol.

    PubMed

    Lim, S P; Andrews, F J; O'Brien, P E

    1995-12-01

    Studies into the mechanism of acetaminophen (APAP)-induced hepatotoxicity have focused mainly at the hepatocellular level. This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was administered at a dose of 650 mg/kg body weight (intraperitoneally) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug administration. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hours after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hours after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids including areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol (a prostaglandin E1 analog) treatment (6 x 25 micrograms/kg) given before and after acetaminophen administration markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with APAP resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level. PMID:7489988

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice

    PubMed Central

    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

  3. Apoptosis-Inducing Factor Modulates Mitochondrial Oxidant Stress in Acetaminophen Hepatotoxicity

    PubMed Central

    Bajt, Mary Lynn; Ramachandran, Anup; Yan, Hui-Min; Lebofsky, Margitta; Farhood, Anwar; Lemasters, John J.; Jaeschke, Hartmut

    2011-01-01

    Acetaminophen (APAP) overdose causes liver injury in humans and mice. DNA fragmentation is a hallmark of APAP-induced cell death, and nuclear translocation of apoptosis-inducing factor (AIF) correlates with DNA fragmentation after APAP overdose. To test the hypothesis that AIF may be a critical mediator of APAP-induced cell death, fasted male AIF-deficient Harlequin (Hq) mice and respective wild-type (WT) animals were treated with 200 mg/kg APAP. At 6 h after APAP, WT animals developed severe liver injury as indicated by the increase in plasma alanine aminotransferase (ALT) activities (8600 ± 1870 U/l) and 61 ± 8% necrosis. This injury was accompanied by massive DNA strand breaks in centrilobular hepatocytes (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL] assay) and release of DNA fragments into the cytosol (anti-histone ELISA). In addition, there was formation of reactive oxygen (increase in liver glutathione disulfide (GSSG) levels and mitochondrial protein carbonyls) and peroxynitrite (nitrotyrosine [NT] staining) together with mitochondrial translocation of activated c-jun-N-terminal kinase (P-JNK) and release of AIF from the mitochondria. In contrast, Hq mice had significantly less liver injury (ALT: 330 ± 130 U/l; necrosis: 4 ± 2%), minimal nuclear DNA damage, and drastically reduced oxidant stress (based on all parameters) at 6 h. WT and Hq mice had the same baseline levels of cyp2E1 and of glutathione. The initial depletion of glutathione (20 min after APAP) was the same in both groups suggesting that there was no relevant difference in metabolic activation of APAP. Thus, AIF has a critical function in APAP hepatotoxicity by facilitating generation of reactive oxygen in mitochondria and, after nuclear translocation, AIF can be involved in DNA fragmentation. PMID:21572097

  4. Apoptosis-inducing factor modulates mitochondrial oxidant stress in acetaminophen hepatotoxicity.

    PubMed

    Bajt, Mary Lynn; Ramachandran, Anup; Yan, Hui-Min; Lebofsky, Margitta; Farhood, Anwar; Lemasters, John J; Jaeschke, Hartmut

    2011-08-01

    Acetaminophen (APAP) overdose causes liver injury in humans and mice. DNA fragmentation is a hallmark of APAP-induced cell death, and nuclear translocation of apoptosis-inducing factor (AIF) correlates with DNA fragmentation after APAP overdose. To test the hypothesis that AIF may be a critical mediator of APAP-induced cell death, fasted male AIF-deficient Harlequin (Hq) mice and respective wild-type (WT) animals were treated with 200 mg/kg APAP. At 6 h after APAP, WT animals developed severe liver injury as indicated by the increase in plasma alanine aminotransferase (ALT) activities (8600 ± 1870 U/l) and 61 ± 8% necrosis. This injury was accompanied by massive DNA strand breaks in centrilobular hepatocytes (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL] assay) and release of DNA fragments into the cytosol (anti-histone ELISA). In addition, there was formation of reactive oxygen (increase in liver glutathione disulfide (GSSG) levels and mitochondrial protein carbonyls) and peroxynitrite (nitrotyrosine [NT] staining) together with mitochondrial translocation of activated c-jun-N-terminal kinase (P-JNK) and release of AIF from the mitochondria. In contrast, Hq mice had significantly less liver injury (ALT: 330 ± 130 U/l; necrosis: 4 ± 2%), minimal nuclear DNA damage, and drastically reduced oxidant stress (based on all parameters) at 6 h. WT and Hq mice had the same baseline levels of cyp2E1 and of glutathione. The initial depletion of glutathione (20 min after APAP) was the same in both groups suggesting that there was no relevant difference in metabolic activation of APAP. Thus, AIF has a critical function in APAP hepatotoxicity by facilitating generation of reactive oxygen in mitochondria and, after nuclear translocation, AIF can be involved in DNA fragmentation. PMID:21572097

  5. Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase

    PubMed Central

    Agarwal, Rakhee; MacMillan-Crow, Lee Ann; Rafferty, Tonya M.; Saba, Hamida; Roberts, Dean W.; Fifer, E. Kim; James, Laura P.

    2011-01-01

    In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by initial hepatic metabolism to N-acetyl-p-benzoquinone imine (NAPQI). After low doses NAPQI is efficiently detoxified by GSH. However, in overdose GSH is depleted, NAPQI covalently binds to proteins as APAP adducts, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. Manganese superoxide dismutase (MnSOD) inactivation by protein nitration has been reported to occur during other oxidant stress-mediated diseases. MnSOD is a critical mitochondrial antioxidant enzyme that prevents peroxynitrite formation within the mitochondria. To examine the role of MnSOD in APAP toxicity, mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1 to 4 h. Serum alanine aminotransferase did not significantly increase until 4 h and was 2290 IU/liter at 6 h. MnSOD activity was significantly reduced by 50% at 1 and 2 h. At 1 h, GSH was significantly depleted by 62 and 80% at nontoxic doses of 50 and 100 mg/kg, respectively. No further GSH depletion occurred with hepatotoxic doses of 200 and 300 mg/kg APAP. A dose response decrease in MnSOD activity was observed for APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected. Treatment of recombinant MnSOD with NAPQI did not produce APAP protein adducts. The data indicate that MnSOD inactivation by nitration is an early event in APAP-induced hepatic toxicity. PMID:21205919

  6. Attenuating Oxidative Stress by Paeonol Protected against Acetaminophen-Induced Hepatotoxicity in Mice

    PubMed Central

    Chen, Yuning; Deng, Yue; Zhi, Feng; Qian, Ke

    2016-01-01

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. The purpose of this study was to investigate whether paeonol protected against APAP-induced hepatotoxicity. Mice treated with paeonol (25, 50, 100 mg/kg) received 400 mg/kg acetaminophen intraperitoneally (i.p.) and hepatotoxicity was assessed. Pre-treatment with paeonol for 6 and 24 h ameliorated APAP-induced hepatic necrosis and significantly reduced the serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels in a dose-dependent manner. Post-treatment with 100 mg/kg paeonol ameliorated APAP-induced hepatic necrosis and reduced AST and ALT levels in the serum after APAP administration for 24 h. Western blot revealed that paeonol inhibited APAP-induced phosphorylated JNK protein expression but not p38 and Erk1/2. Moreover, paeonol showed anti-oxidant activities with reducing hepatic MDA contents and increasing hepatic SOD, GSH-PX and GSH levels. Paeonol dose-dependently prevented against H2O2 or APAP-induced LDH releasing and ROS production in primary mouse hepatocytes. In addition, the mRNA levels of pro-inflammatory genes such as TNF-α, MCP-1, IL-1β and IL-6 in the liver were dose-dependently reduced by paeonol pre-treatment. Pre-treatment with paeonol significantly inhibited IKKα/β, IκBα and p65 phosphorylation which contributed to ameliorating APAP-induced hepatic inflammation. Collectively, the present study demonstrates paeonol has a protective ability against APAP-induced hepatotoxicity and might be an effective candidate compound against drug-induced acute liver failure. PMID:27144271

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

    PubMed

    Tobwala, Shakila; Khayyat, Ahdab; Fan, Weili; Ercal, Nuran

    2015-02-01

    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

  8. 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

  9. 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.

  10. 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, ...

  11. Acetaminophen

    MedlinePlus

    ... use the device that comes in the product packaging.To insert an acetaminophen suppository into the rectum, ... U.S. be shown to be both safe and effective prior to marketing. Please see the FDA website ...

  12. 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

  13. 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

  14. Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice.

    PubMed

    Knight, Tamara R; Fariss, Marc W; Farhood, Anwar; Jaeschke, Hartmut

    2003-11-01

    Mitochondrial oxidant stress and peroxynitrite formation have been implicated in the pathophysiology of acetaminophen-induced (AAP-induced) liver injury. Therefore, we tested the hypothesis that lipid peroxidation (LPO) might be involved in the injury mechanism. Male C3Heb/FeJ mice fed a diet high in vitamin E (1 g d-alpha-tocopheryl acetate/kg diet) for 1 week had 6.7-fold higher hepatic tocopherol levels than animals on the control diet (8.2 +/- 0.1 nmol/g liver). Treatment of fasted mice with 300 mg/kg AAP caused centrilobular necrosis with high plasma alanine aminotransferase (ALT) activities at 6 h (3280 +/- 570 U/l) but no evidence of LPO (hepatic malondialdehyde, 4-hydroxynonenal). Animals on the vitamin E diet had similar injury and LPO as mice on the control diet. To verify a potential effect of the vitamin E diet on drug-induced liver injury, animals were pretreated with a combination of phorone, FeSO4, and allyl alcohol. We observed, 2 h after allyl alcohol, massive LPO and liver cell injury in the livers of animals on the control diet, as indicated by a 32-fold increase in malondialdehyde levels, extensive staining for 4-hydroxynonenal, and ALT activities of 2310 +/- 340 U/l. Animals on the vitamin E diet had 40% lower hepatic malondialdehyde levels and 85% lower ALT values. Similar results were obtained when animals were treated for 3 days with alpha- or gamma-tocopherol (0.19 mmol/kg, ip). Both treatments reduced LPO and injury after allyl alcohol but had no effect on AAP hepatotoxicity. Thus, despite the previously shown mitochondrial oxidant stress and peroxynitrite formation, LPO does not appear to be a critical event in AAP-induced hepatotoxicity. PMID:12944590

  15. Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice.

    PubMed

    Aubert, Jacinthe; Begriche, Karima; Delannoy, Matthieu; Morel, Isabelle; Pajaud, Julie; Ribault, Catherine; Lepage, Sylvie; McGill, Mitchell R; Lucas-Clerc, Catherine; Turlin, Bruno; Robin, Marie-Anne; Jaeschke, Hartmut; Fromenty, Bernard

    2012-09-01

    Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The pre-existence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and β-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders. PMID:22647274

  16. Inhibitor of Apoptosis Signal-Regulating Kinase 1 Protects Against Acetaminophen-induced Liver Injury

    PubMed Central

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

    2015-01-01

    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 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affected the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h 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. PMID:25818599

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

    PubMed

    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 24h 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 1.5h 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. PMID:25818599

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

    PubMed

    Jing, Yuping; Wu, Kunwei; Liu, Jiashuo; Ai, Qing; Ge, Pu; Dai, Jie; Jiang, Rong; Zhou, Dan; Che, Qian; Wan, Jingyuan; Zhang, Li

    2015-01-01

    Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation. PMID:25884831

  19. 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 ...

  20. Acetaminophen and codeine overdose

    MedlinePlus

    ... If the medicine was prescribed for the person Poison Control Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere ...

  1. Hydrocodone and acetaminophen overdose

    MedlinePlus

    ... Saunders; 2014:chap148. Miner JR, Burton J. Pain management. In: Marx JA, Hockberger RS, Walls RM, et al, eds. Rosen's Emergency Medicine: Concepts and Clinical Practice . 8th ed. Philadelphia, PA: Elsevier ...

  2. 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

  3. 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

  4. Mechanism of protection by metallothionein against acetaminophen hepatotoxicity.

    PubMed

    Saito, Chieko; Yan, Hui-Min; 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 micromol/kg ZnCl2 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. PMID:19835899

  5. MECHANISM OF PROTECTION BY METALLOTHIONEIN AGAINST ACETAMINOPHEN HEPATOTOXICITY

    PubMed Central

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

    2009-01-01

    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 µmol/kg ZnCl2 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-benzoquinoneimine (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. PMID:19835899

  6. 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.

  7. Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice.

    PubMed

    Bektur, Nuriye Ezgi; Sahin, Erhan; Baycu, Cengiz; Unver, Gonul

    2016-04-01

    This study was designed to estimate protective effects of silymarin on acetaminophen (N-acetyl-p-aminophenol, paracetamol; APAP)-induced hepatotoxicity and nephrotoxicity in mice. Treatment of mice with overdose of APAP resulted in the elevation of aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCr) levels in serum, liver, and kidney nitric oxide (NO) levels and significant histological changes including decreased body weight, swelling of hepatocytes, cell infiltration, dilatation and congestion, necrosis and apoptosis in liver, and dilatation of Bowman's capsular space and glomerular capillaries, pale-stained tubules epithelium, cell infiltration, and apoptosis in kidney. Posttreatment with silymarin 1 h after APAP injectionfor 7 days, however, significantly normalized the body weight, histological damage, serum ALT, AST, BUN, SCr, and tissue NO levels. Our observation suggested that silymarin ameliorated the toxic effects of APAP-induced hepatotoxicity and nephrotoxicity in mice. The protective role of silymarin against APAP-induced damages might result from its antioxidative and anti-inflammatory effects. PMID:24193058

  8. 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

  9. Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity.

    PubMed

    Bajt, Mary Lynn; Farhood, Anwar; Lemasters, John J; Jaeschke, Hartmut

    2008-01-01

    Mitochondria generate reactive oxygen and peroxynitrite and release endonucleases during acetaminophen (APAP) hepatotoxicity. Because mitochondrial translocation of Bax can initiate these events, we investigated the potential role of Bax in the pathophysiology of hepatic necrosis after 300 mg/kg APAP in fasted C57BL/6 mice. APAP overdose induced Bax translocation from the cytosol to the mitochondria as early as 1 h after APAP injection. At 6 h, there was extensive centrilobular nitrotyrosine staining (indicator for peroxynitrite formation) and nuclear DNA fragmentation. In addition, mitochondrial intermembrane proteins were released into the cytosol. Plasma alanine aminotransferase (ALT) activities of 5610 +/- 600 U/l indicated extensive necrotic cell death. Conversely, Bax gene knockout (Bax(-/-)) mice had 80% lower ALT activities, less DNA fragmentation, and less intermembrane protein release at 6 h. However, immunohistochemical staining for nitrotyrosine or APAP protein adducts did not show differences between wild-type and Bax(-/-) mice. In contrast to the early hepatoprotection in Bax(-/-) mice, plasma ALT activities (7605 +/- 480 U/l) and area of necrosis (53 +/- 6% hepatocytes) in wild-type animals was similar to values in Bax(-/-) mice at 12 h. In addition, there was no difference in DNA fragmentation or nitrotyrosine immunostaining. We concluded that the rapid mitochondrial Bax translocation after APAP overdose has no effect on peroxynitrite formation but that it contributes to the mitochondrial release of proteins, which cause nuclear DNA fragmentation. However, the persistent oxidant stress and peroxynitrite formation in mitochondria may eventually trigger the permeability transition pore opening and release intermembrane proteins independently of Bax. PMID:17906064

  10. Patient knowledge and use of acetaminophen in over-the-counter medications.

    PubMed

    Hurwitz, Jason; Sands, Shannon; Davis, Erica; Nielsen, Joel; Warholak, Terri

    2014-01-01

    OBJECTIVES To evaluate patient knowledge of over-the-counter (OTC) products containing acetaminophen and to determine patients' accuracy in dosing adult, child, and infant formulations. DESIGN Cross-sectional study. SETTING Six community pharmacies in Tucson, AZ, between February and May 2011. PARTICIPANTS 88 adults aged 19 to 89 years. INTERVENTION Investigator-administered, semistructured interviews. MAIN OUTCOME MEASURES Patient knowledge of and ability to safely use OTC products containing acetaminophen, including understanding risks, identifying products, and dosing different formulations. RESULTS Although most (86%) participants heard of acetaminophen, only 68% understood at least one of its uses and only 9% knew the abbreviation APAP. Virtually all knew that consuming too much acetaminophen in 1 day could be harmful, but only 17% and 35% knew that overdoses could result in death or liver damage, respectively. On average, participants correctly identified 80% (range 27-100%) of products with and without acetaminophen from a lineup of 11 OTC products. Although 38% (n = 84) of participants correctly measured both the child and infant doses of acetaminophen, doses ranged from one-half to twice the amount of the labeled child dose and one-third of the labeled infant dose. Findings from the regression analysis suggested that on average, women and those with college degrees had higher overall scores, while participants' age or parent status were nonsignificant predictors. CONCLUSION Many patients remain confused about using acetaminophen safely, signaling the need for greater patient education to prevent unintentional harm. The results further specify common misunderstandings to address during patient contact, which also includes replacing "APAP" with "acetaminophen" on any prescription bottle labels or patient-directed information. PMID:24362497

  11. 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

  12. The proper use of acetaminophen

    PubMed Central

    James, Laura; Sullivan, Janice E; Roberts, Dean

    2011-01-01

    Acetaminophen (N-acetyl-p-aminophenol, paracetamol [APAP])-induced acute liver failure is the most common cause of acute liver failure in adults. In children, APAP accounts for 25% of all cases of acute liver failure. The high mortality rate associated with this preventable condition makes it vital that paediatricians are aware of the potential adverse effects associated with this widely used drug. While APAP is generally considered to be safe when used as directed, its inclusion in multiple over-the-counter medications, as well as in prescription drugs, mandates that physicians promote and educate the general public about the proper use of acetaminophen in children. PMID:23115492

  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 Central

    Jiang, Yiming; Fan, Xiaomei; Wang, Ying; Chen, Pan; Zeng, Hang; Tan, Huasen; Gonzalez, Frank J.; 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

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

    PubMed Central

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

    2010-01-01

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

  16. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity.

    PubMed

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

    2010-01-01

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

  17. 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.

  18. 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.

  19. 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 ...

  20. Dextromethorphan overdose

    MedlinePlus

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

  1. 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 ofCajanus cajanandCaesalpinia 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

  2. Fas Receptor-deficient lpr Mice are protected against Acetaminophen Hepatotoxicity due to Higher Glutathione Synthesis and Enhanced Detoxification of Oxidant Stress

    PubMed Central

    Williams, C. David; McGill, Mitchell R.; Farhood, Anwar; Jaeschke, Hartmut

    2013-01-01

    Acetaminophen (APAP) overdose is a classical model of hepatocellular necrosis; however, the involvement of the Fas receptor in the pathophysiology remains controversial. Fas receptor-deficient (lpr) and C57BL/6 mice were treated with APAP to compare the mechanisms of hepatotoxicity. Lpr mice were partially protected against APAP hepatotoxicity as indicated by reduced plasma ALT and GDH levels and liver necrosis. Hepatic Cyp2e1 protein, adduct formation and hepatic glutathione (GSH) depletion were similar, demonstrating equivalent reactive metabolite generation. There was no difference in cytokine formation or hepatic neutrophil recruitment. Interestingly, hepatic GSH recovered faster in lpr mice than in wild type animals resulting in enhanced detoxification of reactive oxygen species. Driving the increased GSH levels, mRNA induction and protein expression of glutamate-cysteine ligase (gclc) were higher in lpr mice. Inducible nitric oxide synthase (iNOS) mRNA and protein levels at 6h were significantly lower in lpr mice, which correlated with reduced nitrotyrosine staining. Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP. Conclusion: Our data suggest that the faster recovery of hepatic GSH levels during oxidant stress and peroxynitrite formation, reduced iNOS expression and enhanced induction of Hsp70 attenuated the susceptibility to APAP-induced cell death in lpr mice. PMID:23628456

  3. 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

  4. 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

  5. Acetaminophen: old drug, new warnings.

    PubMed

    Schilling, Amy; Corey, Rebecca; Leonard, Mandy; Eghtesad, Bijan

    2010-01-01

    The US Food and Drug Administration (FDA), concerned about the incidence of acute liver failure due to acetaminophen (Tylenol) overdose, has mandated new labeling on acetaminophen packaging. It is also considering (but has not enacted) reducing the maximum daily dose from 4 g (possibly to 3,250 mg), banning acetaminophen-narcotic combination products, and changing the current maximum single dose of 1 g to prescription status, making 650 mg the highest recommended nonprescription dose. We review the epidemiology, toxicology, and management of acetaminophen overdose and steps the FDA and physicians can take to prevent it. PMID:20048026

  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. PMID:26286854

  7. 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

  8. 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

  9. 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 ...

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

    PubMed Central

    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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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. PMID:25983262

  17. Drug interactions: inhibition of acetaminophen glucuronidation by drugs.

    PubMed

    Bolanowska, W; Gessner, T

    1978-07-01

    Glucuronidation of [3H]acetaminophen (APAP) was studied in rat liver preparations. Both Triton X-100 and UDP-N acetylglucosamine (UDPAG) activated 3- to 4-fold the glucuronidation of APAP by liver homogenates or microsomes. Prednisolone inhibited microsomal glucuronidation of APAP, yielding apparent noncompetitive kinetics in native and in UDPAG-activated microsomes. Studies with UDPAG-activated microsomal preparations show that many drugs can inhibit glucuronidation of APAP markedly; among the most poten inhibitors are: morphine, dicumarol, hydroxyzine, phenolphthalein, chloramphenicol and tetracycline. PMID:660554

  18. 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...

  19. Diazepam overdose

    MedlinePlus

    ... It is in a class of drugs called benzodiazepines. Diazepam overdose occurs when someone takes more than ... Farrell SE, Fatovich TM. Benzodiazepines. In: Shannon MW, Borron SW, ... Clinical Management of Poisoning and Drug Overdose . 4th ed. ...

  20. 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.

  1. 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 ...

  2. Methamphetamine overdose

    MedlinePlus

    ... methamphetamine overdose may be acute (sudden) or chronic (long-term). An acute methamphetamine overdose occurs when someone takes ... kidney failure Paranoia Seizures Severe stomach pain Stroke Long-term use of methamphetamine can lead to significant psychological ...

  3. Aspirin overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002542.htm Aspirin overdose To use the sharing features on this page, please enable JavaScript. An overdose of aspirin means you have too much aspirin in your ...

  4. 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 ...

  5. 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 ...

  6. 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 ...

  7. Bee Venom Phospholipase A2 Protects against Acetaminophen-Induced Acute Liver Injury by Modulating Regulatory T Cells and IL-10 in Mice

    PubMed Central

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

    2014-01-01

    The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10−/−) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10−/− mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production. PMID:25478691

  8. Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice.

    PubMed

    Fiorucci, Stefano; Antonelli, Elisabetta; Distrutti, Eleonora; Mencarelli, Andrea; Farneti, Silvana; Del Soldato, Piero; Morelli, Antonio

    2004-09-01

    1. NCX-1000, (3alpha, 5beta, 7beta)-3,7-dihydroxycholan-24oic acid[2-methoxy-4-[3-[4-(nitroxy)butoxy]-3-oxo-1-propenyl]phenyl ester, is a nitric oxide (NO)-derivative of ursodeoxyxholic acid (UDCA) that selectively release NO in the liver. 2. Here, we demonstrated that administering mice with 40 micromol kg(-1) NCX-1000, but not UDCA, improves liver histopathology and reduces mortality caused by 330 micromol kg(-1) APAP from 60 to 25% (P<0.01). Administration of NCX-1000, in a therapeutic manner, that is, 2 h after acetaminophen (APAP) intoxication reduced mortality, improved liver histopathology and prevented liver IFN-gamma, TNF-alpha, Fas/Fas ligand and inducible nitric oxide synthase (iNOS) mRNA accumulation caused by APAP. 3. In vitro exposure of primary cultures of mouse hepatocytes to APAP, 6.6 mm, resulted in apoptosis followed by necrosis. Loss of cell viability correlates with early mitochondrial membrane potential (Deltapsi(m)) hyperpolarization followed by depolarization and cytochrome c translocation from mitochondria to cytosol. APAP-induced apoptosis associated with procaspase-3 and -9 cleavage, appearance of truncated Bid and activation of poly(ADP-ribose) polymerase (PARP). 4. Treating primary culture of hepatocytes with 5 microm cyclosporine and 10 microm trifluoperazine for eight resulted in significant reduction of apoptosis induced by APAP suggesting that loss of Deltapsim was mechanistically involved in apoptosis induced by APAP in vitro. 5. NCX-1000, but not UDCA, concentration-dependently (ED(50)=16 microm) protected against Deltapsi(m) depolarization and reduced transition from apoptosis to necrosis caused by 6.6 mm APAP. 6. Treating primary cultures of hepatocytes with the NO-donor DETA-NO, 100 microm, reduced apoptosis induced by APAP and prevented caspase activation. 7. In conclusion, NCX-1000 is effective in protecting against APAP-induced hepatotoxicity when administered in a therapeutic manner. This protection may involve the

  9. Zinc oxide overdose

    MedlinePlus

    Desitin overdose; Calamine lotion overdose; Zinaderm overdose; Amalox overdose; Azo 22 overdose ... oxide ointment Diaper rash medicines Hemorrhoid medicines Skin lotions Calamine lotion Caladryl lotion Sunscreen lotion Cosmetics Paint ...

  10. Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats.

    PubMed

    Pradhan, Shrabani; Mandal, Shreya; Roy, Suchismita; Mandal, Arpita; Das, Koushik; Nandi, Dilip K

    2013-04-01

    Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control - receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats. PMID:23960834

  11. 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

  12. 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

  13. Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats.

    PubMed

    Smith, G S; Nadig, D E; Kokoska, E R; Solomon, H; Tiniakos, D G; Miller, T A

    1998-12-01

    Acetaminophen (APAP) is a common analgesic and antipyretic compound which, when administered in high doses, has been associated with significant morbidity and mortality, secondary to hepatic toxicity. To date, the mechanism(s) whereby APAP induces liver injury remains to be delineated. This study investigated the potential role of neutrophils as contributors to liver injury in rats administered sublethal doses of APAP. Oral APAP administration (650 mg/kg) was associated with increases in serum alanine transaminase (ALT) levels indicating biochemical evidence of significant liver damage. Furthermore, histological analyses verified significant hepatocellular necrosis as well as enhanced myeloperoxidase staining in these liver specimens. However, if animals were pretreated with antineutrophil sera prior to APAP administration, neutrophil counts remained depressed, ALT levels were significantly decreased, and the degree of liver injury was attenuated on a histological level. Taken together these data suggest that neutrophils mediate, at least in part, the hepatotoxic effects of oral acetaminophen administration in rats. PMID:9878321

  14. Oxazepam overdose

    MedlinePlus

    ... belongs to the class of medicines known as benzodiazepines. Oxazepam overdose occurs when someone accidentally or intentionally takes too much of this medicine. Benzodiazepines are the most common prescription drugs used in ...

  15. 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 ...

  16. Pentobarbital overdose

    MedlinePlus

    Symptoms of a pentobarbital overdose may include: Coma Confusion Decreased energy Delirium (confusion and agitation) Difficulty breathing Headache Large blisters Rash Sleepiness Slowed or stopped breathing Slurred speech Unsteady gait

  17. Phenothiazine overdose

    MedlinePlus

    ... RD, ed. Conn's Current Therapy 2015 . Philadelphia, PA: Elsevier Saunders; 2015:chap 21. Levine M, Burns MJ. ... Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 38. Nockowitz RA, Rund DA. ...

  18. Lomotil overdose

    MedlinePlus

    ... Concepts and Clinical Practice . 8th ed. Philadelphia, PA: Elsevier Saunders; 2014:chap 162. Kirk MA, Baer AB. ... Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 39. Velez LI, Feng S-Y. ...

  19. Codeine overdose

    MedlinePlus

    ... 184. Murphy NG, Benowitz NL, Goldschlager N. Cardiovascular toxicology. In: Shannon MW, Borron SW, Burns MJ, eds. Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. ...

  20. Iron overdose

    MedlinePlus

    ... 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 al, eds. Rosen's Emergency Medicine: Concepts and Clinical Practice . ...

  1. Bacitracin overdose

    MedlinePlus

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

  2. 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.

  3. 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 ...

  4. 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. ...

  5. 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 ...

  6. 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 ...

  7. Caffeine overdose

    MedlinePlus

    Caffeine is a substance that exists naturally in certain plants. It can also be man-made and ... is a diuretic, which means it increases urination. Caffeine overdose occurs when someone takes in more than ...

  8. Chlordiazepoxide overdose

    MedlinePlus

    With proper care, full recovery is likely. But people with aplastic anemia (suppression of red blood cell production by the bone marrow) or those who overdose on many different substances may not recover fully.

  9. 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

  10. Contac overdose

    MedlinePlus

    Hendrickson RG, McKeown NJ. Acetaminophen. In: Marx JA, Hockberger RS, Walls RM, et al, eds. Rosen's Emergency Medicine: Concepts and Clinical Practice . 8th ed. Philadelphia, PA: Elsevier Mosby; 2014: ...

  11. 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.

  12. 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.

  13. Acetaminophen: a practical pharmacologic overview.

    PubMed Central

    Jackson, C H; MacDonald, N C; Cornett, J W

    1984-01-01

    Acetaminophen is an effective analgesic and antipyretic agent with few adverse effects when used in recommended dosages. The drug is metabolized mainly in the liver, and the several end products have no harmful effects. An intermediate compound in a minor metabolic pathway, however, is toxic; it is normally inactivated by glutathione. In the case of an acetaminophen overdose the hepatic stores of glutathione seem to become depleted, leaving the toxic intermediate free to damage liver tissue. Such damage is unlikely to occur unless the plasma concentration of acetaminophen peaks above 150 micrograms/mL--a level far in excess of the 5 to 20 micrograms/mL achieved with therapeutic doses of the drug. Long-term therapeutic use of acetaminophen does not appear to be associated with liver damage, although some case reports suggest the possibility. Acetaminophen poisoning follows an acute overdose and, if untreated, is manifested clinically by an initial phase of nonspecific signs and symptoms, a latent period in which the liver transaminase levels rise and then, 3 to 5 days after the ingestion, signs of more serious hepatic dysfunction. Most patients do not progress beyond the first or second phase. They and those who survive the third phase recover with no residual injury to the liver. Appropriate antidotal therapy markedly reduces the severity of the initial damage. PMID:6733646

  14. 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.

  15. Methadone overdose

    MedlinePlus

    ... doses of the antidote. People who take a large overdose may stop breathing. They may have seizures if they do not get the antidote quickly. Complications such as pneumonia, muscle damage from lying on a hard surface for a long time, or brain damage from ...

  16. Nitroglycerin overdose

    MedlinePlus

    ... If you or someone you are with overdoses, call your local emergency number (such as 911), or your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States.

  17. Estrogen overdose

    MedlinePlus

    ... someone you are with overdoses, call your local emergency number (such as 911), or your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States.

  18. A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

    PubMed Central

    Patel, Suraj J; Luther, Jay; Bohr, Stefan; Iracheta-Vellve, Arvin; Li, Matthew; King, Kevin R; Chung, Raymond T; Yarmush, Martin L

    2016-01-01

    Objectives: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity. Methods: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed. Results: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP. Conclusions: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role. PMID:26986653

  19. Risk of Acute Kidney Injury and Long-Term Outcome in Patients With Acetaminophen Intoxication

    PubMed Central

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

    2015-01-01

    Abstract 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

  20. A Cytochrome P450-Independent Mechanism of Acetaminophen-Induced Injury in Cultured Mouse Hepatocytes.

    PubMed

    Miyakawa, Kazuhisa; Albee, Ryan; Letzig, Lynda G; Lehner, Andreas F; Scott, Michael A; Buchweitz, John P; James, Laura P; Ganey, Patricia E; Roth, Robert A

    2015-08-01

    Mouse hepatic parenchymal cells (HPCs) have become the most frequently used in vitro model to study mechanisms of acetaminophen (APAP)-induced hepatotoxicity. It is universally accepted that APAP hepatocellular injury requires bioactivation by cytochromes P450 (P450s), but this remains unproven in primary mouse HPCs in vitro, especially over the wide range of concentrations that have been employed in published reports. The aim of this work was to test the hypothesis that APAP-induced hepatocellular death in vitro depends solely on P450s. We evaluated APAP cytotoxicity and APAP-protein adducts (a biomarker of metabolic bioactivation by P450) using primary mouse HPCs in the presence and absence of a broad-spectrum inhibitor of P450s, 1-aminobenzotriazole (1-ABT). 1-ABT abolished formation of APAP-protein adducts at all concentrations of APAP (0-14 mM), but eliminated cytotoxicity only at small concentrations (≦5 mM), indicating the presence of a P450-independent mechanism at larger APAP concentrations. P450-independent cell death was delayed in onset relative to toxicity observed at smaller concentrations. p-Aminophenol was detected in primary mouse HPCs exposed to large concentrations of APAP, and a deacetylase inhibitor [bis (4-nitrophenyl) phosphate (BNPP)] significantly reduced cytotoxicity. In conclusion, APAP hepatocellular injury in vitro occurs by at least two mechanisms, a P450-dependent mechanism that operates at concentrations of APAP ≦ 5 mM and a P450-independent mechanism that predominates at larger concentrations and is slower in onset. p-Aminophenol most likely contributes to the latter mechanism. These findings should be considered in interpreting results from APAP cytotoxicity studies in vitro and in selecting APAP concentrations for use in such studies. PMID:26065700

  1. Glycodeoxycholic Acid Levels as Prognostic Biomarker in Acetaminophen-Induced Acute Liver Failure Patients

    PubMed Central

    Woolbright, Benjamin L.; McGill, Mitchell R.; Staggs, Vincent S.; Winefield, Robert D.; Gholami, Parviz; Olyaee, Mojtaba; Sharpe, Matthew R.; Curry, Steven C.; Lee, William M.; Jaeschke, Hartmut

    2014-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5–80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury. PMID:25239633

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

    PubMed

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

    2013-06-01

    Renal failure secondary to acetaminophen poisoning is rare and occurs in approximately 1-2 % of patients with acetaminophen overdose. The pathophysiology is still being debated, and renal acetaminophen toxicity consists of acute tubular necrosis, without complication if treated promptly. Renal involvement can sometimes occur without prior liver disease, and early renal manifestations usually occur between the 2nd and 7th day after the acute acetaminophen poisoning. While therapy is exclusively symptomatic, sometimes serious metabolic complications can be observed. The monitoring of renal function should therefore be considered as an integral part of the management of children with acute, severe acetaminophen intoxication. We report 3 cases of adolescents who presented with acute renal failure as a result of voluntary drug intoxication with acetaminophen. One of these 3 girls developed severe renal injury without elevated hepatic transaminases. None of the 3 girls' renal function required hemodialysis, but one of the 3 patients had metabolic complications after her acetaminophen poisoning. PMID:23628119

  3. 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

  4. TRPM2 channels mediate acetaminophen-induced liver damage.

    PubMed

    Kheradpezhouh, Ehsan; Ma, Linlin; Morphett, Arthur; Barritt, Greg J; Rychkov, Grigori Y

    2014-02-25

    Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca(2+) homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca(2+) concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca(2+) rise. Here we report that the channel responsible for Ca(2+) entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H2O2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H2O2. In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wild-type mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death. PMID:24569808

  5. Acetaminophen induces accumulation of functional rat CYP3A via polyubiquitination dysfunction.

    PubMed

    Santoh, Masataka; Sanoh, Seigo; Takagi, Masashi; Ejiri, Yoko; Kotake, Yaichiro; Ohta, Shigeru

    2016-01-01

    Acetaminophen (APAP) is extensively used as an analgesic and antipyretic drug. APAP is partly metabolized to N-acetyl-p-benzoquinone imine, a reactive metabolite, by cytochrome P450 (CYP) 1A2, 2E1 and 3A4. Some reports have indicated that CYP3A protein production and its metabolic activity are induced by APAP in rats in vivo. The CYP3A subfamily is believed to be transcriptionally regulated by chemical compounds. However, the mechanism underlying these responses is not completely understood. To clarify these mechanisms, we assessed the effects of APAP on CYP3A1/23 protein levels according to mRNA synthesis and protein degradation in rat hepatocyte spheroids, a model of liver tissue, in vivo. APAP induced CYP3A1/23 protein levels and metabolic activity. However, no change in CYP3A1/23 mRNA levels was observed. Moreover, APAP prolonged the half-life of CYP3A1/23 protein. CYP3A is known to be degraded via the ubiquitin-proteasome system. APAP significantly was found to decrease levels of polyubiquitinated CYP3A1/23 and glycoprotein 78, an E3 ligase of CYP3A1/23. These findings demonstrate that APAP induces accumulation of functional CYP3A protein via inhibition of protein degradation. Our findings may lead to the determination of novel drug-drug interactions with APAP. PMID:26900149

  6. Acetaminophen induces accumulation of functional rat CYP3A via polyubiquitination dysfunction

    PubMed Central

    Santoh, Masataka; Sanoh, Seigo; Takagi, Masashi; Ejiri, Yoko; Kotake, Yaichiro; Ohta, Shigeru

    2016-01-01

    Acetaminophen (APAP) is extensively used as an analgesic and antipyretic drug. APAP is partly metabolized to N-acetyl-p-benzoquinone imine, a reactive metabolite, by cytochrome P450 (CYP) 1A2, 2E1 and 3A4. Some reports have indicated that CYP3A protein production and its metabolic activity are induced by APAP in rats in vivo. The CYP3A subfamily is believed to be transcriptionally regulated by chemical compounds. However, the mechanism underlying these responses is not completely understood. To clarify these mechanisms, we assessed the effects of APAP on CYP3A1/23 protein levels according to mRNA synthesis and protein degradation in rat hepatocyte spheroids, a model of liver tissue, in vivo. APAP induced CYP3A1/23 protein levels and metabolic activity. However, no change in CYP3A1/23 mRNA levels was observed. Moreover, APAP prolonged the half-life of CYP3A1/23 protein. CYP3A is known to be degraded via the ubiquitin-proteasome system. APAP significantly was found to decrease levels of polyubiquitinated CYP3A1/23 and glycoprotein 78, an E3 ligase of CYP3A1/23. These findings demonstrate that APAP induces accumulation of functional CYP3A protein via inhibition of protein degradation. Our findings may lead to the determination of novel drug–drug interactions with APAP. PMID:26900149

  7. Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level.

    PubMed

    Fakurazi, S; Hairuszah, I; Nanthini, U

    2008-08-01

    Initiation of acetaminophen (APAP) toxicities is believed to be promoted by oxidative stress during the event of overdosage. The aim of the present study was to evaluate the hepatoprotective action of Moringa oleifera Lam (MO), an Asian plant of high medicinal value, against a single high dose of APAP. Groups of five male Sprague-Dawley rats were pre-administered with MO (200 and 800 mg/kg) prior to a single dose of APAP (3g/kg body weight; p.o). Silymarin was used as an established hepatoprotective drug against APAP induced liver injury. The hepatoprotective activity of MO extract was observed following significant histopathological analysis and reduction of the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in groups pretreated with MO compared to those treated with APAP alone. Meanwhile, the level of glutathione (GSH) was found to be restored in MO-treated animals compared to the groups treated with APAP alone. These observations were comparable to the group pretreated with silymarin prior to APAP administration. Group that was treated with APAP alone exhibited high level of transaminases and ALP activities besides reduction in the GSH level. The histological hepatocellular deterioration was also evidenced. The results from the present study suggested that the leaves of MO can prevent hepatic injuries from APAP induced through preventing the decline of glutathione level. PMID:18514995

  8. 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

  9. 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

  10. 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

  11. Acetaminophen Attenuates Lipid Peroxidation in Children Undergoing Cardiopulmonary Bypass

    PubMed Central

    Simpson, Scott A.; Zaccagni, Hayden; Bichell, David P.; Christian, Karla G.; Mettler, Bret A.; Donahue, Brian S.; Roberts, L. Jackson; Pretorius, Mias

    2014-01-01

    Objective Hemolysis, occurring during cardiopulmonary bypass (CPB), is associated with lipid peroxidation and postoperative acute kidney injury (AKI). Acetaminophen (ApAP) inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced AKI. This pilot study tests the hypothesis that ApAP attenuates lipid peroxidation in children undergoing CPB. Design Single center prospective randomized double blinded study. Setting University-affiliated pediatric hospital. Patients Thirty children undergoing elective surgical correction of a congenital heart defect. Interventions Patients were randomized to ApAP (OFIRMEV® (acetaminophen) injection, Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for 4 doses starting before the onset of CPB. Measurement and Main Results Markers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes) and AKI were measured throughout the perioperative period. CPB was associated with a significant increase in free hemoglobin (from a pre-bypass level of 9.8±6.2 mg/dl to a peak of 201.5±42.6 mg/dl post-bypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. ApAP attenuated the increase in plasma isofurans compared to placebo (P=0.02 for effect of study drug). There was no significant effect of ApAP on plasma F2-isoprostanes or urinary makers of lipid peroxidation. ApAP did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin or prevalence of AKI. Conclusion CPB in children is associated with hemolysis and lipid peroxidation. ApAP attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients

  12. A Cytochrome P450–Independent Mechanism of Acetaminophen-Induced Injury in Cultured Mouse Hepatocytes

    PubMed Central

    Miyakawa, Kazuhisa; Albee, Ryan; Letzig, Lynda G.; Lehner, Andreas F.; Scott, Michael A.; Buchweitz, John P.; James, Laura P.; Ganey, Patricia E.

    2015-01-01

    Mouse hepatic parenchymal cells (HPCs) have become the most frequently used in vitro model to study mechanisms of acetaminophen (APAP)-induced hepatotoxicity. It is universally accepted that APAP hepatocellular injury requires bioactivation by cytochromes P450 (P450s), but this remains unproven in primary mouse HPCs in vitro, especially over the wide range of concentrations that have been employed in published reports. The aim of this work was to test the hypothesis that APAP-induced hepatocellular death in vitro depends solely on P450s. We evaluated APAP cytotoxicity and APAP-protein adducts (a biomarker of metabolic bioactivation by P450) using primary mouse HPCs in the presence and absence of a broad-spectrum inhibitor of P450s, 1-aminobenzotriazole (1-ABT). 1-ABT abolished formation of APAP-protein adducts at all concentrations of APAP (0–14 mM), but eliminated cytotoxicity only at small concentrations (≦5 mM), indicating the presence of a P450-independent mechanism at larger APAP concentrations. P450-independent cell death was delayed in onset relative to toxicity observed at smaller concentrations. p-Aminophenol was detected in primary mouse HPCs exposed to large concentrations of APAP, and a deacetylase inhibitor [bis (4-nitrophenyl) phosphate (BNPP)] significantly reduced cytotoxicity. In conclusion, APAP hepatocellular injury in vitro occurs by at least two mechanisms, a P450-dependent mechanism that operates at concentrations of APAP ≦ 5 mM and a P450-independent mechanism that predominates at larger concentrations and is slower in onset. p-Aminophenol most likely contributes to the latter mechanism. These findings should be considered in interpreting results from APAP cytotoxicity studies in vitro and in selecting APAP concentrations for use in such studies. PMID:26065700

  13. 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

  14. 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

  15. 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

  16. 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. PMID:25788542

  17. Inhibition of human platelet function in vitro and ex vivo by acetaminophen.

    PubMed

    Lages, B; Weiss, H J

    1989-03-15

    The effects of acetaminophen (APAP) in vitro, or ex vivo following APAP ingestion, on human platelet aggregation, 14C-5HT secretion, and thromboxane B2 (TxB2) formation were assessed. APAP added in vitro to citrated platelet-rich plasma (PRP) inhibited aggregation, secretion, and TxB2 formation induced by collagen, epinephrine, arachidonate, and the ionophore A23187, but had no effect on the responses induced by the endoperoxide analog U44069. Arachidonate-induced responses were inhibited by lower concentrations of APAP than were the responses to the other agonists. In PRP obtained 1 hour after ingestion of 650 mg or 1000 mg APAP, arachidonate-induced TxB2 formation was inhibited by 40-99% in five subjects tested, whereas inhibition of collagen- or epinephrine-induced TxB2 formation was less consistent. Aggregation and secretion responses were not altered by APAP ingestion in 4 of the 5 subjects, but were inhibited in the remaining subject, who had the highest plasma APAP levels. In contrast to aspirin and indomethacin, APAP-induced inhibition of collagen-stimulated TxB2 formation could be partially overcome with increasing collagen concentrations. No such partial correction occurred with epinephrine, however. In washed platelet suspensions labeled with 3H-arachidonate, both APAP and aspirin inhibited the formation of labeled PGD2 and PGE2, as well as TxB2. These results suggest that APAP acts in human platelets as a reversible inhibitor of cyclo-oxygenase, as found previously in other tissues, and that recent APAP ingestion can, on occasion, produce inhibition of platelet functional responses measured in vitro. PMID:2499947

  18. Altered Protein S-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

    PubMed Central

    McGarry, David J.; Chakravarty, Probir; Wolf, C. Roland

    2015-01-01

    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

  19. 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

  20. 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

  1. Acetaminophen inhibits NF-kappaB activation by interfering with the oxidant signal in murine Hepa 1-6 cells.

    PubMed

    Boulares, A H; Giardina, C; Inan, M S; Khairallah, E A; Cohen, S D

    2000-06-01

    A toxic dose of acetaminophen (APAP) reduces the activity of NF-kappaB in mouse liver. NF-kappaB inactivation may be important for APAP toxicity, as this transcription factor can play a central role in maintaining hepatic viability. We recently reported that APAP likewise inhibits serum growth factor activation of NF-kappaB in a mouse hepatoma cell line (Hepa 1-6 cells). Here we present evidence that APAP's antioxidant activity may be involved in this NF-kappaB inhibition in Hepa 1-6 cells. Like the antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC), APAP was found to suppress the H(2)O(2)-induced oxidation of an intracellular reactive oxygen species probe (dihydrodichlorofluorescein) in Hepa 1-6 cells. Treatment of Hepa 1-6 cells with H(2)O(2) was sufficient for NF-kappaB activation and IkappaBalpha degradation, and APAP was able to block both of these events. The APAP inhibition of NF-kappaB activation by serum growth factors may also be due to APAP's antioxidant activity, as the antioxidants NAC and PDTC likewise inhibit this activation. The potential role of NF-kappaB and oxidant-based growth factor signal transduction in APAP toxicity is discussed. PMID:10828269

  2. 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 ...

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

    PubMed Central

    Rudraiah, Swetha; Rohrer, Philip R.; Gurevich, Igor; Goedken, Michael J.; Rasmussen, Theodore; Hines, Ronald N.; Manautou, José E.

    2014-01-01

    Acetaminophen (APAP) pretreatment with a hepatotoxic dose (400 mg/kg) in mice results in resistance to a second, higher dose (600 mg/kg) of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in our mouse model of APAP autoprotection. The role of liver Fmo3, which detoxifies xenobiotics, in APAP autoprotection is unknown. The purpose of this study was to characterize the gene regulation and protein expression of liver Fmo3 during APAP hepatotoxicity. The functional consequences of Fmo3 induction were also investigated. Plasma and livers were collected from male C57BL/6J mice over a period of 72 h following a single dose of APAP (400 mg/kg) to measure Fmo3 mRNA and protein expression. Although Fmo3 mRNA levels increased significantly following APAP treatment, protein expression changed marginally. In contrast, both Fmo3 mRNA and protein expression were significantly higher in APAP autoprotected livers. Unlike male C57BL/6J mice, female mice have ∼80-times higher constitutive Fmo3 mRNA levels and are highly resistant to APAP hepatotoxicity. Coadministration of APAP with the FMO inhibitor methimazole rendered female mice susceptible to APAP hepatotoxicity, with no changes in susceptibility detected in male mice. Furthermore, a human hepatocyte cell line (HC-04) clone over-expressing human FMO3 showed enhanced resistance to APAP cytotoxicity. Taken together, these findings establish for the first time induction of Fmo3 protein expression and function by xenobiotic treatment. Our results also indicate that Fmo3 expression and function plays a role in protecting the liver from APAP-induced toxicity. Although the mechanism(s) of this protection remains to be elucidated, this work describes a novel protective function for this enzyme. PMID:24973094

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

    PubMed

    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 1hour (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 (15ml/kg water, ip), SAMe (1.25mmol/kg, ip), APAP (250mg/kg), and SAMe given 1h after APAP (S+A). APAP toxicity was confirmed by an increase (p<0.05) in plasma ALT (U/l) and liver weight/10g body weight relative to the Veh, SAMe and S+A groups 4h following APAP treatment. SAMe administered 1h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10g 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. PMID:25246065

  5. S-Adenosyl-L-Methionine Protection of Acetaminophen Mediated Oxidative Stress and Identification of Hepatic 4-Hydroxynonenal Protein Adducts by Mass Spectrometry

    PubMed Central

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

    2015-01-01

    Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-L-methionine (SAMe) treatment 1 hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n=5/group) were divided into the following groups and treated as indicated: Veh (15 ml/kg water, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg), and SAMe given 1 h after APAP (S+A). APAP toxicity was confirmed by an increase (p<0.05) in plasma ALT (U/L) and liver weight/10 g body weight relative to the Veh, SAMe and S+A groups 4 h following APAP treatment. SAMe administered 1 h post APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10 g body weights were lower in the S+A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S+A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1. PMID:25246065

  6. 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 ...

  7. 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 ...

  8. Acetaminophen Modulates the Transcriptional Response to Recombinant Interferon-β

    PubMed Central

    Farnsworth, Aaron; Flaman, Anathea S.; Prasad, Shiv S.; Gravel, Caroline; Williams, Andrew; Yauk, Carole L.; Li, Xuguang

    2010-01-01

    Background Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. Methodology/Principal Findings We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-β treatment. CD-1 mice were administered acetaminophen (APAP), interferon-β (IFN-β) or a combination of IFN-β+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-β. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IκBK/NF-κB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. Conclusions/Significance A significant change in the transcriptional response was observed following co-administration of IFN-β+APAP relative to IFN-β treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-β treatment. PMID:20544007

  9. 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

  10. 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. PMID:23562611

  11. Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice1

    PubMed Central

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

    2012-01-01

    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 A2, and cytosolic and secretory PLA2 activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E2 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 PGE2 expression and hepatocyte regeneration, likely through a mechanism involving PLA2. PMID:22902588

  12. 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

  13. Nephroprotective and antioxidant activities of Salacia oblonga on acetaminophen-induced toxicity in rats.

    PubMed

    Palani, S; Raja, S; Kumar, S Nirmal; Kumar, B Senthil

    2011-11-01

    Salacia oblonga, a woody climbing plant belonging to the family Celastaceae, is widely distributed in India and other southeast Asian countries. The genus Salacia have been used particularly for the treatment of diabetes, obesity, gonorrhoea, rheumatism, pruritus and asthma. Acetaminophen (APAP), used as an analgesic drug, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective and antioxidant activities of the ethanol extract of Salacia oblonga (EESO) at the two dose levels of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. The results showed that APAP significantly increases the levels of serum urea, creatinine, and reduces levels of uric acid concentration. The EESO reduces these by increasing anti-oxidative responses as assessed by biochemical and histopathological parameters. In conclusion, our results suggest that the EESO possesses nephroprotective and antioxidant effects against APAP-induced nephrotoxicity in rats. PMID:21848492

  14. 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

  15. 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

  16. Atomic Physics with Accelerators: Projectile Electron Spectroscopy (APAPES)

    NASA Astrophysics Data System (ADS)

    Madesis, I.; Dimitriou, A.; Laoutaris, A.; Lagoyannis, A.; Axiotis, M.; Mertzimekis, T.; Andrianis, M.; Harissopulos, S.; Benis, E. P.; Sulik, B.; Valastyán, I.; Zouros, T. J. M.

    2015-01-01

    The new research initiative APAPES (http://apapes.physics.uoc.gr/) has already established a new experimental station with a beam line dedicated for atomic collisions physics research, at the 5 MV TANDEM accelerator of the National Research Centre "Demokritos" in Athens, Greece. A complete zero-degree Auger projectile spectroscopy (ZAPS) apparatus has been put together to perform high resolution studies of electrons emitted in ion-atom collisions. A single stage hemispherical spectrometer with a 2-dimensional Position Sensitive Detector (PSD) combined with a doubly-differentially pumped gas target will be used to perform a systematic isoelectronic investigation of K-Auger spectra emitted from collisions of preexcited and ground state He-like ions with gas targets using novel techniques. Our intention is to provide a more thorough understanding of cascade feeding of the 1s2s2p 4P metastable states produced by electron capture in collisions of He-like ions with gas targets and further elucidate their role in the non-statistical production of excited three-electron 1s2s2p states by electron capture, recently a field of conflicting interpretations awaiting further resolution. At the moment, the apparatus is being completed and the spectrometer will soon be fully operational. Here we present the project progress and the recent high resolution spectrum obtained in collisions of 12 MeV C4+ on a Neon gas target.

  17. Deficiency of interleukin-15 enhances susceptibility to acetaminophen-induced liver injury in mice.

    PubMed

    Hou, Hsein-San; Liao, Ching-Len; Sytwu, Huey-Kang; Liao, Nan-Shih; Huang, Tien-Yu; Hsieh, Tsai-Yuan; Chu, Heng-Cheng

    2012-01-01

    Hepatocytes have a direct necrotic role in acetaminophen (APAP)-induced liver injury (AILI), prolonged secondary inflammatory response through innate immune cells and cytokines also significantly contributes to APAP hepatotoxicity. Interleukin 15 (IL-15), a multifunction cytokine, regulates the adaptive immune system and influences development and function of innate immune cells. To better understand the role of IL-15 in liver injury, we treated wild-type (WT) and IL-15-knockout (Il15⁻/⁻) mice with a hepatotoxic dose of APAP to induce AILI and evaluated animal survival, liver damage, APAP metabolism in livers and the inflammatory response. Production of pro-inflammatory cytokines/chemokines was greater in Il15⁻/⁻ than WT mice. Subanalysis of hepatic infiltrated monocytes revealed greater neutrophil influx, along with greater hepatic induction of inducible nitric oxide synthase (iNOS), in Il15⁻/⁻ than WT mice. In addition, the level of hepatic hemeoxygenase 1 (HO-1) was partially suppressed in Il15⁻/⁻ mice, but not in WT mice. Interestingly, elimination of Kupffer cells and neutrophils did not alter the vulnerability to excess APAP in Il15⁻/⁻ mice. However, injection of galactosamine, a hepatic transcription inhibitor, significantly reduced the increased APAP sensitivity in Il15⁻/⁻ mice but had minor effect on WT mice. We demonstrated that deficiency of IL-15 increased mouse susceptibility to AILI. Moreover, Kupffer cell might affect APAP hepatotoxicity through IL-15. PMID:23028657

  18. 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. PMID:25534769

  19. 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.

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

    PubMed Central

    Kim, Yu Ri; Ban, Jung Ok; Yoo, Hwan Soo; Lee, Yong Moon; Yoon, Yeo Pyo; Eum, So Young; Jeong, Heon Sang; Yoon, Do-young; Han, Sang Bae; Hong, Jin Tae

    2013-01-01

    High doses of acetaminophen (APAP; N-acetyl-p-aminophenol) cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg). Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity. PMID:23935693

  1. Quantification of acetaminophen and two of its metabolites in human plasma by ultra-high performance liquid chromatography-low and high resolution tandem mass spectrometry.

    PubMed

    Tonoli, David; Varesio, Emmanuel; Hopfgartner, Gérard

    2012-09-01

    The quantification of acetaminophen (APAP) and two of its metabolites, i.e. acetaminophen-glucuronide (APAP-GLUC) and acetaminophen-cysteine (APAP-CYS), is described in human plasma using ultra-high performance liquid chromatography coupled to a triple quadrupole linear ion trap mass spectrometer operating in the selected reaction monitoring (SRM/MS) mode and to a high resolution quadrupole time-of -flight mass spectrometer operating in the MS/MS (HR-SRM/MS) mode. Starting with a 50 μL plasma aliquot, a generic sample preparation was performed using protein precipitation with methanol/ethanol. Both methods were found to be linear over 2.5 orders of magnitude. Similar performances to the SRM/MS assay were obtained for APAP, APAP-CYS and APAP-GLUC using high resolution-selected reaction monitoring mode with LLOQ of 20, 50 and 50 ng/mL, respectively. For all analytes, precision was found to be better than 12% and accuracy in the range 90.3-109%. The present study demonstrates the ability of QqTOF platforms for accurate and precise quantification in MS/MS mode using short duty cycle with similar sensitivity to LC-SRM/MS. Additionally, as full scan data MS(ALL) are available qualitative and quantitative information on metabolites can also be obtained in a single LC-MS run. PMID:22867840

  2. Birth control pill overdose

    MedlinePlus

    Birth control pills, also called oral contraceptives, are prescription medicines used to prevent pregnancy. Birth control pill overdose occurs when someone takes more than the normal or recommended ...

  3. 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.

  4. 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.

  5. 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

  6. Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1*

    PubMed Central

    Shinohara, Mie; Ybanez, Maria D.; Win, Sanda; Than, Tin Aung; Jain, Shilpa; Gaarde, William A.; Han, Derick; Kaplowitz, Neil

    2010-01-01

    Previously we demonstrated that c-Jun N-terminal kinase (JNK) plays a central role in acetaminophen (APAP)-induced liver injury. In the current work, we examined other possible signaling pathways that may also contribute to APAP hepatotoxicity. APAP treatment to mice caused glycogen synthase kinase-3β (GSK-3β) activation and translocation to mitochondria during the initial phase of APAP-induced liver injury (∼1 h). The silencing of GSK-3β, but not Akt-2 (protein kinase B) or glycogen synthase kinase-3α (GSK-3α), using antisense significantly protected mice from APAP-induced liver injury. The silencing of GSK-3β affected several key pathways important in conferring protection against APAP-induced liver injury. APAP treatment was observed to promote the loss of glutamate cysteine ligase (GCL, rate-limiting enzyme in GSH synthesis) in liver. The silencing of GSK-3β decreased the loss of hepatic GCL, and promoted greater GSH recovery in liver following APAP treatment. Silencing JNK1 and -2 also prevented the loss of GCL. APAP treatment also resulted in GSK-3β translocation to mitochondria and the degradation of myeloid cell leukemia sequence 1 (Mcl-1) in mitochondrial membranes in liver. The silencing of GSK-3β reduced Mcl-1 degradation caused by APAP treatment. The silencing of GSK-3β also resulted in an inhibition of the early phase (0–2 h), and blunted the late phase (after 4 h) of JNK activation and translocation to mitochondria in liver following APAP treatment. Taken together our results suggest that activation of GSK-3β is a key mediator of the initial phase of APAP-induced liver injury through modulating GCL and Mcl-1 degradation, as well as JNK activation in liver. PMID:20061376

  7. 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

  8. 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

  9. Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury

    PubMed Central

    Abdelmegeed, Mohamed A.; Jang, Sehwan; Banerjee, Atrayee; Hardwick, James P.; Song, Byoung-Joon

    2013-01-01

    Acetaminophen (APAP), a widely-used analgesic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an anti-oxidant N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2 h in mice exposed to a single APAP dose (350 mg/kg ip), which caused severe liver necrosis at 24 h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase involved in anti-oxidant defense, energy supply, and fatty acid metabolism, respectively. Immunoprecipitation followed by immunoblot with anti-3-NT antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-co-treated mice. Consistently, NAC co-treatment significantly restored the suppressed activities of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activities promotes APAP-induced mitochondrial dysfunction and hepatotoxicity. PMID:23454065

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

    PubMed Central

    He, Yue-Ying; Zhang, Bao-Xu; Jia, Feng-Lan

    2011-01-01

    AIM: To examine the effects of 2,4-dihydroxybenzophenone (BP-1), a benzophenone derivative used as an ultraviolet light absorbent, on acetaminophen (APAP)-induced hepatotoxicity in C57BL/6J mice. METHODS: Mice were administered orally with BP-1 at doses of 200, 400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP (350 mg/kg body weight) was given subcutaneously. Twenty four hours after APAP intoxication, the serum enzyme including serum alaine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) were measured and liver histopathologic changes were examined. RESULTS: BP-1 administration dramatically reduced serum ALT, AST and LDH levels. Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner. Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment, and glutathione depletion was ameliorated obviously. CONCLUSION: BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity, and reduction of oxidative stress might be part of the protection mechanism. PMID:21677837

  11. 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

  12. Possible fatal acetaminophen intoxication with atypical clinical presentation.

    PubMed

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

    2013-09-01

    Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. We present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 μg/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria. PMID:23822653

  13. Zinc Supplementation with Polaprezinc Protects Mouse Hepatocytes against Acetaminophen-Induced Toxicity via Induction of Heat Shock Protein 70.

    PubMed

    Nishida, Tadashi; Ohata, Shuzo; Kusumoto, Chiaki; Mochida, Shinsuke; Nakada, Junya; Inagaki, Yoshimi; Ohta, Yoshiji; Matsura, Tatsuya

    2010-01-01

    Polaprezinc, a chelate compound consisting of zinc and l-carnosine, is clinically used as a medicine for gastric ulcers. It has been shown that induction of heat shock protein (HSP) is involved in protective effects of polaprezinc against gastric mucosal injury. In the present study, we investigated whether polaprezinc and its components could induce HSP70 and prevent acetaminophen (APAP) toxicity in mouse primary cultured hepatocytes. Hepatocytes were treated with polaprezinc, zinc sulfate or l-carnosine at the concentration of 100 microM for 9 h, and then exposed to 10 mM APAP. Polaprezinc or zinc sulfate increased cellular HSP70 expression. However, l-carnosine had no influence on it. Pretreatment of the cells with polaprezinc or zinc sulfate significantly suppressed cell death as well as cellular lipid peroxidation after APAP treatment. In contrast, pretreatment with polaprezinc did not affect decrease in intracellular glutathione after APAP. Furthermore, treatment with KNK437, an HSP inhibitor, attenuated increase in HSP70 expression induced by polaprezinc, and abolished protective effect of polaprezinc on cell death after APAP. These results suggested that polaprezinc, in particular its zinc component, induces HSP70 expression in mouse primary cultured hepatocytes, and inhibits lipid peroxidation after APAP treatment, resulting in protection against APAP toxicity. PMID:20104264

  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 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

  16. Comparison of single-dose and multiple-dose pharmacokinetics between two formulations of hydrocodone bitartrate/acetaminophen: immediate-release versus biphasic immediate-release/extended release

    PubMed Central

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

    2015-01-01

    Objective This study aimed to compare the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) and IR HB/APAP. Setting The study was conducted in a contract research center. Participants The study included healthy adults. Interventions In a three-way crossover study, Study 1, participants received the following treatments: (A1) a single dose of IR/ER HB/APAP 7.5/325 mg one tablet, followed by one tablet every 12 hours (q12h); (B1) a single dose of IR/ER HB/APAP 7.5/325 mg two tablets, followed by two tablets q12h; (C1) a single dose of IR HB/APAP 7.5/325 mg two tablets (one tablet at hours 0 and 6), followed by one tablet q6h. In a two-way crossover study, Study 2, participants received the following treatments: (A2) an initial dose of IR/ER HB/APAP 7.5/325 mg three tablets, followed by two tablets q12h; (B2) three doses of IR HB/APAP 7.5/325 mg one tablet q4h, followed by one tablet q6h. Main outcome measures PK values were compared, and adverse events were assessed. Results Single-dose and steady-state area under the concentration–time curves for hydrocodone and APAP were similar for IR/ER and IR HB/APAP; the steady-state peak plasma concentrations (Cmax) at steady state were also similar, but single-dose Cmax for hydrocodone was lower for IR/ER HB/APAP. For most PK parameters, 90% confidence intervals for geometric least squares mean ratios were not meaningfully different (80%–125%). Steady state was achieved in 2−3 days for IR/ER HB/APAP and in 2 days for IR HB/APAP. Median time to Cmax was longer for IR/ER HB/APAP versus IR HB/APAP (P,0.05). Adverse events were similar across treatments. Conclusion PK outcomes and tolerability were similar for IR/ER HB/APAP and IR HB/APAP. PMID:26392786

  17. Effect of S-methylisothiourea in acetaminophen-induced hepatotoxicity in rat.

    PubMed

    More, Amar S; Kumari, Rashmi R; Gupta, Gaurav; Kathirvel, Kandasamy; Lonare, Milindmitra K; Dhayagude, Rohini S; Kumar, Dhirendra; Kumar, Dinesh; Sharma, Anil K; Tandan, Surendra K

    2012-11-01

    Nitric oxide synthesized from inducible nitric oxide synthase (iNOS) plays role in acetaminophen (APAP)-induced liver damage. The present study was undertaken to evaluate the effect of iNOS inhibitor S-methylisothiourea (SMT) in APAP-induced hepatotoxicity in rats (1 g/kg, i.p.). SMT was (10, 30, and 100 mg/kg; i.p.) given 30 min before and 3 h after APAP administration. At 6 and 24 h, blood was collected to measure alanine transaminase (ALT), aspartate transaminase (AST), and nitrate plus nitrite (NOx) levels in serum. At 48 h, animals were sacrificed, and blood and liver tissues were collected for biochemical estimation. SMT reduced significantly the serum ALT, AST, and NOx levels at 24 and 48 h and liver NOx levels at 48 h as compared with APAP-treated control. The amount of peroxynitrite measured by rhodamine assay was significantly reduced by SMT, as compared with APAP-treated control group. SMT treatment (30 mg/kg) has significantly reduced the lipid peroxidation and protein carbonyl levels, increased SOD and catalase, and reduced glutathione and total thiol levels significantly as compared with APAP-treated control. SMT 30 mg/kg dose has protected animals from APAP-induced hypotension and reduced iNOS gene expression. Hepatocytes were isolated from animals, and effect of SMT on apoptosis, MTP, and ROS generation was studied, and their increased value in APAP intoxicated group was found to be significantly decreased by SMT (30 mg/kg) at 24 and 48 h. In conclusion, nitric oxide produced from iNOS plays important role in toxicity at late hours (24 to 48 h), and SMT inhibits iNOS and reduces oxidative and nitrosative stress. PMID:22885820

  18. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury.

    PubMed

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

    2016-06-01

    Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP upregulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepatoprotective agent. PMID:27161000

  19. 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

  20. Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans.

    PubMed

    Mannery, Yanci O; Ziegler, Thomas R; Park, Youngja; Jones, Dean P

    2010-06-01

    Variations in plasma sulfur amino acid (SAA) pools are associated with disease risks, but little information is available about the factors affecting plasma SAA pools. Drug metabolism by glutathione (GSH) and sulfate conjugation can, in principle, represent a quantitatively important burden on SAA supply. The present study was designed to determine whether therapeutic doses of acetaminophen (APAP) alter SAA metabolism in healthy human adults. A double-blind, crossover design incorporating four treatment periods with diets providing 100% of the recommended dietary allowance (RDA) for SAA without or with APAP (15 mg/kg) and 0% RDA for SAA without or with APAP, in randomized order. After a 3-day equilibration period, chemically defined diets with 100 or 0% RDA for SAA were given for 2 complete days. On day 3, APAP or placebo was given in two successive doses (6-h interval), and timed plasma samples were collected. With SAA intake at 100% RDA, APAP administration oxidized the plasma cysteine/cystine redox potential (E(h)CySS) but not the plasma GSH/GSSG redox potential (E(h)GSSG). The extent of oxidation caused by APAP was similar to that seen with 0% SAA and no APAP. However, APAP administration with 0% SAA did not cause further oxidation beyond APAP or 0% SAA alone. In contrast, an oxidation of the plasma E(h)GSSG was apparent for SAA insufficiency only with APAP. The results suggest a need to evaluate possible effects of APAP in association with SAA insufficiency as a contributing factor in disease risk. PMID:20207721

  1. Oxidation of Plasma Cysteine/Cystine and GSH/GSSG Redox Potentials by Acetaminophen and Sulfur Amino Acid Insufficiency in Humans

    PubMed Central

    Mannery, Yanci O.; Ziegler, Thomas R.; Park, Youngja

    2010-01-01

    Variations in plasma sulfur amino acid (SAA) pools are associated with disease risks, but little information is available about the factors affecting plasma SAA pools. Drug metabolism by glutathione (GSH) and sulfate conjugation can, in principle, represent a quantitatively important burden on SAA supply. The present study was designed to determine whether therapeutic doses of acetaminophen (APAP) alter SAA metabolism in healthy human adults. A double-blind, crossover design incorporating four treatment periods with diets providing 100% of the recommended dietary allowance (RDA) for SAA without or with APAP (15 mg/kg) and 0% RDA for SAA without or with APAP, in randomized order. After a 3-day equilibration period, chemically defined diets with 100 or 0% RDA for SAA were given for 2 complete days. On day 3, APAP or placebo was given in two successive doses (6-h interval), and timed plasma samples were collected. With SAA intake at 100% RDA, APAP administration oxidized the plasma cysteine/cystine redox potential (EhCySS) but not the plasma GSH/GSSG redox potential (EhGSSG). The extent of oxidation caused by APAP was similar to that seen with 0% SAA and no APAP. However, APAP administration with 0% SAA did not cause further oxidation beyond APAP or 0% SAA alone. In contrast, an oxidation of the plasma EhGSSG was apparent for SAA insufficiency only with APAP. The results suggest a need to evaluate possible effects of APAP in association with SAA insufficiency as a contributing factor in disease risk. PMID:20207721

  2. '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.

  3. Castor oil overdose

    MedlinePlus

    Castor oil is a yellowish liquid often used as a lubricant and in laxatives. This article discusses poisoning from swallowing a large amount (overdose) of castor oil. This is for information only and not for ...

  4. Barbiturate intoxication and overdose

    MedlinePlus

    Symptoms of barbiturate intoxication and overdose include: Altered level of consciousness Difficulty in thinking Drowsiness or coma Faulty judgment Lack of coordination Shallow breathing Slow, slurred speech Sluggishness Staggering Excessive and long-term use ...

  5. Birth control pills overdose

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    ... this page: //medlineplus.gov/ency/article/002599.htm Birth control pill overdose To use the sharing features on this page, please enable JavaScript. Birth control pills, also called oral contraceptives, are prescription medicines ...

  6. Thyroid preparation overdose

    MedlinePlus

    Thyroid preparations are medicines used to treat thyroid gland disorders. Overdose occurs when someone takes more than the normal or recommended amount of this medicine. This can be by accident or ...

  7. Eucalyptus oil overdose

    MedlinePlus

    ... PS, ed. Wilderness Medicine . 6th ed. Philadelphia, PA: Elsevier Mosby; 2012:chap 64. Maypole J, Woolf AD. ... Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 101. McMullan JT, Duvivier EH, ...

  8. Sassafras oil overdose

    MedlinePlus

    ... Medicine for the Outdoors . 6th ed. Philadelphia, PA: Elsevier Mosby; 2016:374-404. Kingston RL, Foley C. ... Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier Saunders; 2007:chap 68. Smolinske SC, Daubert GP, ...

  9. 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.

  10. Methyl salicylate overdose

    MedlinePlus

    Methyl salicylate (oil of wintergreen) is a chemical that smells like wintergreen. It is used in many over- ... muscle ache creams. It is related to aspirin. Methyl salicylate overdose occurs when someone swallows a dangerous amount ...

  11. 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 ...

  12. 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 ...

  13. Calcium channel blocker overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002580.htm Calcium channel blocker overdose To use the sharing features on this page, please enable JavaScript. Calcium channel blockers are a type of medicine used ...

  14. Fenoprofen calcium overdose

    MedlinePlus

    Fenoprofen calcium is a type of medicine called a nonsteroidal anti-inflammatory drug. It is a prescription pain medicine used to relieve symptoms of arthritis . Fenoprofen calcium overdose occurs when someone takes more than the ...

  15. Cardiac glycoside overdose

    MedlinePlus

    ... usually occur only in chronic overdoses. EYES, EARS, NOSE, AND THROAT Blurred vision Halos around objects (yellow, green, white) * SKIN Allergic reaction, including possible Stevens-Johnson syndrome Hives Rash STOMACH AND INTESTINES Diarrhea Loss of ...

  16. Diclofenac sodium overdose

    MedlinePlus

    Diclofenac sodium is a prescription medicine used to relieve pain and swelling. It is a nonsteroidal anti-inflammatory drug (NSAID). Diclofenac sodium overdose occurs when someone takes more than the ...

  17. 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 ...

  18. 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 ...

  19. 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

  20. 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

  1. [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

  2. 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

  3. 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

  4. 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

  5. Therapeutic efficacy of Rosa damascena Mill. on acetaminophen-induced oxidative stress in albino rats.

    PubMed

    Saxena, Monika; Shakya, Arvind Kumar; Sharma, Neetu; Shrivastava, Sadhana; Shukla, Sangeeta

    2012-01-01

    Rosa damascena (RD) is a widely cultivated ornamental plant. It acts as an astringent, aperients, carminative, and refrigerant and is used in respiratory disorders, tonsillitis, eye disorders, migraines, gynecological disorders, and menopausal symptoms. The aim of this study is to investigate the hepatoprotective activity of the aqueous extract of RD flowers at different oral dose levels (250, 500, and 1000 mg/kg body weight) on acetaminophen (2 g/kg oral N-acetyl-p-aminophenol [APAP])-induced toxicity in rats. APAP administration altered various biochemical parameters, including serum transaminases, serum alkaline phosphatase, lactate dehydrogenase, albumin, bilirubin, urea and creatinine, hepatic lipid peroxidation, and reduced glutathione levels. Adenosine triphosphatase and glucose-6-phosphatase activity in the liver was decreased significantly in animals treated with APAP. These values are retrieved significantly by treatment with RD extract at all 3 doses in dose-dependant manner. Apart from these, histopathological changes also reveal the protective nature of the RD extract against acetaminophen-induced necrotic damage of hepatic tissues. In conclusion, these data suggest that the aqueous extract of RD may prevent hepatic damage from APAP-induced toxicity in rats and is likely to be mediated through its antioxidant activities. PMID:23339694

  6. Mouse liver protein sulfhydryl depletion after acetaminophen exposure.

    PubMed

    Yang, Xi; Greenhaw, James; Shi, Qiang; Roberts, Dean W; Hinson, Jack A; Muskhelishvili, Levan; Davis, Kelly; Salminen, William F

    2013-01-01

    Acetaminophen (APAP)-induced liver injury is the leading cause of acute liver failure in many countries. This study determined the extent of liver protein sulfhydryl depletion not only in whole liver homogenate but also in the zonal pattern of sulfhydryl depletion within the liver lobule. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase levels, liver necrosis, and glutathione depletion in a dose-dependent manner. Free protein sulfhydryls were measured in liver protein homogenates by labeling with maleimide linked to a near infrared fluorescent dye followed by SDS-polyacrylamide gel electrophoresis. Global protein sulfhydryl levels were decreased significantly (48.4%) starting at 1 hour after the APAP dose and maintained at this reduced level through 24 hours. To visualize the specific hepatocytes that had reduced protein sulfhydryl levels, frozen liver sections were labeled with maleimide linked to horseradish peroxidase. The centrilobular areas exhibited dramatic decreases in free protein sulfhydryls while the periportal regions were essentially spared. These protein sulfhydryl-depleted regions correlated with areas exhibiting histopathologic injury and APAP binding to protein. The majority of protein sulfhydryl depletion was due to reversible oxidation since the global- and lobule-specific effects were essentially reversed when the samples were reduced with tris(2-carboxyethy)phosphine before maleimide labeling. These temporal and zonal pattern changes in protein sulfhydryl oxidation shed new light on the importance that changes in protein redox status might play in the pathogenesis of APAP hepatotoxicity. PMID:23093024

  7. Acetaminophen dosing for children

    MedlinePlus

    Taking acetaminophen (Tylenol) can help children with colds and fever feel better. As with all drugs, it is important to give children the correct dose. Acetaminophen is safe when taken as directed. But taking ...

  8. Acetaminophen, Butalbital, and Caffeine

    MedlinePlus

    The combination of acetaminophen, Butalbital, Caffeine comes as a capsule and tablet to take by mouth. It usually is taken every 4 hours ... explain any part you do not understand. Take acetaminophen, Butalbital, Caffeine exactly as directed. Do not take ...

  9. 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. PMID:26969520

  10. 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

  11. A retrospective analysis of intravenous acetaminophen use in spinal surgery patients

    PubMed Central

    Smith, April N.; Hoefling, Vie C.

    2014-01-01

    Objective This study aimed to determine if intravenous acetaminophen [paracetamol] (IV APAP) could decrease visual analog pain scores (VAS), opioid exposure and subsequent opioid related adverse effects (nausea, vomiting, constipation) in spinal surgery patients. Methods Thirty four spinal surgery patients to date have received IV APAP since its addition to the formulary at our institution. The electronic medical record was accessed on all patients who received at least one dose pre or post operatively to collect postoperative opioid consumption (in morphine equivalents), number of antiemetic and laxative doses, use of naloxone, and VAS pain scores from arrival to surgical unit through postop day two. An equivalent number of patients who did not receive any IV APAP were selected and matched on the basis of opioid use prior to admission, surgery type, surgeon, age, and sex to constitute the control group. Results The IV APAP group used significantly less opioids than the control group (p=0.015). Frequency of antiemetic and laxative use and VAS pain scores did not differ significantly between the two groups. Conclusions It appears IV APAP can be used effectively as an adjuvant pain management therapy in spinal surgery patients to decrease opioid exposure, but does not necessarily reduce the incidence of opioid related adverse effects or VAS pain scores. PMID:25243029

  12. 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. PMID:24878114

  13. Physiologically based modeling of the pharmacokinetics of acetaminophen and its major metabolites in humans using a Bayesian population approach.

    PubMed

    Zurlinden, Todd J; Reisfeld, Brad

    2016-06-01

    The principal aim of this study was to develop, validate, and demonstrate a physiologically based pharmacokinetic (PBPK) model to predict and characterize the absorption, distribution, metabolism, and excretion of acetaminophen (APAP) in humans. A PBPK model was created that included pharmacologically and toxicologically relevant tissue compartments and incorporated mechanistic descriptions of the absorption and metabolism of APAP, such as gastric emptying time, cofactor kinetics, and transporter-mediated movement of conjugated metabolites in the liver. Through the use of a hierarchical Bayesian framework, unknown model parameters were estimated using a large training set of data from human pharmacokinetic studies, resulting in parameter distributions that account for data uncertainty and inter-study variability. Predictions from the model showed good agreement to a diverse test set of data across several measures, including plasma concentrations over time, renal clearance, APAP absorption, and pharmacokinetic and exposure metrics. The utility of the model was then demonstrated through predictions of cofactor depletion, dose response of several pharmacokinetic endpoints, and the relationship between APAP biomarker levels in the plasma and those in the liver. The model addressed several limitations in previous PBPK models for APAP, and it is anticipated that it will be useful in predicting the pharmacokinetics of APAP in a number of contexts, such as extrapolating across doses, estimating internal concentrations, quantifying population variability, assessing possible impacts of drug coadministration, and, when coupled with a suitable pharmacodynamic model, predicting toxicity. PMID:25636597

  14. 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. PMID:16140478

  15. ACETAMINOPHEN-INDUCED HEPATIC NEUTROPHIL ACCUMULATION AND INFLAMMATORY LIVER INJURY IN CD18-DEFICIENT MICE

    PubMed Central

    Williams, C. David; Bajt, Mary Lynn; Farhood, Anwar; Jaeschke, Hartmut

    2014-01-01

    Background Acetaminophen (APAP) hepatotoxicity is currently the most frequent cause of acute liver failure in the US and many European countries. Although intracellular signaling mechanisms are critical for hepatocellular injury, a contribution of inflammatory cells, especially neutrophils, has been suggested. However, conflicting results were obtained when using immunological intervention strategies. Aims The role of neutrophils was investigated using a CD18-deficient mouse model. Results Treatment of C57Bl/6 wild type mice with 300 mg/kg APAP resulted in severe liver cell necrosis at 12 and 24 h. This injury was accompanied by formation of cytokines and chemokines and accumulation of neutrophils in the liver. However, there was no difference in the inflammatory response or liver injury in CD18-deficient mice compared to wild type animals. In contrast to treatment with endotoxin, no upregulation of CD11b or priming for reactive oxygen was observed on neutrophils isolated from the peripheral blood or the liver after APAP administration. Furthermore, animals treated with endotoxin 3 h after APAP experienced an exaggerated inflammatory response as indicated by substantially higher cytokine and chemokine formation and twice the number of neutrophils in the liver. However, liver injury in the two-hit model was the same as with APAP alone. Conclusions Our data do not support the hypothesis that neutrophils contribute to APAP hepatotoxicity or that a neutrophil-mediated injury phase could be provoked by a second, pro-inflammatory hit. Thus, APAP-induced liver injury in mice is dominated by intracellular mechanisms of cell death rather than by neutrophilic inflammation. PMID:20500806

  16. Identification of Identical Transcript Changes in Liver and Whole Blood during Acetaminophen Toxicity

    PubMed Central

    Zhang, Liwen; Bushel, Pierre R.; Chou, Jeff; Zhou, Tong; Watkins, Paul B.

    2012-01-01

    The ability to identify mechanisms underlying drug-induced liver injury (DILI) in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a non-invasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG) to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP). In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose) with similar patterns of expression in blood and liver during APAP-induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP-induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only 38 genes were common to both the 6 and 24-h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined. PMID:22973295

  17. 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

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

    PubMed

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

    2016-08-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. PMID:27163765

  19. 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

  20. Target biomarker profile for the clinical management of paracetamol overdose.

    PubMed

    Vliegenthart, A D Bastiaan; Antoine, Daniel J; Dear, James W

    2015-09-01

    Paracetamol (acetaminophen) overdose is one of the most common causes of acute liver injury in the Western world. To improve patient care and reduce pressure on already stretched health care providers new biomarkers are needed that identify or exclude liver injury soon after an overdose of paracetamol is ingested. This review highlights the current state of paracetamol poisoning management and how novel biomarkers could improve patient care and save healthcare providers money. Based on the widely used concept of defining a target product profile, a target biomarker profile is proposed that identifies desirable and acceptable key properties for a biomarker in development to enable the improved treatment of this patient population. The current biomarker candidates, with improved hepatic specificity and based on the fundamental mechanistic basis of paracetamol-induced liver injury, are reviewed and their performance compared with our target profile. PMID:26076366

  1. 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

  2. Sassafras oil overdose

    MedlinePlus

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

  3. MOUSE STRAIN-DEPENDENT CASPASE ACTIVATION DURING ACETAMINOPHEN HEPATOTOXICITY DOES NOT RESULT IN APOPTOSIS OR MODULATION OF INFLAMMATION

    PubMed Central

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

    2011-01-01

    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. PMID:22023962

  4. Pharmacokinetics and bioavailability of oxycodone and acetaminophen following single-dose administration of MNK-795, a dual-layer biphasic IR/ER combination formulation, under fed and fasted conditions

    PubMed Central

    Devarakonda, Krishna; Morton, Terri; Margulis, Rachel; Giuliani, Michael; Barrett, Thomas

    2014-01-01

    Background XARTEMIS™ XR (formerly MNK-795) is a combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (ER OC/APAP). The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK) of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets) versus fasted conditions on the PK of ER OC/APAP was performed. Methods This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48) were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP. Results Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC]) from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food. Conclusion The findings from this study suggest that ER OC/APAP can be administered with or without food. PMID:25170252

  5. 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

  6. 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

  7. Effect of acetaminophen exposure in Oncorhynchus mykiss gills and liver: detoxification mechanisms, oxidative defence system and peroxidative damage.

    PubMed

    Ramos, A S; Correia, A T; Antunes, S C; Gonçalves, F; Nunes, B

    2014-05-01

    The increasing presence of pharmaceutical drugs in nature is cause of concern due to the occurrence of oxidative stress in non-target species. Acetaminophen is widely used in human medicine as an analgesic and antipyretic drug, and it is one of the most sold non-prescription drugs. The present study aimed to assess the toxic effects of acetaminophen (APAP) in Oncorhynchus mykiss following acute and chronic exposures in realistic levels. In order to evaluate the APAP effects in the rainbow trout, gills and liver were analyzed with biochemical biomarkers, such as catalase (CAT), total and selenium-dependent glutathione peroxidase (GPx), glutathione reductase (GRed) and glutathione-S-transferases (GSTs) activity and also lipid peroxidation levels (TBARS). The results obtained in all tests indicate that a significant response of oxidative stress was established, along with the increase of APAP concentrations. The establishment of an oxidative stress scenario occurred with the involvement of all tested biomarkers, sustaining a generalized set of pro-oxidative effects elicited by APAP. Additionally, the occurrence of oxidative damage strongly suggests the impairment of the antioxidant defense mechanism of O. mykiss. It is important to note that the occurrence of oxidative deleterious effects and peroxidative damages occurred for concentrations similar to those already reported for several freshwater ecosystems. The importance of these assumptions is further discussed under the scope of ecological relevance of the assessment of effects caused by pharmaceuticals in non-target organisms. PMID:24816177

  8. Chronic Acetaminophen Exposure in Pediatric Acute Liver Failure

    PubMed Central

    Alonso, Estella M.; Im, Kelly; Belle, Steven H.; Squires, Robert H.

    2013-01-01

    BACKGROUND: Acetaminophen (N-acetyl-p-aminophenol [APAP]) is a widely used medication that can cause hepatotoxicity. We examined characteristics and outcomes of children with chronic exposure (CE) to APAP in the multinational Pediatric Acute Liver Failure (PALF) Study. METHODS: A total of 895 children enrolled from 2002 to 2009 were grouped by APAP exposure history as: CE (received multiple doses \\x{2265}2 days; n = 83), single dose exposure (SE; n = 85), and no exposure (NE; n = 498). CE was the reference group for pairwise comparisons. Median values are shown. RESULTS: Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008). CONCLUSIONS: Children in the PALF study with CE had lower bilirubin and higher alanine aminotransferase than those with NE. Outcomes with CE were worse than with SE but better than with NE. Potential reasons for this outcomes advantage over non–APAP-exposed subjects should be explored. PMID:23439908

  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. 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

  11. Evaluation of the stability of acetaminophen in pluronic lecithin organogel and the determination of an appropriate beyond-use date.

    PubMed

    Peacock, Gina F; Sauvageot, Jurgita

    2012-01-01

    Transdermal acetaminophen in Pluronic lecithin organogel (APAP-PLO) has been anecdotally reported as beneficial when used in cancer patients in the hospice setting. However, there is currently no published information regarding the stability of APAP-PLO. The objective of this study was to identify an appropriate formulation of APAP-PLO and to evaluate the stability of that formulation in order to determine an appropriate beyond-use date. APAP-PLO 50% was prepared by a local compounding pharmacy and analyzed at 0, 7, 14, 28, 45, 60, 90, and 180 days using a stability-indicating high-performance liquid chromatographic method. The mean concentrations and standard deviations were determined for each time point. Physical stability was also assessed by visual observation at each time point. The beyond-use date was determined as the time period that the samples maintained at least 90 percent of the initial concentration. At 180 days, the APAP-PLO was physically stable as noted by visual observation, and the concentration was 102 +/- 4.8 percent of initial concentration indicating that a beyond-use date of 180 days would be appropriate for this formulation. PMID:23072202

  12. 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

  13. 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

  14. New insights into the primary phototransformation of acetaminophen by UV/H2O2: photo-Fries rearrangement versus hydroxyl radical induced hydroxylation.

    PubMed

    Feng, Shixiang; Zhang, Xu; Liu, Yanxiang

    2015-12-01

    The phototransformation of acetaminophen (APAP) by UV/H2O2 in deionized water and sewage treatment plant (STP) effluents was studied systematically by a combination of analysis of the reaction intermediates and kinetic study. 1-(2-amino-5-hydroxyphenyl)ethanone (P1) and the reported N-(3,4-dihydroxyphenyl)acetamide (P2) were identified as the main transformation intermediates during the transformation of APAP by UV/H2O2. There was no influence of OH on the formation kinetics of P1, while its decay was promoted. The formation and decay kinetics of P2 were accelerated by increases in the concentration of OH. The second-order rate constants for the reaction of OH with APAP, P1, and P2 were 3.9 × 10(9), 8.1 × 10(9), and 4.7 × 10(9) M(-1) s(-1), respectively. The kinetic study indicated that the main transformation of APAP also included transformation to 1,4-hydroquinone, although the accumulated concentration of 1,4-hydroquinone was quite low. The presence of anions (Cl(-), HCO3(-)/CO3(2-) NO2(-)/NO3(-)), humic acid, commercial drug components or adjuvants, and dissolved organic matters in STP effluents not only changed the transformation kinetics of APAP, but also altered the distribution of the intermediates. The kinetics and pathway of APAP transformation in STP effluent were markedly different from those in deionized water. PMID:25997748

  15. 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 ...

  16. Acetaminophen by infusion.

    PubMed

    Turkoski, Beatrice B

    2015-01-01

    Acetaminophen is a nonsteroidal, nonsalicylate analgesic and antipyretic that is, today, the most common medication ingredient found in oral and rectal over-the-counter and prescription drugs. However, it was not until 2010 that Ofirmev (acetaminophen), an injection form of acetaminophen, was approved for treating mild to moderate pain, as an adjunct to opioids for severe pain, and reduction of fever in those younger than 2 years. Thus, intravenous acetaminophen may be appropriately used in a wide variety of settings and nurses who are knowledgeable and informed about the correct use of intravenous acetaminophen will be able to reduce the potential for medication misadventures. In this article, the uses and cautions for Ofirmev are discussed. PMID:25989127

  17. 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

  18. [Vitamin K antagonists overdose].

    PubMed

    Groszek, Barbara; Piszczek, Paweł

    2015-01-01

    Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed

  19. The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure.

    PubMed

    Court, Michael H; Freytsis, Marina; Wang, Xueding; Peter, Inga; Guillemette, Chantal; Hazarika, Suwagmani; Duan, Su X; Greenblatt, David J; Lee, William M

    2013-05-01

    Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3'UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3'UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, χ(2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual's risk for acetaminophen-induced liver injury. PMID:23408116

  20. 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 Central

    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. PMID:26316698

  1. 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. PMID:26316698

  2. 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

  3. 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

  4. Protective effect of nifedipine against cytotoxicity and intracellular calcium alterations induced by acetaminophen in rat hepatocyte cultures.

    PubMed

    Ellouk-Achard, S; Mawet, E; Thibault, N; Dutertre-Catella, H; Thevenin, M; Claude, J R

    1995-01-01

    Alteration of calcium homeostasis has been proposed to play a major role in cell necrosis induced by a variety of chemical agents such as acetaminophen (APAP). In this study, a potential protective effect of the dihydropyridine calcium channel blocking agent, nifedipine, was investigated in vitro on acetaminophen-induced hepatocyte damage. Rat hepatocytes were exposed during 20 hours to various concentrations of APAP (0.50 to 4.00 mM). The following metabolic and functional parameters were investigated: -lactate dehydrogenase (LDH) release as an indicator of plasma membrane integrity, -cell viability evaluated by the colorimetric MTT assay, and intracellular calcium concentration as evaluated by two fluorimetric methods: a scanning laser cytometer using indo-1-AM as fluorescent probe and a fluorescence plate reader using fluo-3-AM as calcium indicator. Incubation of hepatocytes with APAP alone in the range 0.50 to 4.00mM resulted in a dose-response relationship with regard to LDH release (243% to 750% of control) and to the loss of cell viability (0 to 67% of control). Moreover these results were correlated with a significant increase in cytosolic calcium content (189 to 406 nM). Nifedipine treatment prior to APAP exposure, partially prevented LDH release, the plasma membrane blebbing, and thereby the loss of viability. In addition, intracellular calcium level progressively returned within the limits of the control values with increasing concentrations of nifedipine. It can be concluded that, in vitro conditions, nifedipine pretreatment exhibits a preventive effect against acetaminophen hepatocyte injury. PMID:7497906

  5. 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

  6. 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 ...

  7. 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

  8. 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. PMID:26212553

  9. Intravenous N-acetylcysteine in Pediatric Patients with Non-Acetaminophen Acute Liver Failure: A Placebo-Controlled Clinical Trial

    PubMed Central

    Squires, Robert H.; Dhawan, Anil; Alonso, Estella; Narkewicz, Michael R.; Shneider, Benjamin L.; Rodriguez-Baez, Norberto; Olio, Dominic Dell; Karpen, Saul; Bucuvalas, John; Lobritto, Steven; Rand, Elizabeth; Rosenthal, Philip; Horslen, Simon; Ng, Vicky; Subbarao, Girish; Kerkar, Nanda; Rudnick, David; Lopez, M. James; Schwarz, Kathleen; Romero, Rene; Elisofon, Scott; Doo, Edward; Robuck, Patricia R.; Lawlor, Sharon; Belle, Steven H.

    2012-01-01

    N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with non-acetaminophen (non-APAP) acute liver failure (ALF) and grade 1–2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of ICU and hospital stays, organ system failure and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (p=0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (p=0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0–1 (NAC 25%; placebo 60%; p=0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. Conclusion NAC did not improve 1-year survival in non-APAP PALF. 1-year LTx-free survival was significantly lower with NAC, particularly among those < 2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults. PMID:22886633

  10. A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain.

    PubMed

    Fricke, James R; Hewitt, David J; Jordan, Donna M; Fisher, Alan; Rosenthal, Norman R

    2004-06-01

    The objective of this study was to compare the analgesic efficacy of tramadol/acetaminophen (APAP) (total dose 75 mg/650 mg) and tramadol (total dose 100 mg) for the control of pain after oral surgery. A total of 456 patients with moderate-to-severe pain within 5 h after extraction of two or more third molars were randomized to receive two identical encapsulated tablets containing tramadol/APAP 37.5 mg/325 mg, tramadol 50 mg, or placebo. Tramadol/APAP was superior to tramadol (P < 0.001) or placebo (P < 0.001) on all efficacy measures: total pain relief (PAR) over 6 h (7.4, 2.5, and 1.5, respectively, on a scale of 0-24); sum of pain intensity differences (PIDs) (3.1, 0.6, and 0.1, respectively, on a scale of -6 to 18); and sum of PAR and PID (10.5, 3.1, and 1.6, respectively, on a scale of -6 to 42). Median times to onset of perceptible and meaningful PAR were 37.6 and 126.5 min, respectively, for the tramadol/APAP group (P < 0.001) for each, compared with tramadol and placebo arms). The most common adverse events with active treatment were nausea, dizziness, and vomiting; these events occurred more frequently in the tramadol group than in the tramadol/APAP group. This study established the superiority of tramadol/APAP 75 mg/650 mg over tramadol 100 mg in the treatment of acute pain following oral surgery. PMID:15157685

  11. 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

  12. 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 (5-500μg/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

  13. 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

  14. Understanding a Substrate’s Product Regioselectivity in a Family of Enzymes: A Case Study of Acetaminophen Binding in Cytochrome P450s

    PubMed Central

    Yang, Yue; Wong, Sergio E.; Lightstone, Felice C.

    2014-01-01

    Abstract Product regioselectivity as influenced by molecular recognition is a key aspect of enzyme catalysis. We applied large-scale two-dimensional (2D) umbrella sampling (USP) simulations to characterize acetaminophen (APAP) binding in the active sites of the family of Cytochrome P450 (CYP) enzymes as a case study to show the different regioselectivity exhibited by a single substrate in comparative enzymes. Our results successfully explain the experimentally observed product regioselectivity for all five human CYPs included in this study, demonstrating that binding events play an important role in determining regioselectivity. In CYP2C9 and CYP3A4, weak interactions in an overall large active site cavity result in a fairly small binding free energy difference between APAP reactive binding states, consistent with experimental results that show little preference for resulting metabolites. In contrast, in CYP1A2 and CYP2E1, APAP is strongly restrained by a compact binding pocket, leading to a preferred binding conformation. The calculated binding equilibrium of APAP within the compact active site of CYP2A6 is able to predict the experimentally documented product ratios and is also applied to explain APAP regioselectivity in CYP1A2 and CYP2C9. APAP regioselectivity seems to be related to the selectivity for one binding conformation over another binding conformation as dictated by the size and shape of the active site. Additionally, unlike docking and molecular dynamics (MD), our free energy calculations successfully reproduced a unique APAP pose in CYP3A4 that had been reported experimentally, suggesting this approach is well suited to find the realistic binding pose and the lowest-energy starting structure for studying the chemical reaction step in the future. PMID:24498291

  15. Hepatoprotective effects of Chai-Hu-Ching-Kan-Tang on acetaminophen-induced acute liver injury in rats.

    PubMed

    Lin, Tzu-Hsiang; Ng, Lean-Teik; Yen, Feng-Lin; Lin, Chun-Ching

    2007-01-01

    Chai-Hu-Ching-Kan-Tang (CHCKT) is one of the traditional Chinese medicine prescriptions commonly used to treat liver diseases. In this study, we evaluated the hepatoprotective effects of aqueous CHCKT extract at various concentrations (125, 250 and 500 mg/kg body weight) on acetaminophen (APAP)-induced acute liver injury in rats. Results showed that CHCKT treatments significantly decreased the level of serum glutamic oxaloacetic transaminase (sGOT) and glutamic pyruvic transaminase (sGPT) in APAP-treated groups. CHCKT also significantly decreased the level of lipid peroxides and increased the activity of antioxidant enzymes (i.e. SOD and GPx). Histopathological observation further confirmed the hepatoprotective activity of CHCKT as indicated by the amelioration in the central necrosis and fatty changes of the liver after APAP induction. Interestingly, the hepatoprotective activity of CHCKT at concentrations 125~500 mg/kg appeared to be as good as 12.5 mg/kg silymarin (a commercial hepatoprotective agent). Taken together, these results suggest that aqueous extract of CHCKT possesses potent hepatoprotective effects agianst APAP-induced liver injury in rats. PMID:17265552

  16. 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.

  17. Identification of Acetaminophen Adducts of Rat Liver Microsomal Proteins using 2D-LC-MS/MS.

    PubMed

    Golizeh, Makan; LeBlanc, André; Sleno, Lekha

    2015-11-16

    Xenobiotic metabolism in the liver can give rise to reactive metabolites that covalently bind to proteins, and determining which proteins are targeted is important in drug discovery and molecular toxicology. However, there are difficulties in the analysis of these modified proteins in complex biological matrices due to their low abundance. In this study, an analytical approach was developed to systematically identify target proteins of acetaminophen (APAP) in rat liver microsomes (RLM) using two-dimensional chromatography and high-resolution tandem mass spectrometry. In vitro microsomal incubations, with and without APAP, were digested and subjected to strong cation exchange (SCX) fractionation prior to reverse-phase UHPLC-MS/MS. Four data processing strategies were combined into an efficient label-free workflow meant to eliminate potential false positives, using peptide spectral matching, statistical differential analysis, product ion screening, and a custom-built delta-mass filtering tool to pinpoint potential modified peptides. This study revealed four proteins, involved in important cellular processes, to be covalently modified by APAP. Data are available via ProteomeXchange with identifier PXD002590. PMID:26510387

  18. 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

  19. 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

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

    PubMed Central

    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

  1. 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

  2. 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

  3. [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

  4. 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. PMID:24104199

  5. Acute and chronic effects of IL-22 on acetaminophen-induced liver injury.

    PubMed

    Feng, Dechun; Wang, Yan; Wang, Hua; Weng, Honglei; Kong, Xiaoni; Martin-Murphy, Brittany V; Li, Yongmei; Park, Ogyi; Dooley, Steven; Ju, Cynthia; Gao, Bin

    2014-09-01

    Acetaminophen (APAP)-induced liver injury (AILI) accounts for half of the acute liver failure cases in the United States. A better understanding of the underlying mechanisms of AILI is necessary for the development of novel antidotes. We found that pretreatment with IL-22 protected mice from APAP-mediated hepatotoxicity. The protection was dependent on STAT3, as IL-22 failed to reduce APAP hepatotoxicity in liver-specific STAT3 knockout mice. In contrast to the acute exposure to IL-22, the endogenous chronic overexpression of IL-22 in IL-22 transgenic (TG) mice or IL-22 adenovirus treatment for 6 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (Cyp2E1) and Cyp1A2 were much higher in IL-22TG mice. Ablation of Cyp2E1 but not hepatic STAT3 abolished AILI and protein-adduct formation in IL-22TG mice. Finally, hepatic expression of HNF-1α, a transcriptional factor that is known to control Cyp2E1 expression, was elevated in IL-22TG mice compared with wild-type mice. Upregulation of hepatic Cyp2E1 was only observed in mice with constitutive overexpression of IL-22 but not with short-term treatment with one dose of IL-22 or multiple doses of IL-22 for 2 wk. In conclusion, short-term acute IL-22 exposure protects mice against AILI through STAT3 activation; however, chronic constitutive overexpression of IL-22 exacerbates AILI by increasing Cyp2E1 and toxic reactive APAP metabolite production. These findings may not only enhance our understanding of the effects of chronic inflammation on AILI in patients with liver disease, but are also helpful to identify novel therapeutic targets for the treatment of AILI. PMID:25063867

  6. Pyridine and pyrimidine analogs of acetaminophen as inhibitors of lipid peroxidation and cyclooxygenase and lipoxygenase catalysis†

    PubMed Central

    Nam, Tae-gyu; Nara, Susheel J.; Zagol-Ikapitte, Irène; Cooper, Thomas; Valgimigli, Luca; Oates, John A.; Porter, Ned A.; Boutaud, Olivier; Pratt, Derek A.

    2010-01-01

    Herein we report an investigation of the efficacy of pyridine and pyrimidine analogs of acetaminophen (ApAP) as peroxyl radical-trapping antioxidants and inhibitors of enzyme-catalyzed lipid peroxidation by cyclooxygenases (COX) and lipoxygenases (LOX). In inhibited autoxidations we find that ApAP, the common analgesic and antipyretic agent, is a very good antioxidant with a rate constant for reaction with peroxyl radicals (kinh = 5 × 105 M−1 s−1) that is higher than many widely-used phenolic antioxidants, such as the ubiquitous butylated hydroxytoluene (BHT). This reactivity is reduced substantially upon incorporation of nitrogen into the phenolic ring, owing to an increase in the O–H bond dissociation enthalpy of pyridinols and pyrimidinols with respect to phenols. Incorporation of nitrogen into the phenolic ring of ApAP was also found to decrease its efficacy as an inhibitor of prostaglandin biosynthesis by ovine COX-1 (oCOX-1). This is explained on the basis of an increase in its oxidation potential and its reduced reactivity as a reducing co-substrate of the peroxidase protoporphyrin. In contrast, the efficacy of ApAP as an inhibitor of lipid hydroperoxide biosynthesis by soybean LOX-1 (sLOX-1) increased upon incorporation of nitrogen into the ring, suggesting a different mechanism of inhibition dependent on the acidity of the phenolic O–H which may involve chelation of the catalytic non-heme iron atom. The greater stability of the 3-pyridinols and 5-pyrimidinols to air oxidation as compared to phenols allowed us to evaluate some electron-rich pyridinols and pyrimidinols as inhibitors of oCOX-1 and sLOX-1. While the pyridinols had the best combination of activities as antioxidants and inhibitors of oCOX-1 and sLOX-1, they were found to be more toxic than ApAP in preliminary assays in human hepatocellular carcinoma (HepG2) cell culture. The pyrimidinols, however, were up to 17-fold more reactive to peroxyl radicals and up to 25-fold better inhibitors

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. THE GAP JUNCTION INHIBITOR 2-AMINOETHOXY-DIPHENYL-BORATE PROTECTS AGAINST ACETAMINOPHEN HEPATOTOXICITY BY INHIBITING CYTOCHROME P450 ENZYMES AND C-JUN N-TERMINAL KINASE ACTIVATION

    PubMed Central

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

    2013-01-01

    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 1.5h after APAP. However, the protection was completely lost when 2-APB was given 4–6h 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. PMID:24070586

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

    PubMed

    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. PMID:24070586

  15. Assessment of hepatic function, oxidant/antioxidant status, and histopathological changes in rats treated with atorvastatin: Effect of dose and acute intoxication with acetaminophen.

    PubMed

    Farag, M M; Mohamed, M B; Youssef, E A

    2015-08-01

    A major disadvantage that may occur in association with atorvastatin (ATV) therapy is elevation of serum transaminases. This study was designed to evaluate the effects of treatment of rats with various doses of ATV (2, 5, and 10 mg/kg/day) on liver function, oxidative stress, and histology and on the severity of acetaminophen (APAP) hepatotoxicity. ATV administration for 21 days resulted in a dose-dependent significant rise in serum activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Only ATV at 10 mg/kg/day decreased reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity, increased malondialdehyde (MDA) levels, and elicited histopathological changes in the liver. In rats challenged with APAP (500 mg/kg), the livers showed centrilobular necrosis with evident oxidative stress and liver dysfunction after 24 h. Rats challenged with APAP after pretreatment with ATV 2 or 5 mg/kg/day showed significantly lower activities of serum enzymes, higher hepatic GSH levels and SOD activities, lower MDA levels and milder histopathological changes compared with rats challenged with APAP after pretreatment with ATV 10 mg/kg/day or without drug pretreatment. In conclusion, the effect of ATV on the liver is dose dependent. Our results showed that ATV, at the highest dose used, induced hepatic lipid peroxidation and injury, suggesting a role for oxidative stress in ATV-induced hepatotoxicity. However, lower doses of ATV attenuated APAP-induced hepatotoxicity via a mechanism related, at least in part, to a reduction of APAP-induced hepatic oxidative stress. These results are of practical interest as both drugs may be used concurrently in clinical practice. PMID:25425547

  16. Methadone and prescription drug overdose.

    PubMed

    Hendrikson, Hollie; Hansen, Melissa

    2014-12-01

    (1) Methadone accounted for 2 percent of painkiller prescriptions and more than 30 percent of prescription painkiller deaths in 2009. (2) Data suggest that the rise in deaths from methadone overdose is not related to its use in treating drug abuse but, rather, to its use for pain management. (3) Preferred drug lists in most Medicaid programs identify methadone as a preferred drug for managing chronic pain, but most experts do no recommend it as a first choice. PMID:25556261

  17. 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. PMID:26035501

  18. Cognitive impairment in patients clinically recovered from central nervous system depressant drug overdose.

    PubMed

    Dassanayake, Tharaka L; Michie, Patricia T; Jones, Alison; Carter, Gregory; Mallard, Trevor; Whyte, Ian

    2012-08-01

    Central nervous system depressant drugs (CNS-Ds) are known to impair cognitive functions. Overdose of these drugs is common, and most of the hospital-treated patients are discharged within 24 to 48 hours. No previous studies have examined whether they have residual impairment at the time of discharge. Our aim was to evaluate whether patients with CNS-D overdose are impaired in cognitive domains important in daily activities at that time. We compared visuomotor skills (Trail-Making Test A and Choice Reaction Time), executive functions (viz attentional set-shifting: Trail-Making Test B; and planning: Stockings of Cambridge Task from the Cambridge Neuropsychological Test Automated Battery), working memory (Letter-Number Sequencing), and impulsivity and decision making (Cambridge Neuropsychological Test Automated Battery Information Sampling) in 107 patients with CNS-D overdose (benzodiazepines, opioids, or antipsychotics) with a control group of 68 with non-CNS-D overdose (acetaminophen, selective serotonin reuptake inhibitors, and serotonin noradrenaline reuptake inhibitors) on discharge from hospital. Outcome measures were adjusted for demographic and clinical covariates in multivariate regression models. Compared with the controls, patients in the CNS-D group were significantly impaired in all domains: they had prolonged Trail-Making completion times and reaction times, poorer working memory and planning and were more impulsive in decision making. Their Stockings of Cambridge Task performance was comparable to that of the control group for simple problems but worsened with increasing task complexity. The results show that patients with CNS-D overdose could be impaired in multiple cognitive domains underlying everyday functioning even at the time they are deemed medically fit to be discharged. Such impairments could adversely affect social and professional lives of this relatively young population during the immediate postdischarge period. PMID:22722510

  19. 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

  20. Hemodynamic instability following intentional nadolol overdose.

    PubMed

    Ehgartner, G R; Zelinka, M A

    1988-04-01

    Hemodynamic compromise developed following intentional overdose with nadolol in a 57-year-old woman. Nadolol is a nonselective beta-adrenergic blocking agent. Intravenous infusion of glucagon hydrochloride was effective in restoring hemodynamic stability after intravenous fluid loading and catecholamine infusions had failed. To our knowledge, this is the first reported case of nadolol overdose. PMID:3355299

  1. Transformation of acetaminophen by chlorination produces the toxicants 1,4-benzoquinone and N-acetyl-p-benzoquinone imine.

    PubMed

    Bedner, Mary; MacCrehan, William A

    2006-01-15

    The reaction of the common pain reliever acetaminophen (paracetamol, 4-acetamidophenol) with hypochlorite was investigated over time under conditions that simulate wastewater disinfection. Initially, the reaction was studied in pure water at neutral pH (7.0), a range of reaction times (2-90 min), and a molar excess of hypochlorite (2-57 times) relative to the acetaminophen concentration. The reaction was monitored using reversed-phase liquid chromatography (LC) with ultraviolet absorbance, electrochemical, and mass spectrometric detection. At 1 micromol/L (150 ppb) and 10 micromol/L (1.5 ppm) levels, acetaminophen readily reacted to form at least 11 discernible products, all of which exhibited greater LC retention than the parent. Two of the products were unequivocally identified as the toxic compounds 1,4-benzoquinone and N-acetyl-p-benzoquinone imine (NAPQI), which is the toxicant associated with lethality in acetaminophen overdoses. With a hypochlorite dose of 57 micromol/L (4 ppm as Cl2), 88% of the acetaminophen (10 micromol/L initial) was transformed in 1 h. The two quinoidal oxidation products 1,4-benzoquinone and NAPQI accounted for 25% and 1.5% of the initial acetaminophen concentration, respectively, at a 1 h reaction time. Other products that were identified included two ring chlorination products, chloro-4-acetamidophenol and dichloro-4-acetamidophenol, which combined were approximately 7% of the initial acetaminophen concentration at 1 h. The reaction was also studied in wastewater, where similar reactivity was noted. These results demonstrate that acetaminophen is likely to be transformed significantly during wastewater chlorination. The reactivity of the chlorine-transformation products was also studied with sulfite to simulate dechlorination, and 1,4-benzoquinone and NAPQI were completely reduced. PMID:16468397

  2. 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.

  3. Hydrogen-rich water protects against acetaminophen-induced hepatotoxicity in mice

    PubMed Central

    Zhang, Jing-Yao; Song, Si-Dong; Pang, Qing; Zhang, Rui-Yao; Wan, Yong; Yuan, Da-Wei; Wu, Qi-Fei; Liu, Chang

    2015-01-01

    AIM: To investigate the hepatoprotective effects and mechanisms of hydrogen-rich water (HRW) in acetaminophen (APAP)-induced liver injury in mice. METHODS: Male mice were randomly divided into the following four groups: normal saline (NS) control group, mice received equivalent volumes of NS intraperitoneally (ip); HRW control group, mice were given HRW (same volume as the NS group); APAP + NS group, mice received NS ip for 3 d (5 mL/kg body weight, twice a day at 8 am and 5 pm) after APAP injection; APAP + HRW group, mice received HRW for 3 d (same as NS treatment) after APAP challenge. In the first experiment, mice were injected ip with a lethal dose of 750 mg/kg APAP to determine the 5-d survival rates. In the second experiment, mice were injected ip with a sub-lethal dose of 500 mg/kg. Blood and liver samples were collected at 24, 48, and 72 h after APAP injection to determine the degree of liver injury. RESULTS: Treatment with HRW resulted in a significant increase in the 5-d survival rate compared with the APAP + NS treatment group (60% vs 26.67%, P < 0.05). HRW could significantly decrease the serum alanine aminotransferase level (24 h: 4442 ± 714.3 U/L vs 6909 ± 304.8 U/L, P < 0.01; 48 h: 3782 ± 557.5 U/L vs 5111 ± 404 U/L, P < 0.01; and 3255 ± 337.4 U/L vs 3814 ± 250.2 U/L, P < 0.05, respectively) and aspartate aminotransferase level (24 h: 4683 ± 443.4 U/L vs 5307 ± 408.4 U/L, P < 0.05; 48 h: 3392 ± 377.6 U/L vs 4458 ± 423.6 U/L, P < 0.01; and 3354 ± 399.4 U/L vs 3778 ± 358 U/L, respectively) compared with the APAP treatment group. The alkaline phosphatase, total bilirubin and lactate dehydrogenase levels had the same result. Seventy-two hours after APAP administration, liver samples were collected for pathological examination and serum was collected to detect the cytokine levels. The liver index (5.16% ± 0.26% vs 5.88% ± 0.073%, P < 0.05) and percentage of liver necrosis area (27.73% ± 0.58% vs 36.87% ± 0.49%, P < 0.01) were significantly

  4. 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.

  5. 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

  6. A Massive Overdose of Dalfampridine.

    PubMed

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

    2015-12-01

    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 530 ng/mL (25 ng/mL and 49 ng/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

  7. Effects of risperidone in overdose.

    PubMed

    Acri, A A; Henretig, F M

    1998-09-01

    This study was a 13-month prospective, descriptive case series of risperidone overdose reported by telephone to a regional poison control center (PCC) serving Philadelphia, PA. Patients were seen in local Philadelphia-area emergency departments. The variables examined were medical history, therapeutic use of risperidone, time postingestion, reported coingestants, clinical findings, decontamination and treatment, electrocardiograph results, laboratory data, standard toxicologic screen results, and length of time in hospital. Thirty-one patients (29 adult/adolescent, 2 pediatric) with reported risperidone overdose were identified. Risperidone was the sole ingestant in 15 cases (1 mg to 180 mg). The major observed effects in this group included lethargy (7), spasm/dystonia (3), hypotension (2), tachycardia (6), and dysrhythmia (1). Sixteen cases involved coingestants, including benzodiazepines, selective serotonin reuptake inhibitors, ethanol, tricyclic antidepressants, lithium, anticonvulsants, diphenhydramine, ibuprofen, and anticholinergic agents. Major effects in these patients included lethargy (10), coma (1), seizure (1), tachycardia (7), bradycardia (1), hypotension (4), and a syndrome of muscle spasms, diaphoresis, and fever. Treatment provided for patients in this study included antiarrhythmics (1), diphenhydramine (2), anticonvulsant (1), vasopressor agent (1), endotracheal intubation/assisted ventilation (5), and supportive care. One patient who coingested imipramine died of medical complications. In the remaining patients, symptoms resolved with 24 hours in the majority, with all patients asymptomatic at 72 hours postingestion. These data show that risperidone toxicity manifests primarily as mild central nervous system effects and reversible neuromuscular and cardiovascular effects. PMID:9725965

  8. How to Safely Give Acetaminophen

    MedlinePlus

    ... up a dose of acetaminophen within the first 20 minutes, it's usually safe to give your child another ... holds the first dose down for longer than 20 minutes before spitting up, you should wait 4 hours ...

  9. 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

  10. Acetaminophen kinetics in the elderly.

    PubMed

    Divoll, M; Abernethy, D R; Ameer, B; Greenblatt, D J

    1982-02-01

    Thirty-two healthy men and women, 23 to 78 yr old, received single 650-mg intravenous doses of acetaminophen and the drug's kinetics were determined from multiple plasma samples drawn over the next 8 to 12 hr. Acetaminophen elimination half-life averaged 2.7 hr (range, 1.9 to 4.3 hr) and was not related to age or sex. Volume of distribution (corrected for weight) was larger in men than in women (0.99 and 0.86 l/kg) and declined with age in both sexes. This probably reflects increased fat per kilogram body weight in women and in the elderly, together with incomplete distribution of this nonlipophilic drug into body fat. Acetaminophen clearance tended to decline with age in both sexes, but differences were of borderline significance. On the basis of kinetics data alone, adjustment of acetaminophen dosage for the elderly is generally not necessary. PMID:7056022

  11. Study of a Novel APAP Algorithm for the Treatment of Obstructive Sleep Apnea in Women

    PubMed Central

    McArdle, Nigel; King, Stuart; Shepherd, Kelly; Baker, Vanessa; Ramanan, Dinesh; Ketheeswaran, Sahisha; Bateman, Peter; Wimms, Alison; Armitstead, Jeff; Richards, Glenn; Hillman, David; Eastwood, Peter

    2015-01-01

    , Hillman D, Eastwood P. Study of a novel APAP algorithm for the treatment of obstructive sleep apnea in women. SLEEP 2015;38(11):1775–1781. PMID:26039968

  12. Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats

    PubMed Central

    Lu, Xiaoyan; Hu, Bin; Zheng, Jie; Ji, Cai; Fan, Xiaohui; Gao, Yue

    2015-01-01

    The extent of drug-induced liver injury (DILI) can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP) as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI. PMID:26512990

  13. 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

  14. Kids with Mild Asthma Can Take Acetaminophen

    MedlinePlus

    ... gov/news/fullstory_160475.html Kids With Mild Asthma Can Take Acetaminophen: Study Finding counters past research ... 17, 2016 (HealthDay News) -- Acetaminophen does not worsen asthma symptoms in young children, a new study finds. ...

  15. 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 ...

  16. 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

  17. 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

  18. 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

  19. 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. PMID:25111742

  20. 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

  1. Paracetamol overdose: the liver unit perspective.

    PubMed

    Iqbal, M; Cash, W J; Sarwar, S; McCormick, P A

    2012-09-01

    Liver failure resulting from deliberate or accidental paracetamol overdose continues to be an important reason for referral to liver transplant centres. Severe hepatic dysfunction often appears 72-96 h after overdose. Liver injury can be prevented by timely administration of the specific antidote, N-acetylcysteine. Unfortunately, administration of N-acetylcysteine is frequently delayed due to late presentation or late administration. While N-acetylcysteine works best if given within 8 h of overdose, it is beneficial at any time period and should always be given if there is concern about significant overdose, irrespective of interval from time of ingestion. Early discussion with liver transplant unit is suggested if there is any doubt or evidence of liver failure. PMID:22072400

  2. 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 ...

  3. Multiple-dose acetaminophen pharmacokinetics.

    PubMed

    Sahajwalla, C G; Ayres, J W

    1991-09-01

    Four different treatments of acetaminophen (Tylenol) were administered in multiple doses to eight healthy volunteers. Each treatment (325, 650, 825, and 1000 mg) was administered five times at 6-h intervals. Saliva acetaminophen concentration versus time profiles were determined. Noncompartmental pharmacokinetic parameters were calculated and compared to determine whether acetaminophen exhibited linear or dose-dependent pharmacokinetics. For doses less than or equal to 18 mg/kg, area under the curve (AUC), half-life (t1/2), mean residence time (MRT), and ratio of AUC to dose for the first dose were compared with the last dose. No statistically significant differences were observed in dose-corrected AUC for the first or last dose among subjects or treatments. Half-lives and MRT were not significantly different among treatments for the first or the last dose. Statistically significant differences in t1/2 and MRT were noted (p less than 0.05) among subjects for the last dose. A plot of AUC versus dose for the first and the last doses exhibited a linear relationship. Dose-corrected saliva concentration versus time curves for the treatments were superimposable. Thus, acetaminophen exhibits linear pharmacokinetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one subject who received doses higher than 18 mg/kg were curved, suggesting nonlinear behavior of acetaminophen in this subject. PMID:1800709

  4. 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

  5. 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

  6. Clinical and economic characteristics of emergency department visits due to acetaminophen toxicity in the USA

    PubMed Central

    Altyar, Ahmed; Kordi, Lama; Skrepnek, Grant

    2015-01-01

    Objectives To estimate the number of acetaminophen (APAP) toxicity-related emergency department (ED) visits, and to assess their associated clinical and economic burden in the USA from 2006 to 2010. Design Cross-sectional, retrospective, large-scale database study. Setting Non-federal, non-rehabilitation, community EDs in the USA. Participants Inclusion criteria included any listed diagnosis identifying poisoning by aromatic analgesics paracetamol/APAP or associated supplementary code. Generalised linear models were used to investigate the association between outcomes of inpatient admission, mortality, requirement of invasive mechanical ventilation, charges and inpatient lengths of stay based on patient, hospital and clinical characteristics. Results Across the 625.2 million ED visits in the USA from 2006 to 2010, 411 811 APAP-related toxicity ED visits were observed, with 45.5% resulting in inpatient admission, 4.7% requiring invasive mechanical ventilation and 0.6% involving death. Overall, the incidence proportion was 27.10 per 100 000 US population, exceeding 70 per 100 000 at age 2 years and ages 16–18 years. The total national bill was $1.06 billion per year (US$ 2014), and predominantly involved females (65.5%) and intentional self-harm (58.4%), which were notably higher within the 12–20 years age category (female12–20 years=74.8%, intentional self-harm12–20 years=71.4%). Behavioural and mental health comorbidities were relatively common and associated with an increased relative risk of admission and likelihood of charges almost entirely across all age categories of ≥12 years within the multivariable analyses. The number of ED visits did not appreciably change over time, decreasing by <2% from 2006 to 2010 (n=1351). Multivariable results also suggested no consistent change in outcomes across the study's time horizon. Conclusions A substantial public health impact of APAP toxicity-related cases was observed in the US from 2006 to

  7. Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues*

    PubMed Central

    Bruderer, Roland; Bernhardt, Oliver M.; Gandhi, Tejas; Miladinović, Saša M.; Cheng, Lin-Yang; Messner, Simon; Ehrenberger, Tobias; Zanotelli, Vito; Butscheid, Yulia; Escher, Claudia; Vitek, Olga; Rinner, Oliver; Reiter, Lukas

    2015-01-01

    The data-independent acquisition (DIA) approach has recently been introduced as a novel mass spectrometric method that promises to combine the high content aspect of shotgun proteomics with the reproducibility and precision of selected reaction monitoring. Here, we evaluate, whether SWATH-MS type DIA effectively translates into a better protein profiling as compared with the established shotgun proteomics. We implemented a novel DIA method on the widely used Orbitrap platform and used retention-time-normalized (iRT) spectral libraries for targeted data extraction using Spectronaut. We call this combination hyper reaction monitoring (HRM). Using a controlled sample set, we show that HRM outperformed shotgun proteomics both in the number of consistently identified peptides across multiple measurements and quantification of differentially abundant proteins. The reproducibility of HRM in peptide detection was above 98%, resulting in quasi complete data sets compared with 49% of shotgun proteomics. Utilizing HRM, we profiled acetaminophen (APAP)1-treated three-dimensional human liver microtissues. An early onset of relevant proteome changes was revealed at subtoxic doses of APAP. Further, we detected and quantified for the first time human NAPQI-protein adducts that might be relevant for the toxicity of APAP. The adducts were identified on four mitochondrial oxidative stress related proteins (GATM, PARK7, PRDX6, and VDAC2) and two other proteins (ANXA2 and FTCD). Our findings imply that DIA should be the preferred method for quantitative protein profiling. PMID:25724911

  8. Comparative Hepatoprotective Activity of Ethanolic Extracts of Cuscuta australis against Acetaminophen Intoxication in Wistar Rats

    PubMed Central

    Folarin, Rachael O.; Omirinde, Jamiu O.; Bejide, Ronald; Isola, Tajudeen O.; Usende, Levi I.; Basiru, Afisu

    2014-01-01

    This study investigates the comparative hepatoprotective activity of crude ethanol extracts of Cuscuta australis against acetaminophen (APAP) intoxication. Thirty-six rats were randomly divided into six groups of 6 replicates: Group 1 which served as control received water. Group 2 was orally administered 835 mg/kg body wt. of paracetamol on day 8. Groups 3 and 4 were orally administered ethanolic extracts of the seed of Cuscuta australis in doses of 125 mg/kg and 250 mg/kg, respectively, for 7 days and then intoxicated as in Group 2 on the 8th day. Groups 5 and 6 received similar oral doses of Cuscuta australis stem extracts for 7 days and then intoxicated as in Groups 3 and 4. Group 2 rats showed severe periportal hepatic necrosis, significantly elevated serum hepatic injury markers, markedly increased lipid peroxidation, and decreased hepatic antioxidant enzymes activities. Remarkably, Cuscuta australis (seed and stem) extract pretreatments in Groups 3, 4, 5, and 6, most especially, the stem extract pretreatment in Groups 5 and 6, improved better the hepatic histoarchitecture, the hepatocellular, and the oxidative stress injury markers in a dose-dependent manner. Conclusively, ethanol extractions of Cuscuta australis stem appear to protect the liver from acetaminophen intoxication better than the seed counterpart. PMID:27433518

  9. A qualitative study of overdose responses among Chicago IDUs

    PubMed Central

    Sherman, Susan G; Gann, Donald S; Scott, Gregory; Carlberg, Suzanne; Bigg, Dan; Heimer, Robert

    2008-01-01

    Background Opioid overdose is a leading cause of death among injection drug users. Over half of injection drug users report at least one nonfatal overdose during their lifetime. Death from opioid overdose rarely occurs instantaneously, but rather over the course of one to three hours, allowing ample time for providing life-saving measures. In response to the prevalence of overdoses in the U.S., there are a growing number of overdose prevention and naloxone distribution programs targeting the injection drug using community. Methods We explored injection drug users' experiences with opioid overdose response, examining differences between overdose responses in which naloxone was and was not used. The current study is based upon qualitative interviews (N = 31) with clients of the Chicago Recovery Alliance needle exchange program who had witnessed an overdose in the past six months. The interviews explored participants' drug use history, personal overdose experiences, and details concerning their last witnessed overdose. Verbatim transcripts were coded and analyzed thematically to address major study questions. Results Participants were 81% were male, their median age was 38. They reported having injected a median of 10 years and having witnessed a median of six overdoses in their lifetime. All described overdoses were recognized and responded to quickly. None of the overdoses resulted in a fatality and naloxone was successfully administered in 58% of the last witnessed overdoses. Administering naloxone for the first time was characterized by trepidation, but this feeling dissipated as the naloxone quickly took effect. Emergency medical personnel were called in 10 of the 31 described overdoses, including four in which participants administered naloxone. The overwhelming majority of experiences with police and paramedics were positive Conclusion Overall, our small study found that the overdose prevention efforts build on extensive knowledge possessed by IDUs. Teaching

  10. [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

  11. Syndrome of inappropriate antidiuresis in doxylamine overdose.

    PubMed

    Carrascosa, Miguel F; Caviedes, José-Ramón Salcines; Lucena, M Isabel; Cuadrado-Lavín, Antonio

    2012-01-01

    Doxylamine succinate, an H(1)-antihistamine drug, is commonly used as sleep-inducing agent as well as therapy for nausea and vomiting in pregnancy. At usual doses, it may cause impairment of cognitive and psychomotor performance, anticholinergic effects, agitation and postural hypotension. Besides, since this drug is frequently involved in either accidental or intentional overdoses, it seems relevant to bear in mind other possible toxic effects. We report a case of acute severe hyponatremia in the setting of a syndrome of inappropriate antidiuresis (SIAD), an apparent new adverse effect linked to doxylamine overdose. The Naranjo adverse drug reaction probability scale indicated a probable relationship between doxylamine intake and SIAD development. SIAD may be considered as a potential, serious adverse reaction of doxylamine overdose. Clinicians should consider this aetiological possibility when attending patients suffering from hyponatremia. PMID:23166178

  12. Management of calcium channel blocker overdoses.

    PubMed

    Shenoy, Sundeep; Lankala, Shilpa; Adigopula, Sasikanth

    2014-10-01

    Calcium channel blockers (CCBs) are some of the most commonly used medications in clinical practice to treat hypertension, angina, cardiac arrhythmias, and some cases of heart failure. Recent data show that CCBs are the most common of the cardiovascular medications noted in intentional or unintentional overdoses.(1) Novel treatment approaches in the form of glucagon, high-dose insulin therapy, and intravenous lipid emulsion therapies have been tried and have been successful. However, the evidence for these are limited to case reports and case series. We take this opportunity to review the various treatment options in the management of CCB overdoses with a special focus on high-dose insulin therapy as the emerging choice for initial therapy in severe overdoses. PMID:25066023

  13. 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

  14. 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

  15. 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.

  16. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity.

    PubMed

    Cover, Cathleen; Liu, Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P; Bajt, Mary Lynn; Jaeschke, Hartmut

    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-1beta 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. PMID:16781746

  17. Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2

    PubMed Central

    Huang, Renwei; Wang, Yan; Liang, Yaolong; Liao, Xiaorong; Li, Mingyi

    2016-01-01

    Hepatic stellate cells (HSCs), previously described for liver-specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP) or H2O2 treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2) HSC-MVs dose-dependently improved the viability of hepatocytes in both injury models; (3) HSC-MVs dose-dependently inhibited the APAP/H2O2 induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury. PMID:27239205

  18. High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo.

    PubMed

    Antoine, Daniel J; Williams, Dominic P; Kipar, Anja; Jenkins, Rosalind E; Regan, Sophie L; Sathish, Jean G; Kitteringham, Neil R; Park, B Kevin

    2009-12-01

    Drug-induced hepatotoxicity represents a major clinical problem and an impediment to new medicine development. Serum biomarkers hold the potential to provide information about pathways leading to cellular responses within inaccessible tissues, which can inform the medicinal chemist and the clinician with respect to safe drug design and use. Hepatocyte apoptosis, necrosis, and innate immune activation have been defined as features of the toxicological response associated with the hepatotoxin acetaminophen (APAP). Within this investigation, we have unambiguously identified and characterized by liquid chromatography-tandem mass spectrometry differing circulating molecular forms of high-mobility group box-1 protein (HMGB1) and keratin-18 (K18), which are linked to the mechanisms and pathological changes induced by APAP in the mouse. Hypoacetylated HMGB1 (necrosis indicator), caspase-cleaved K18 (apoptosis indicator), and full-length K18 (necrosis indicator) present in serum showed strong correlations with the histological time course of cell death and was more sensitive than alanine aminotransferase activity. We have further identified a hyperacetylated form of HMGB1 (inflammatory indicator) in serum, which indicated that hepatotoxicity was associated with an inflammatory response. The inhibition of APAP-induced apoptosis and K18 cleavage by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethyl ketone are associated with increased hepatic damage, by a shift to necrotic cell death only. These findings illustrate the initial verification of K18 and HMGB1 molecular forms as serum-based sensitive tools that provide insights into the cellular dynamics involved in APAP hepatotoxicity within an inaccessible tissue. Based on these findings, potential exists for the qualification and measurement of these proteins to further assist in vitro, in vivo, and clinical bridging in toxicological research. PMID:19783637

  19. 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

  20. 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

  1. 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

  2. Prediction of acetaminophen's solubility in poly(ethylene oxide) at room temperature using the Flory-Huggins theory.

    PubMed

    Yang, Min; Wang, Peng; Gogos, Costas

    2013-01-01

    Solid dispersion technologies such as hot-melt extrusion and spray drying are often used to enhance the solubility of poorly soluble drugs. The biggest challenge associated with solid dispersion systems is that amorphous drugs may phase-separate from the polymeric matrix and recrystallize during storage. A more fundamental understanding of drug-polymer mixtures is needed for the industry to embrace the solid dispersion technologies. In this study, a theoretical model based on Flory-Huggins lattice theory was utilized to predict the solubility of a model drug acetaminophen (APAP) in a semi-crystalline polymer poly(ethylene oxide) (PEO) at 300 K. The interaction parameter χ was calculated to be -1.65 from the depression of drug's melting temperature determined from rheological and differential scanning calorimetry analysis. The equilibrium solubility in amorphous PEO was estimated to be 11.7% at 300 K. Assuming no APAP molecules dissolve in the crystalline part of PEO, the adjusted theoretical solubility is around 2.3% considering PEO being 80% crystalline. The solubility of APAP in PEG 400 was calculated to be 14.6% by using the same χ value, close to the experimental measurement 17.1%. The drug's solubility could be altered noticeably by the change of both χ and polymer molecular weight. The study also suggests that the depression of drug's melting point is a good indicator for preliminary polymer screening. The polymer that reduces the melting point the most is likely to be most miscible with the drug. PMID:22356356

  3. 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. PMID:25272938

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

    PubMed

    Kienhuis, Anne S; van de Poll, Marcel C G; Wortelboer, Heleen; van Herwijnen, Marcel; Gottschalk, Ralph; Dejong, Cornelis H C; Boorsma, André; Paules, Richard S; Kleinjans, Jos C S; Stierum, Rob H; van Delft, Joost H M

    2009-02-01

    The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo. PMID:19008212

  5. 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°.

  6. 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

  7. Direct Protection Against Acetaminophen Hepatotoxicity by Propylthiouracil

    PubMed Central

    Yamada, Tadataka; Ludwig, Shelly; Kuhlenkamp, John; Kaplowitz, Neil

    1981-01-01

    Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [3H]acetaminophen, liver microsomes from phenobarbital-pretreated rats, and an NADPH-generating system, we found that PTU had a dose-dependent additive effect with GSH on inhibition of acetaminophen covalent binding. PTU administration also resulted in a dose-dependent decrease in both GSH depletion and covalent binding in vivo in acetaminophen-treated mice. To examine the possible mechanisms by which PTU exerts its protective effect, we studied the action of PTU on both acetaminophen conjugation and metabolic activation. PTU had no effect upon acetaminophen pharmacokinetics in phenobarbital-pretreated rats, as examined by measuring acetaminophen concentration in bile, urine, and blood after an intraperitoneal dose, nor did it alter the total amount of polar conjugates formed. Microsomes from PTU-treated rats were unaltered in cytochrome P-450 concentrations and p-nitroanisole-O-demethylase, benzo-α-pyrene hydroxylase, and cytochrome c-reductase activities. Furthermore PTU did not decrease acetaminophen-GSH adduct formation in vitro, suggesting that there was no reduction in drug activation. However, in bile from [35S]PTU and [3H]acetaminophen treated rats, as well as in incubates of the two drugs with liver microsomes, a new 35S- and 3H-containing product could be identified. By both thin layer chromatography and high pressure liquid chromatography this new product, which co-eluted with [3H]acetaminophen, was separated from unreacted [35S]PTU. The formation of this product in vitro was

  8. Salty broth for salicylate poisoning? Adequacy of overdose management advice in the 2001 Compendiumof Pharmaceuticals and Specialties

    PubMed Central

    Brubacher, Jeffrey R.; Purssell, Roy; Kent, Debra A.

    2002-01-01

    Background The Compendium of Pharmaceuticals and Specialties (CPS) is a collection of monographs written by pharmaceutical companies and published by the Canadian Pharmacists Association. The CPS is widely available and is consulted frequently by Canadian physicians. We examined overdose management advice contained in the CPS to see whether it reflects current standards. Methods We restricted our review to 10 classes of medication for which an overdose is frequently fatal: acetaminophen, β-blockers, calcium-channel blockers, digoxin, lithium, opioids, salicylates, tricyclic antidepressants, theophylline and valproic acid. A panel of 3 toxicologists arrived at a consensus on indicated, contraindicated and futile interventions for each of these classes of drug. Monographs were then rated for their inclusion of essential interventions as excellent (listed all interventions and unique supportive care issues and gave correct and complete indications), good (listed the key interventions and gave correct and complete indications), fair (listed the key indications but failed to give proper indications) or poor (failed to list the key interventions). Monographs were also rated on how well they warned against contraindicated interventions as excellent (did not advocate any futile or contraindicated treatments and warned against contraindicated treatments), good (did not advocate any futile or contraindicated treatments), fair (did not advocate any contraindicated treatments but did list some simple futile treatments) or poor (advocated contraindicated or complicated futile treatments, such as unnecessary hemodialysis). We also considered whether the monograph would allow a clinician to manage an overdose, whether it served to refresh one's memory and whether it was simply misleading or dangerous. Results We reviewed 119 monographs, of which 25 (21%) were adequate to allow a clinician to manage an overdose. Another 25 monographs were not adequate to allow a clinician to

  9. Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

    PubMed Central

    Zanobbio, Laura; Palazzo, Marco; Gariboldi, Silvia; Dusio, Giuseppina F.; Cardani, Diego; Mauro, Valentina; Marcucci, Fabrizio; Balsari, Andrea; Rumio, Cristiano

    2009-01-01

    We have recently observed that oral administration of d-glucose saves animals from lipopolysaccharide (LPS)-induced death. This effect is the likely consequence of glucose-induced activation of the sodium-dependent glucose transporter-1. In this study, we investigated possible hepatoprotective effects of glucose-induced, sodium-dependent, glucose transporter-1 activation. We show that oral administration of d-glucose, but not of either d-fructose or sucrose, prevents LPS-induced liver injury, as well as liver injury and death induced by an overdose of acetaminophen. In both of these models, physiological liver morphology is maintained and organ protection is confirmed by unchanged levels of the circulating markers of hepatotoxicity, such as alanine transaminase or lactate dehydrogenase. In addition, d-glucose was found to protect the liver from α-amanitin-induced liver injury. In this case, in contrast to the previously described models, a second signal had to be present in addition to glucose to achieve protective efficacy. Toll-like receptor 4 stimulation that was induced by low doses of LPS was identified as such a second signal. Eventually, the protective effect of orally administered glucose on liver injury induced by LPS, overdose of acetaminophen, or α-amanitin was shown to be mediated by the anti-inflammatory cytokine interleukin-10. These findings, showing glucose-induced protective effects in several animal models of liver injury, might be relevant in view of possible therapeutic interventions against different forms of acute hepatic injury. PMID:19700751

  10. Acute liver impairment after sodium valproate overdose

    PubMed Central

    Waring, William Stephen; Nixon, Andrew C

    2009-01-01

    Liver impairment is a recognised adverse effect of long-term sodium valproate treatment, but there are few reports concerning its occurrence after acute overdose. This report describes a 36-year-old woman who deliberately ingested 32 g of sodium valproate (Epilim). Serum valproate concentration was 4370 μmol/l (630 mg/l) at 4.3 h post-ingestion (therapeutic reference range: 300–600 μmol/l), and the elimination half-life was 14.1 h. Liver biochemistry tests were initially normal but gradually became impaired, and highest alanine aminotransferase (761 U/l) occurred 2.3 days after ingestion. Supportive measures alone were sufficient to allow recovery of liver function. This case indicates that sodium valproate overdose may cause acute hepatocellular injury, even in the absence of pre-existing liver disease. PMID:21686945

  11. Risk factors of γ-hydroxybutyrate overdosing.

    PubMed

    Korf, Dirk J; Nabben, Ton; Benschop, Annemieke; Ribbink, Kim; van Amsterdam, Jan G C

    2014-01-01

    The aim of this study was to identify in recreational drug users the factors which increase the risk of overdosing (OD) with γ-hydroxybutyrate (GHB). A purposive sample of 45 experienced GHB users was interviewed, equally divided into three groups (never OD, occasional OD, and repeat OD). The repeat OD group scored highest on many risk factors regarding GHB use, the occasional OD group scored intermediate, and the never OD group scored lowest. Participants, whether or not they had overdosed on GHB, most often perceived GHB use (e.g. using more GHB than usual, using GHB doses too closely together) as the main reason for GHB OD, and many participants who had overdosed on GHB reported that they had taken more GHB than usual at their most recent occasion of GHB OD. No significant differences in co-use of GHB with other substances were found between the three groups. Our findings indicate that using GHB in the company of groups of friends probably reduces, but does not eliminate, the risk of OD. PMID:24080792

  12. Acetaminophen attenuates error evaluation in cortex.

    PubMed

    Randles, Daniel; Kam, Julia W Y; Heine, Steven J; Inzlicht, Michael; Handy, Todd C

    2016-06-01

    Acetaminophen has recently been recognized as having impacts that extend into the affective domain. In particular, double blind placebo controlled trials have revealed that acetaminophen reduces the magnitude of reactivity to social rejection, frustration, dissonance and to both negatively and positively valenced attitude objects. Given this diversity of consequences, it has been proposed that the psychological effects of acetaminophen may reflect a widespread blunting of evaluative processing. We tested this hypothesis using event-related potentials (ERPs). Sixty-two participants received acetaminophen or a placebo in a double-blind protocol and completed the Go/NoGo task. Participants' ERPs were observed following errors on the Go/NoGo task, in particular the error-related negativity (ERN; measured at FCz) and error-related positivity (Pe; measured at Pz and CPz). Results show that acetaminophen inhibits the Pe, but not the ERN, and the magnitude of an individual's Pe correlates positively with omission errors, partially mediating the effects of acetaminophen on the error rate. These results suggest that recently documented affective blunting caused by acetaminophen may best be described as an inhibition of evaluative processing. They also contribute to the growing work suggesting that the Pe is more strongly associated with conscious awareness of errors relative to the ERN. PMID:26892161

  13. Outpatient provider contact prior to unintentional opioid overdose

    PubMed Central

    Lin, Lewei (Allison); Bohnert, Amy; Ilgen, Mark; Pfeiffer, Paul Nelson; Ganoczy, Dara; Blow, Fred

    2015-01-01

    Objectives Prescribed opioid medications are the most commonly implicated substances in unintentional overdoses. Outpatient health care encounters represent a potential opportunity to intervene to reduce opioid overdose risk. This study assessed the timing and type of outpatient provider contacts prior to overdose. Methods This study examined all adult patients nationally in the Veterans Health Administration (VHA) who died from unintentional prescription opioid overdose in fiscal years 2004–2007 and used VHA services anytime within two years of their deaths (n=1,813). For those whose last treatment contact was in an outpatient setting (n=1,457), demographic, clinical and treatment characteristics were compared among patients categorized by the location of their last contact. Results 33% (N=479) of those last seen in outpatient settings were seen within one week and 62% (N=910) within one month of their overdose. A substantial proportion of patients were last seen within one month of death in mental health or substance disorder outpatient settings (30% N=438). The majority of patients did not fill an opioid prescription on their last outpatient visit prior to unintentional opioid overdose. Conclusions The majority of patients who died by unintentional overdose on prescription opioids were seen within a month of their overdose in outpatient settings. These settings may provide an opportunity to prevent patients from dying from prescription opioid overdoses, and interventions to reduce risk should not be limited to visits that resulted in an opioid prescription. PMID:26129993

  14. 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

  15. 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

  16. Risk factors for opioid overdose and awareness of overdose risk among veterans prescribed chronic opioids for addiction or pain.

    PubMed

    Wilder, Christine M; Miller, Shannon C; Tiffany, Elizabeth; Winhusen, Theresa; Winstanley, Erin L; Stein, Michael D

    2016-01-01

    Rising overdose fatalities among U.S. 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. 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. In the current study, 90 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. 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 versus 8.5, p < .0001). On average, participants treated for pain management scored slightly but significantly lower on knowledge of opioid overdose risk factors (12.1 versus 13.5, p < .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. 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

  17. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury.

    PubMed

    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

  18. 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

  19. 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.

  20. Don't Double Up on Acetaminophen

    MedlinePlus

    ... be sure to talk to your health care professional before you use a medicine containing acetaminophen. This article appears on FDA's Consumer Updates page , which features the latest on all FDA-regulated products. January ...

  1. 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? PMID:20030462

  2. The Psychological and Social Characteristics of Asian Adolescent Overdose.

    ERIC Educational Resources Information Center

    Kingsbury, Stephen

    1994-01-01

    Compared social and psychological features of Asian (n=13) and Caucasian (n=37) adolescents who had taken drug overdoses. Found that Asians were more socially isolated than Caucasians and that, despite Asians having low suicidal intent, they had higher rates of depression, hopelessness, long premeditation time, and previous overdose. (Author/NB)

  3. 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

  4. 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…

  5. 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.

  6. Vasopressin treatment for cyclic antidepressant overdose.

    PubMed

    Barry, James David; Durkovich, David W; Williams, Saralyn R

    2006-07-01

    Due to neurotransmitter reuptake inhibition, peripheral alpha receptor blocking effects, and sodium channel blockade, severe cyclic antidepressant poisoning may lead to intractable hypotension. We report a case of severe amitriptyline toxicity, with hypotension unresponsive to direct alpha receptor agonists after pH manipulation, but improved with intravenous vasopressin. Vasopressin use in the setting of cyclic antidepressant toxicity has not been previously reported. Vasopressin may be a beneficial agent in the treatment of recalcitrant hypotension associated with poisoning or overdose. The anecdotal nature of this report must be emphasized and the use of vasopressin requires further research to define efficacy, dose, and potential side effects. PMID:16798158

  7. Seizures After Overdoses of Bupropion Intake

    PubMed Central

    Kara, Hasan; Ak, Ahmet; Bayır, Ayşegül; Acar, Demet; İstanbulluoğlu, Rabia; Değirmenci, Selim

    2013-01-01

    Background: Bupropion is a new-generation monocyclic antidepressant that has been accidentally found to have potential effects on reducing nicotine addiction. It is structurally similar to stimulants such as amphetamine and inhibits dopamine and noradrenalin reuptake selectively. Case Reports: We report two cases with no history of epilepsy who took oral bupropion for depression and had generalised tonic-clonic type of seizures in their follow-ups. Conclusion: After an overdose of bupropion, clinical effects are seen primarily on the neurological, cardiovascular, and gastrointestinal systems. Neurological effects can include tremor, confusion, agitation, hallucinations, coma, and seizures. PMID:25207109

  8. Serial monitoring of sedation scores in benzodiazepine overdose.

    PubMed

    Kyong, Yeon Young; Park, Jeng Tak; Choi, Kyoung Ho

    2014-11-01

    Benzodiazepines are widely used for many diseases, and benzodiazepine overdose is globally increasing in proportion to its prescriptions. Although most benzodiazepine overdoses are known to be safe and nonfatal without coingestions, morbidity or mortality after benzodiazepine overdose is closely related with the duration of unconsciousness or depth of compromised airway. Proper use of flumazenil, a potent antidote of benzodiazepine, seems to accelerate the recovery from the toxicity after benzodiazepine overdose.However, as the case we present demonstrates, careful attention and repetitive evaluations before and after use of flumazenil may be needed in benzodiazepine overdose because resedation occurs in approximately 30% of total flumazenil-treated cases, which suggests that the risk of aspiration or incidental death after administrating flumazenil might be significant without careful monitoring. PMID:24908447

  9. Analysis Of Electronic Medication Orders With Large Overdoses

    PubMed Central

    Kirkendall, E.S.; Kouril, M.; Minich, T.; Spooner, SA.

    2014-01-01

    Summary Background Users of electronic health record (EHR) systems frequently prescribe doses outside recommended dose ranges, and tend to ignore the alerts that result. Since some of these dosing errors are the result of system design flaws, analysis of large overdoses can lead to the discovery of needed system changes. Objectives To develop database techniques for detecting and extracting large overdose orders from our EHR. To identify and characterize users’ responses to these large overdoses. To identify possible causes of large-overdose errors and to mitigate them. Methods We constructed a data mart of medication-order and dosing-alert data from a quaternary pediatric hospital from June 2011 to May 2013. The data mart was used along with a test version of the EHR to explain how orders were processed and alerts were generated for large (>500%) and extreme (>10,000%) overdoses. User response was characterized by the dosing alert salience rate, which expresses the proportion of time users take corrective action. Results We constructed an advanced analytic framework based on workflow analysis and order simulation, and evaluated all 5,402,504 medication orders placed within the 2 year timeframe as well as 2,232,492 dose alerts associated with some of the orders. 8% of orders generated a visible alert, with ¼ of these related to overdosing. Alerts presented to trainees had higher salience rates than those presented to senior colleagues. Salience rates were low, varying between 4–10%, and were lower with larger overdoses. Extreme overdoses fell into eight causal categories, each with a system design mitigation. Conclusions Novel analytic systems are required to accurately understand prescriber behavior and interactions with medication-dosing CDS. We described a novel analytic system that can detect apparent large overdoses (≥500%) and explain the sociotechnical factors that drove the error. Some of these large overdoses can be mitigated by system changes. EHR

  10. Policing and risk of overdose mortality in urban neighborhoods

    PubMed Central

    Bohnert, Amy S.B.; Nandi, Arijit; Tracy, Melissa; Cerdá, Magdalena; Tardiff, Kenneth J; Vlahov, David; Galea, Sandro

    2010-01-01

    Background Accidental drug overdose is a major cause of mortality among drug users. Fears of police arrest may deter witnesses of drug overdose from calling for medical help and may be a determinant of drug overdose mortality. To our knowledge, no studies have empirically assessed the relation between levels of policing and drug overdose mortality. We hypothesized that levels of police activity, congruent with fears of police arrest, are positively associated with drug overdose mortality. Methods We assembled cross-sectional time-series data for 74 New York City (NYC) police precincts over the period 1990–1999 using data collected from the Office of the Chief Medical Examiner of NYC, the NYC Police Department, and the US Census Bureau. Misdemeanor arrest rate—reflecting police activity—was our primary independent variable of interest, and overdose rate our primary dependent variable of interest. Results The mean overdose rate per 100,000 among police precincts in NYC between 1990 and 1999 was 10.8 (standard deviation = 10.0). In a Bayesian hierarchical model that included random spatial and temporal effects and a space-time interaction, the misdemeanor arrest rate per 1,000 was associated with higher overdose mortality (posterior median = 0.003, 95% Credible Interval = 0.001, 0.005) after adjustment for overall drug use in the precinct and demographic characteristics. Conclusions Levels of police activity in a precinct are associated with accidental drug overdose mortality. Future research should examine aspects of police-community interactions that contribute to higher overdose mortality. PMID:20727684

  11. “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

  12. 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 ...

  13. 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

  14. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis

    PubMed Central

    Xuan, Ziming; Hackman, H Holly; Quinn, Emily; Doe-Simkins, Maya; Sorensen-Alawad, Amy; Ruiz, Sarah; Ozonoff, Al

    2013-01-01

    Objective To evaluate the impact of state supported overdose education and nasal naloxone distribution (OEND) programs on rates of opioid related death from overdose and acute care utilization in Massachusetts. Design Interrupted time series analysis of opioid related overdose death and acute care utilization rates from 2002 to 2009 comparing community-year strata with high and low rates of OEND implementation to those with no implementation. Setting 19 Massachusetts communities (geographically distinct cities and towns) with at least five fatal opioid overdoses in each of the years 2004 to 2006. Participants OEND was implemented among opioid users at risk for overdose, social service agency staff, family, and friends of opioid users. Intervention OEND programs equipped people at risk for overdose and bystanders with nasal naloxone rescue kits and trained them how to prevent, recognize, and respond to an overdose by engaging emergency medical services, providing rescue breathing, and delivering naloxone. Main outcome measures Adjusted rate ratios for annual deaths related to opioid overdose and utilization of acute care hospitals. Results Among these communities, OEND programs trained 2912 potential bystanders who reported 327 rescues. Both community-year strata with 1-100 enrollments per 100 000 population (adjusted rate ratio 0.73, 95% confidence interval 0.57 to 0.91) and community-year strata with greater than 100 enrollments per 100 000 population (0.54, 0.39 to 0.76) had significantly reduced adjusted rate ratios compared with communities with no implementation. Differences in rates of acute care hospital utilization were not significant. Conclusions Opioid overdose death rates were reduced in communities where OEND was implemented. This study provides observational evidence that by training potential bystanders to prevent, recognize, and respond to opioid overdoses, OEND is an effective intervention. PMID:23372174

  15. 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…

  16. Clinical and economic evidence for intravenous acetaminophen.

    PubMed

    Yeh, Yu-Chen; Reddy, Prabashni

    2012-06-01

    Intravenous acetaminophen received United States Food and Drug Administration approval in November 2010 for the management of mild-to-moderate pain, management of moderate-to-severe pain with adjunctive opioid analgesics, and reduction of fever. Although intravenous acetaminophen generally improved pain relief and demonstrated opioid-sparing effects compared with placebo, it did not consistently reduce the frequency of opioid-related adverse events (e.g., postoperative nausea and vomiting). The safety and efficacy of intravenous acetaminophen as an antipyretic agent have been documented in adults and children; however, its cost is several-fold higher than that of the oral and rectal formulations. Although use of intravenous acetaminophen has reduced other postoperative resource utilization (e.g., hospital length of stay) in some studies outside the United States in patients undergoing abdominal surgery, a full economic evaluation in the United States has yet to be undertaken. In addition, its administration time (15-min infusion) and packaging (glass, single-use vial) have the potential to adversely affect patient flow in the postanesthesia care unit, create burden on patient care units, and lead to drug waste. Furthermore, 1 g of intravenous acetaminophen is formulated in 100 ml of solution, which may be an issue for patients with fluid restrictions. Given the clinical and economic evidence currently available, intravenous acetaminophen should not replace oral or rectal acetaminophen, but its use may be considered in a limited number of patients who cannot receive drugs orally and rectally and who cannot tolerate other parenteral nonopioid analgesic or antipyretic agents. PMID:22570116

  17. 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

  18. The Rhode Island community responds to opioid overdose deaths.

    PubMed

    Bowman, Sarah; Engelman, Ariel; Koziol, Jennifer; Mahoney, Linda; Maxwell, Christopher; McKenzie, Michelle

    2014-10-01

    The challenge of addressing the epidemic of opioid overdose in Rhode Island, and nationwide, is only possible through collaborative efforts among a wide breadth of stakeholders. This article describes the range of efforts by numerous partners that have come together to facilitate community, and treatment-related approaches to address opioid-involved overdose and substance use disorder. Strategies to address this crisis have largely focused on increasing access both to the opioid overdose antidote naloxone and to high quality and timely treatment and recovery services. [Full text available at http://rimed.org/rimedicaljournal-2014-10.asp, free with no login]. PMID:25271658

  19. 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

  20. Immunopharmacotherapeutic Manifolds and Modulation of Cocaine Overdose

    PubMed Central

    Treweek, Jennifer B.; Roberts, Amanda J.; Janda, Kim D.

    2011-01-01

    Cocaine achieves its psychostimulant, reinforcing properties through selectively blocking dopamine transporters, and this neurobiological mechanism impedes the use of classical receptor-antagonist pharmacotherapies to outcompete cocaine at CNS sites. Passive immunization with monoclonal antibodies (mAb) specific for cocaine circumvents this problem as drug is sequestered in the periphery prior to entry into the brain. To optimize an immunopharmacotherapeutic strategy for reversing severe cocaine toxicity, the therapeutic properties of mAb GNC92H2 IgG were compared to those of its engineered formats in a mouse overdose model. Whereas the extended half-life of an IgG justifies its application to the prophylactic treatment of addiction, the rapid, thorough biodistribution of mAb-based fragments, including F(ab')2, Fab and scFv, may correlate to accelerated scavenging of cocaine and reversal of toxicity. To test this hypothesis, mice were administered the anti-cocaine IgG (180 mg/kg, i.v.) or GNC92H2-based agent after receiving an LD50 cocaine dose (93 mg/kg, i.p.), and the timeline of overdose symptoms was recorded. All formats lowered the rate of lethality despite the >100-fold molar excess of drug to antibody binding capacity. However, only F(ab')2-92H2 and Fab-92H2 significantly attenuated the progression of premorbid behaviors, and Fab-92H2 prevented seizure generation in a percentage of mice. The calculation of serum half-life of each format demonstrated that the pharmacokinetic profile of Fab-92H2 (elimination half-life, t1/2 ∼ 100 minutes) best approximated that of cocaine. These results not only confirm the importance of highly specific and tight drug binding by the mAb, but also highlight the benefit of aligning the pharmacokinetic and pharmacodynamic properties of the immunopharmacotherapeutic with the targeted drug. PMID:21356233

  1. 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

  2. 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

  3. Doxylamine overdose as a potential cause of rhabdomyolysis.

    PubMed

    Leybishkis, B; Fasseas, P; Ryan, K F

    2001-07-01

    Doxylamine succinate, an over-the-counter antihistamine, is commonly used as a nighttime sleep aid in the short-term management of insomnia. It is also used in combination with antitussive and decongestant agents for the temporary relief of common cold symptoms. Doxylamine is frequently involved in accidental and intentional overdoses. Rhabdomyolysis and secondary acute renal failure are rare but potentially serious complications, making early recognition and treatment essential. With the large number of nonprescription antihistamines and sleep aids available to the general public, it is important to keep in mind that overdose is a potential problem. The complications associated with overdose of these medications are just as life threatening as those associated with prescription drugs. A high index of suspicion and evaluation of rhabdomyolysis is warranted in antihistamine toxicity. We report an observation of severe rhabdomyolysis associated with doxylamine overdose. PMID:11465247

  4. 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 ...

  5. Drug Monitoring Programs Do Curb Overdose Deaths: Study

    MedlinePlus

    ... 159528.html Drug Monitoring Programs Do Curb Overdose Deaths: Study Opioid epidemic demands such measures, researcher says ... News) -- Drug monitoring programs appear to help reduce deaths from prescription painkillers called opioids, a new study ...

  6. Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity.

    PubMed

    Jaeschke, Hartmut; Williams, C David; McGill, Mitchell R; Farhood, Anwar

    2010-05-21

    Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminophen-induced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature. PMID:20480535

  7. Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity

    PubMed Central

    Jaeschke, Hartmut; Williams, C David; McGill, Mitchell R; Farhood, Anwar

    2010-01-01

    Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminophen-induced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature. PMID:20480535

  8. Alprazolam is relatively more toxic than other benzodiazepines in overdose

    PubMed Central

    Isbister, Geoffrey K; O'Regan, Luke; Sibbritt, David; Whyte, Ian M

    2004-01-01

    Aims To describe alprazolam poisoning and the relative toxicity of alprazolam compared with other benzodiazepines. Methods A database of consecutive poisoning admissions to a regional toxicology service was searched to identify consecutive benzodiazepine deliberate self poisonings, which were coded as alprazolam, diazepam or other benzodiazepine. Major outcomes used were length of stay (LOS), intensive care (ICU) admission, coma (GCS < 9), flumazenil administration and requirement for mechanical ventilation. Prescription data were obtained for benzodiazepines for the study period. Results There were 2063 single benzodiazepine overdose admissions: 131 alprazolam overdoses, 823 diazepam overdoses and 1109 other benzodiazepine overdoses. The median LOS for alprazolam overdoses was 19 h which was 1.27 (95% CI 1.04, 1.54) times longer compared with other benzodiazepines by multiple linear regression. For patients with alprazolam overdoses, 22% were admitted to ICU which was 2.06 (95% CI 1.27, 3.33) times more likely compared with other benzodiazepines after multivariate analysis adjusting for age, dose, gender, time to ingestion and co-ingested drugs. Flumazenil was administered to 14% of alprazolam patients and 16% were ventilated, which was significantly more than for other benzodiazepine overdoses (8% and 11%, respectively). Twelve percent of alprazolam overdoses had a GCS < 9 compared with 10% for other benzodiazepines. From benzodiazepine prescription data, total alprazolam prescriptions in Australia increased from 0.13 million in 1992 to 0.41 million in 2001. Eighty five percent of prescriptions were for panic disorder, anxiety, depression or mixed anxiety/depression. Conclusions Alprazolam was significantly more toxic than other benzodiazepines. The increased prescription of alprazolam to groups with an increased risk of deliberate self poisoning is concerning and needs review. PMID:15206998

  9. Study of an anaphylactoid reaction to acetaminophen.

    PubMed

    Liao, Chien-Ming; Chen, Wu-Charng; Lin, Ching-Yuang

    2002-01-01

    Generalized itching, urticaria and anaphylactic shock developed in a 9-year-old girl on two separate occasions after she ingested acetaminophen. She was admitted to our hospital for observation during oral challenge. Total eosinophil counts, total serum IgE, IgA, IgG, IgM, C3, and C4, specific IgE antibodies to six common allergens, and skin prick tests to purified acetaminophen and acetylsalicylic acid (aspirin) were unremarkable. No reaction occurred on open challenge with acetylsalicylic acid and mefenamic acid. However, urticaria and itching sensation occurred 45 min after ingesting 50 mg of purified acetaminophen. Dizziness, shivering, tachycardia and fainting also developed later. These symptoms resolved after treatment with a diphenhydramine injection and intravenous infusion of normal saline. There was a marked increase in the blood histamine level after challenge. In vitro histamine release before oral challenge was also abnormally as high as 50%. In summary, she had an immediate allergic reaction to acetaminophen but was tolerant to acetylsalicylic acid. PMID:12148965

  10. 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

  11. A Social Gradient in Fatal Opioids and Cocaine Related Overdoses?

    PubMed Central

    Origer, Alain; Le Bihan, Etienne; Baumann, Michèle

    2015-01-01

    Background To determine the existence of a social gradient in fatal overdose cases related to non-prescribed opioids and cocaine use, recorded in Luxembourg between 1994 and 2011. Methods Overdose cases were individually matched with four controls in a nested case-control study design, according to sex, year of birth, drug administration route and duration of drug use. The study sample, composed of 272 cases and 1,056 controls, was stratified according to a Social Inequality Accumulation Score (SIAS), based on educational attainment, employment, income, financial situation of subjects and the professional status of their father or legal guardian. Least squares linear regression analysis on overdose mortality rates and ridit scores were applied to determine the Relative Index of Inequality (RII) of the study sample. Results A negative linear relationship between the overdose mortality rate and the relative socioeconomic position was observed. We found a difference in mortality of 29.22 overdose deaths per 100 drug users in the lowest socioeconomic group compared to the most advantaged group. In terms of the Relative Inequality Index, the overdose mortality rate of opioid and cocaine users with lowest socioeconomic profiles was 9.88 times as high as that of their peers from the highest socioeconomic group (95% CI 6.49–13.26). Conclusions Our findings suggest the existence of a marked social gradient in opioids and cocaine related overdose fatalities. Harm reduction services should integrate socially supportive offers, not only because of their general aim of social (re)integration but crucially in order to meet their most important objective, that is to reduce drug-related mortality. PMID:25938451

  12. Accidental overdose of multiple chemotherapeutic agents.

    PubMed

    Kim, I S; Gratwohl, A; Stebler, C; Hausmann, M; Tichelli, A; Stern, A; Speck, B

    1989-07-01

    A 35-year-old man with refractory low grade diffuse centroblastic centrocytic non-Hodgkin's lymphoma was treated accidentally with an overdose of multiple chemotherapeutic agents. He was given adriamycin 50 mg/m2 and cyclophosphamide 350 mg/m2 for 6 days followed by 4 days of vincristine 1 mg/m2 and bleomycin 10 mg/m2. He was transferred when he developed pancytopenia, fever, severe mucositis, ileus and peripheral neuropathy. He was treated with broad spectrum antibiotics, red cell and single donor platelet transfusions and strict parenteral nutrition. In addition, he was given a continuous infusion of 400 micrograms daily human recombinant granulocyte macrophage-colony stimulating factor (rh GM-CSF) for 17 days. Intractable severe bleeding from his oral mucositis necessitated treatment with a continuous infusion of 8-ornithine-vasopressin for 8 days. He recovered and could be discharged home after 36 days of hospitalization with normal blood counts and without severe sequelae. PMID:2486848

  13. Accidental Overdose of Multiple Chemotherapeutic Agents

    PubMed Central

    Kim, In Soon; Gratwohl, A.; Stebler, C.; Hausmann, M.; Tichelli, A.; Stern, A.; Speck, B.

    1989-01-01

    A 35-year-old man with refractory low grade diffuse centroblastic centrocytic non-Hodgkin’s lymphoma was treated accidentally with an overdose of multiple chemotherapeutic agents. He was given adriamycin 50 mg/m2 and cyclophosphamide 350 mg/m2 for 6 days followed by 4 days of vincristine 1 mg/m2 and bleomycin 10 mg/m2. He was transferred when he developed pancytopenia, fever, severe mucositis, ileus and peripheral neuropathy. He was treated with broad spectrum antibiotics, red cell and single donor platelet transfusions and strict parenteral nutrition. In addition, he was given a continuous infusion of 400 ug daily human recombinant granulocyte macrophage-colony stimulating factor (rh GM-CSF) for 17 days. Intractable severe bleeding from his oral mucositis necessitated treatment with a continuous infusion of 8-ornithine-vasopressin for 8 days. He recovered and could be discharged home after 36 days of hospitalization with normal blood counts and without severe sequelae. PMID:2486848

  14. 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

  15. Fatal caffeine overdose: two case reports.

    PubMed

    Kerrigan, Sarah; Lindsey, Tania

    2005-10-01

    Caffeine is a mild central nervous stimulant that occurs naturally in coffee beans, cocoa beans and tea leaves. In large doses, it can be profoundly toxic, resulting in arrhythmia, tachycardia, vomiting, convulsions, coma and death. The average cup of coffee or tea in the United States is reported to contain between 40 and 150 mg caffeine although specialty coffees may contain much higher doses. Over-the-counter supplements that are used to combat fatigue typically contain 100-200 mg caffeine per tablet and doses of 32-200mg are included in a variety of prescription drug mixtures. Fatal caffeine overdoses in adults are relatively rare and require the ingestion of a large quantity of the drug, typically in excess of 5 g. Over a period of approximately 12 months our office reported two cases of fatal caffeine intoxication. In the first case, the femoral blood of a 39-year-old female with a history of intravenous drug use contained 192 mg/L caffeine. In the second case, femoral blood from a 29-year-old male with a history of obesity and diabetes contained 567 mg/L caffeine. In both cases, the cause of death was ruled as caffeine intoxication and the manner of death was accidental. PMID:15935584

  16. Validation of reference gene stability for APAP hepatotoxicity studies in different in vitro systems and identification of novel potential toxicity biomarkers.

    PubMed

    Fox, Bridget C; Devonshire, Alison S; Schutte, Maaike E; Foy, Carole A; Minguez, Jesus; Przyborski, Stefan; Maltman, Daniel; Bokhari, Maria; Marshall, Damian

    2010-10-01

    Liver cell lines and primary hepatocytes are becoming increasingly valuable for in vitro toxicogenomic studies, with RT-qPCR enabling the analysis of gene expression profiles following exposure to potential hepatotoxicants. Supporting the accurate normalisation of RT-qPCR data requires the identification of reference genes which have stable expression during in vitro toxicology studies. Therefore, we performed a comprehensive analysis of reference gene stability in two routinely used cell types, (HepG2 cells and primary rat hepatocytes), and two in vitro culture systems, (2D monolayer and 3D scaffolds). A robust reference gene validation strategy was performed, consisting of geNorm analysis, to test for pair wise variation in gene expression, and statistical analysis using analysis of variance. This strategy identified stable reference genes with respect to acetaminophen treatment and time in HepG2 cells (GAPDH and PPIA), and with respect to acetaminophen treatment and culture condition in primary hepatocytes (18S rRNA and α-tubulin). Following the selection of reference genes, the novel target genes E2F7 and IL-11RA were identified as potential toxicity biomarkers for acetaminophen treatment. We conclude that accurate quantification of gene expression requires the use of a validated normalisation strategy for each species and experimental system employed. PMID:20732408

  17. Prescription naloxone: a novel approach to heroin overdose prevention.

    PubMed

    Sporer, Karl A; Kral, Alex H

    2007-02-01

    The mortality and morbidity from heroin overdose have increased in the United States and internationally in the last decade. The lipid solubility allows the rapid deposition of heroin and its metabolites into the central nervous system and accounts for the "rush" experienced by users and for the toxicity. Risk factors for fatal and nonfatal heroin overdoses such as recent abstinence, decreased opiate tolerance, and polydrug use have been identified. Opiate substitution treatment such as methadone or buprenorphine is the only proven method of heroin overdose prevention. Death from a heroin overdose most commonly occurs 1 to 3 hours after injection at home in the company of other people. Numerous communities have taken advantage of this opportunity for treatment by implementing overdose prevention education to active heroin users, as well as prescribing naloxone for home use. Naloxone is a specific opiate antagonist without agonist properties or potential for abuse. It is inexpensive and nonscheduled and readily reverses the respiratory depression and sedation caused by heroin, as well as causing transient withdrawal symptoms. Program implementation considerations, legal ramifications, and research needs for prescription naloxone are discussed. PMID:17141138

  18. 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

  19. Unintentional overdose of analgesia secondary to acute dental pain.

    PubMed

    Dodd, M D; Graham, C A

    2002-08-24

    Three cases of unintentional overdose with simple analgesics are presented. Over a two month period, these patients presented to the accident and emergency (A&E) department with acute dental pain, outside normal working hours, having been unable to access emergency dental care. In one case the patient's reason for attendance was to obtain further supplies of analgesics. The patients required admission for assessment of the severity of the overdose in addition to advice about appropriate use of analgesics and advice on access to dental care. None of the patients required treatment for the overdose. These cases serve as a timely reminder of the importance of taking an accurate drug history in emergency situations. They also raise issues of patient education for self medication and access to emergency dental services outside normal working hours. PMID:12222908

  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. Comparative study of flurbiprofen, zomepirac sodium, acetaminophen plus codeine, and acetaminophen for the relief of postsurgical dental pain.

    PubMed

    Sunshine, A; Marrero, I; Olson, N; McCormick, N; Laska, E M

    1986-03-24

    The relative analgesic efficacy and safety of single oral doses of 50 and 100 mg of flurbiprofen (Ansaid, Upjohn) were compared with 100 mg of zomepirac sodium, 650 mg of acetaminophen plus 60 mg of codeine, 650 mg of acetaminophen alone, and placebo in a randomized, double-blind, parallel-group study. A total of 182 patients entered the study with moderate pain from a third molar extraction and were evaluated for six hours. For many efficacy variables, all active treatments were significantly (p less than or equal to 0.05) more effective than placebo. The two doses of flurbiprofen gave approximately similar results, suggesting a plateau effect above 50 mg. With the exception of relief at one hour, there were no significant differences between zomepirac and either dose of flurbiprofen. However, the mean response with zomepirac was greater than with either 50 or 100 mg of flurbiprofen during the first four hours and lower during the last two hours. The analgesic effects of acetaminophen alone were not significantly different from acetaminophen in combination with codeine. At the first hour, acetaminophen plus codeine led to significantly better pain relief than did 100 mg of flurbiprofen. After the first hour, flurbiprofen resulted in greater mean scores than acetaminophen alone or acetaminophen plus codeine, and these differences were significant at the fifth and sixth hours. Five patients had adverse reactions while receiving acetaminophen, acetaminophen plus codeine, or placebo. There were no adverse effects with flurbiprofen or zomepirac. PMID:3515924

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. Development of Maryland Local Overdose Fatality Review Teams: A Localized, Interdisciplinary Approach to Combat the Growing Problem of Drug Overdose Deaths.

    PubMed

    Rebbert-Franklin, Kathleen; Haas, Erin; Singal, Pooja; Cherico-Hsii, Sara; Baier, Michael; Collins, Kenneth; Webner, Karl; Sharfstein, Joshua

    2016-07-01

    The Maryland Local Overdose Fatality Review Teams (LOFRTs) are multiagency, multidisciplinary teams that critically analyze individual cases of drug overdose in their jurisdictions to identify preventable risk factors and missed opportunities for intervention, and to make policy and programmatic recommendations to prevent future overdose deaths. Three Maryland LOFRTs were first piloted in early 2014, and became established in law in May of the same year. LOFRTs provide unique opportunities for enhanced interagency collaboration and locally driven prevention efforts. This study describes the process of establishing LOFRTs in Maryland. The experiences and information regarding LOFRTs may help counties in other states combat the growing problem of deaths by drug overdose. PMID:27091609

  9. 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…

  10. 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…

  11. 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…

  12. Catatonia associated with phenylpropanolamine overdose and fluphenazine treatment: case report.

    PubMed

    Castellani, S

    1985-07-01

    A case is reported in which catatonia and autonomic abnormalities occurred in a patient on long-term fluphenazine decanoate following overdose with an oral anorectic agent containing phenylpropanolamine and caffeine. The catatonic symptoms showed a rapid and complete resolution following intramuscular benztropine. A possible mechanism to explain the catatonic symptoms is discussed. PMID:4008454

  13. Associations among Pain, Non-Medical Prescription Opioid Use, and Drug Overdose History

    PubMed Central

    Bonar, Erin E.; Ilgen, Mark A.; Walton, Maureen; Bohnert, Amy S.B.

    2014-01-01

    Background and Objective Recently, use of prescription opioids (POs) has increased; non-medical PO (NMPO) use is linked to overdose. NMPO use is common among individuals prescribed opioids for pain, and those in Substance Use Disorder (SUD) treatment with pain could be at increased risk for unintentional overdose due to NMPO use. We examined associations between pain, NMPO use, and overdose among SUD treatment patients. Methods Among 342 patients at a residential SUD treatment center, logistic regression examined the association of overdose with pain, adjusting for substance use, suicide attempts, and demographics. Results Pain was positively related to NMPO use. Heroin use, suicide attempts, pain, and NMPO use were positively associated with overdose; but NMPO use attenuated the pain-overdose relationship. Conclusions The relationship between pain and overdose among substance users may be, in part, explained by the association between pain and heavy NMPO use. PMID:24313240

  14. High Prevalence of Psychotropics Overdose among Suicide Attempters in Korea

    PubMed Central

    Kim, Jinyoung; Kim, Minseob; Kim, Yoo-ra; Choi, Kyoung Ho; Lee, Kyoung-Uk

    2015-01-01

    Objective The availability of suicide methods affects the risk of suicide attempts. This study examined the patterns of substances ingested by suicide attempters (SAs) and the characteristics of SAs using psychotropic overdoses. Methods Data for 384 of the 462 eligible SAs who used self-poisoning were analyzed. Demographic variables, clinical characteristics, and factors related to the suicide attempts were examined. Results There were 256 (66.7%) females and 128 (33.3%) males. Roughly half the SAs ingested psychotropics (n=179, 46.6%). Agricultural chemicals (n=84, 21.9%) were the second most frequently ingested substances, followed by analgesics (n=62, 16.1%), household products (n=27, 7.0%), and other prescribed medications (n=23, 6.0%). Among psychotropics, the most frequently overdosed drugs were sedative-hypnotics, including hypnotics (n=104) and benzodiazepines (n=78). SAs favored Z-drugs and alprazolam. When compared with SAs with non-psychotropic overdoses, significantly more SAs with psychotropic overdoses were female (76% vs. 58.5%, p<0.001) and had a psychiatric history (59.8% vs. 29.8%, p<0.001). They had significantly more previous suicide attempts (0.52±1.02 vs. 0.32±0.80, p<0.05) and lower risk (7.96±1.49 vs. 8.44±1.99, p<0.01) and medical severity (3.06±0.81 vs. 3.37±0.93, p<0.005) scores. Conclusion Psychotropic overdose, especially with sedative-hypnotics, was a major method in suicide attempts. It is important that psychiatric patients are carefully evaluated and monitored for suicidality when prescribing psychotropics. PMID:26598590

  15. 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…

  16. Attitudes and knowledge about naloxone and overdose prevention among detained drug users in Ningbo, China

    PubMed Central

    2012-01-01

    Background To date there has been limited research on both the prevalence of overdose and drug user knowledge about overdose prevention and response methods in China. In addition, there has been no effort to integrate naloxone information and distribution into pre-release services for drug users detained in isolated compulsory detoxification facilities in China. Methods The authors conducted a survey of 279 heroin users in isolated compulsory detoxification centers in Ningbo, China in an attempt to evaluate the possibility of conducting prelease peer naloxone programs in Ningbo isolated compulsory detoxification centers. Respondents' demographic background, history of heroin overdoses, and attitudes/knowledge about overdose prevention and response were collected. Results While drug users in Ningbo's compulsory detoxification centers have limited understandings of how to effectively respond to overdoses, they expressed concern about the possibility of overdose, interest in participating in overdose prevention and response programs, and a willingness to help their peers. In general, there was no significant difference in history and attitudes/knowledge of overdose between male and female participants. Conclusion Based on the findings of this research, our survey provides preliminary evidence that detained drug users have considerable interest in overdose prevention and response information and willingness to help peers. However, drug users in Ningbo isolated compulsory detoxification centers currently have limited understandings of effective ways of helping to prevent overdose deaths. PMID:22316338

  17. Nalbuphine, acetaminophen, and their combination in postoperative pain.

    PubMed

    Forbes, J A; Kolodny, A L; Chachich, B M; Beaver, W T

    1984-06-01

    In a double-blind study with the use of subjective reports of patients as indices of analgesia, we compared the analgesic effect of oral nalbuphine and acetaminophen and determined the contribution of each to the efficacy of their combination. In this parallel 2 X 2 factorial study, 129 inpatients after surgery were randomly assigned to treatment with a single oral dose of nalbuphine hydrochloride (30 mg), acetaminophen (650 mg), the combination of nalbuphine (30 mg) and acetaminophen (650 mg), or placebo. In the factorial analysis, both the nalbuphine and acetaminophen effects were significant for virtually every measure of total and peak analgesia, whereas the interaction contrast was not significant for any measure of analgesic effect. This indicates that the analgesic effect of the combination represents the additive effect of its constituents and is consistent with the results of studies of combinations of codeine and other opioids with aspirin or acetaminophen. There were few adverse effects other than sedation, which occurred twice as frequently in patients treated with nalbuphine as in those receiving acetaminophen or placebo. Our data suggest that this combination should prove at least as effective as any currently marketed narcotic-containing combination. Since nalbuphine has less dependence liability than narcotics and exhibits a ceiling on respiratory depression, its combination with acetaminophen should also be safer than comparable narcotic combinations. PMID:6734037

  18. 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

  19. 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.

  20. Potential Role of Caveolin-1 in Acetaminophen-Induced Hepatotoxicity

    PubMed Central

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-01-01

    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−/−) 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−/− 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−/− mice is not due to alterations in anti-oxidant defense. In wild type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β 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−/− mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1−/− 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. PMID:20100502

  1. 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.

  2. 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

  3. Psychosocial and contextual correlates of opioid overdose risk among drug users in St. Petersburg, Russia

    PubMed Central

    Grau, Lauretta E; Green, Traci C; Torban, Mikhail; Blinnikova, Ksenia; Krupitsky, Evgeny; Ilyuk, Ruslan; Kozlov, Andrei P; Heimer, Robert

    2009-01-01

    Background Opioid overdose in Russia is a problem that has grown more severe as heroin abuse expanded over the past decade, yet few studies have explored it in detail. In order to gain a clearer understanding of the situation, 60 drug users, both in and out of drug treatment in St. Petersburg, were interviewed concerning their overdose experience and knowledge about overdose recognition and prevention. Methods Using a semi-structured interview, we sought to identify and describe local attitudes, knowledge and experience (both self-sustained and witnessed) of opioid overdose. Bi-variate and multiple logistic regressions were performed in order to identify the relationship between overdose experience and sociodemographic factors, risk behaviors, and clinical psychiatric measures. Results We found that having experienced or witnessed an opioid overdose within the previous year was common, overdose knowledge was generally high, but nearly half the participants reported low self-efficacy for effectively intervening in an overdose situation. In bivariate analyses, self-reported family problems (i.e., perceived problematic family interactions) were positively associated with both experiencing (t56 = 2.49; p < 0.05) and with witnessing a greater number of overdoses in the previous year (rhos = 0.31; p < 0.05). Having previously overdosed [Adjusted Risk Ratio (ARR) 1.7, 95% Confidence Interval (CI) 1.1–2.6] and higher SCL-90-R somatization scores (ARR 1.2, 95% CI 0.96 – 1.5) were independently associated in multivariable analyses with self-sustained overdose experience in the past year. Greater perceived likelihood of experiencing a future overdose and concern about medical problems were independently associated with witnessing a higher number of overdoses within the previous year. Over two thirds of the participants expressed interest in receiving training in overdose prevention and response. Conclusion Opioid overdose experience is very common among drug users in St

  4. Challenges in a large mixed drug overdose patient.

    PubMed

    Zhang, Paige; Austin, Emily; Thompson, Margaret; Lin, Steve

    2016-01-01

    A 39-year-old homeless man was found confused and incoherent after ingesting an estimated total of 200 tablets of various medications. He presented to the emergency department with delirium, tachycardia, clonus and hyperthermia of 38.0°C. His condition worsened rapidly with his temperature rising to 39.9°C despite active cooling. The patient was subsequently sedated, intubated, paralysed and admitted to the intensive care unit, where he remained for 38 days. His initial presentation of a large mixed drug overdose manifested as serotonin syndrome, which had a protracted course complicated by ethanol withdrawal. He eventually stabilised and was transferred to the general ward, and was subsequently discharged from hospital on day 47 with continuing psychiatric care. This case demonstrates the challenges and considerations in diagnosis and management of large mixed drug overdoses where multiple toxidromes overlap. PMID:27335364

  5. A Response to the Opioid Overdose Epidemic: Naloxone Nasal Spray

    PubMed Central

    Wermeling, Daniel P.

    2012-01-01

    Opioid overdose morbidity and mortality is recognized to have epidemic proportions. Medical and public health agencies are adopting opioid harm reduction strategies to reduce the morbidity and mortality associated with overdose. One strategy developed by emergency medical services and public health agencies is to deliver the opioid antidote naloxone injection intranasally to reverse the effects of opioids. Paramedics have used this route to quickly administer naloxone in a needle-free system and avoiding needle-stick injuries and contracting a blood-born pathogen disease such as hepatitis or human immunodeficiency virus. Public health officials advocate broader lay person access since civilians are likely witnesses or first responders to an opioid overdose in a time-acute setting. The barrier to greater use of naloxone is that a suitable and optimized needlefree drug delivery system is unavailable. The scientific basis for design and study of an intranasal naloxone product is described. Lessons from nasal delivery of opioid analgesics are applied to the consideration of naloxone nasal spray. PMID:23734342

  6. Ketoprofen, acetaminophen plus oxycodone, and acetaminophen in the relief of postoperative pain.

    PubMed

    Sunshine, A; Olson, N Z; Zighelboim, I; De Castro, A

    1993-11-01

    Ketoprofen (Orudis) is a nonsteroidal anti-inflammatory drug that is currently approved in the United States for the management of mild to moderate pain. The objective of this trial was to determine the effectiveness of orally administered ketoprofen in the management of severe postoperative pain. This randomized, double-blind parallel study compared the efficacy and safety of single doses of 100 mg or 50 mg ketoprofen, the combination of 650 mg acetaminophen plus 10 mg oxycodone hydrochloride, 650 mg acetaminophen, or placebo in 240 patients with severe postoperative pain after cesarean section. Analgesia for the first dose was assessed over an 8-hour period. Multiple doses of 100 mg or 50 mg ketoprofen and the combination at half the dose (325 mg acetaminophen plus 5 mg oxycodone) were also assessed for up to 7 days. The 100 and 50 mg doses of ketoprofen and the combination were statistically superior to acetaminophen and placebo for many analgesic measures. A dose response was observed between the two doses of ketoprofen, with the 100 mg dose providing significantly greater analgesia over the lower dose. Ketoprofen, 100 mg, was at least as effective as the combination and its effects lasted longer, with the exception of hour 1 when the combination was superior. Remedication time for the group receiving 100 mg ketoprofen was significantly longer than for the other treatment groups. Significantly more patients who took repeated doses of the combination (84%) than those who took either dose of ketoprofen (70%) had adverse effects. Ketoprofen at both dose levels was shown to be effective, long-lasting, and well tolerated, and it should be considered as a viable option for the management of moderate to severe postoperative pain. PMID:8222498

  7. 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

  8. Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice.

    PubMed

    Cover, Cathleen; Fickert, Peter; Knight, Tamara R; Fuchsbichler, Andrea; Farhood, Anwar; Trauner, Michael; Jaeschke, Hartmut

    2005-03-01

    DNA fragmentation in hepatocytes occurs early after acetaminophen (AAP) overdose in mice. DNA strandbreaks can induce excessive activation of poly(ADP-ribose) polymerases (PARP), which may lead to oncotic necrosis. Based on controversial findings with chemical PARP inhibitors, the role of PARP-1 activation in AAP hepatotoxicity remains unclear. To investigate PARP-1 activation and evaluate a pathophysiological role of PARP-1, we used both PARP inhibitors (3-aminobenzamide; 5-aminoisoquinolinone) and PARP gene knockout mice (PARP-/-). Treatment of C3Heb/FeJ mice with 300 mg/kg AAP resulted in DNA fragmentation and alanine aminotransferase (ALT) release as early as 3 h, with further increase of these parameters up to 12 h. Few nuclei of hepatocytes stained positive for poly-ADP-ribosylated nuclear proteins (PAR) as indicator for PARP-1 activation at 4.5 h. However, the number of PAR-positive cells and staining intensity increased substantially at 6 and 12 h. Pretreatment with 500 mg/kg 3-aminobenzamide before AAP attenuated hepatic glutathione depletion and completely eliminated DNA fragmentation and liver injury. Delayed treatment several hours after AAP was still partially protective. On the other hand, liver injury was not attenuated in PARP-/- mice compared to wild-type animals. Similarly, the specific PARP-1 inhibitor 5-aminoisoquinolinone (5 mg/kg) was not protective. However, 3-aminobenzamide attenuated liver injury in WT and PARP-/- mice. In summary, PARP-1 activation is a consequence of DNA fragmentation after AAP overdose. However, PARP-1 activation is not a relevant event for AAP-induced oncotic necrosis. The protection of 3-aminobenzamide against AAP-induced liver injury was due to reduced metabolic activation and potentially its antioxidant effect but independent of PARP-1 inhibition. PMID:15601672

  9. 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

  10. Peer-initiated overdose resuscitation: fellow drug users could be mobilised to implement resuscitation.

    PubMed

    Strang; Best; Man; Noble; Gossop

    2000-12-01

    Research interviews about overdose experiences were conducted with 115 patients attending a methadone maintenance clinic in south London, UK. While almost half (49.6%) reported having experienced overdose personally (on an average of four occasions each), almost all (97.4%) reported that they had witnessed overdoses (on an average of six occasions each). This represents a total of 706 overdoses witnessed, of which 106 had resulted in fatalities. The vast majority of patients (86/97) reported that they had taken actions when they had witnessed overdoses with those acting taking an average of nearly threee different actions on the last occasion on which they had seen someone overdosing. Most respondents reported that they would be willing to act, even if they did not know the overdose victim personally and that they had not been deterred from acting by the previous response from the emergency services. Fear of punishment was not a strong deterrent from acting certainly not for this sample, with many participants also expressing an interest in expanding their repertoire of overdose interventions, for example through training in resuscitation techniques and by keeping naloxone at home for use in overdose emergency. PMID:11099924

  11. 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

  12. 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. PMID:26519524

  13. Age does not alter acetaminophen absorption.

    PubMed

    Divoll, M; Ameer, B; Abernethy, D R; Greenblatt, D J

    1982-04-01

    Twenty-eight healthy volunteers (age range, 22-78 years) received 650 mg of acetaminophen (AAP) on three separate occasions. The modes of administration were 1) intravenous, 5-minute infusion; 2) oral, with two 325-mg tablets; and 3) oral, with 650 mg as an elixir preparation. Plasma levels of AAP were determined in blood samples drawn up to 12 hours after the dose. The mean (+/- sd) kinetic variables for absorption of AAP from tablets in young and elderly were peak plasma concentration, 11.8 (+/- 4.2) vs 10.9 (+/- 4.1) micrograms/ml; peak time, 0.79 (+/- .54) vs 0.69 (+/- .40) hours after the dose; absorption half-life, 12.6 (+/- 9.8) vs. 8.2 (+/- 5.3) minutes; and absolute systemic availability, 79 (+/- 9) vs 72 (+/- 11) per cent. For AAP elixir, the corresponding values were 12.6 (+/- 5.4) vs 13.7 (+/- 6.0) micrograms/ml; 0.52 (+/- .24) vs 0.54 (+/- .51) hours; 8.6 (+/- 6.2) vs 6.1 (+/- 6.6) minutes; and 87 (+/- 9) vs 80 (+/- 9) per cent. Absolute bioavailability of both oral dosage forms was significantly less then 100 per cent in all groups. Elderly subjects tended to show lower availability of both oral preparations, but the difference was of borderline significance (P less than .50). Age did not influence any other measures of absorption. Since the absorption rate of acetaminophen may be indicative of the gastric emptying rate, age does not appear to alter this rate-limiting step in drug absorption. PMID:7069091

  14. 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

  15. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione.

    PubMed

    Knight, Tamara R; Ho, Ye-Shih; Farhood, Anwar; Jaeschke, Hartmut

    2002-11-01

    Acetaminophen (AAP) overdose causes formation of nitrotyrosine, a footprint of peroxynitrite, in centrilobular hepatocytes. The importance of peroxynitrite for the pathophysiology, however, is unclear. C3Heb/FeJ mice were treated with 300 mg/kg AAP. To accelerate the restoration of hepatic glutathione (GSH) levels as potential endogenous scavengers of peroxynitrite, some groups of animals received 200 mg of GSH/kg i.v. at different time points after AAP. AAP induced severe liver cell damage at 6 h. Total liver and mitochondrial glutathione levels decreased by >90% at 1 h but recovered to 75 and 45%, respectively, of untreated values at 6 h after AAP. In addition, the hepatic and mitochondrial glutathione disulfide (GSSG) content was significantly increased over baseline, suggesting a mitochondrial oxidant stress. Moreover, centrilobular hepatocytes stained for nitrotyrosine. Treatment with GSH at t = 0 restored hepatic GSH levels and completely prevented the mitochondrial oxidant stress, peroxynitrite formation, and liver cell injury. In contrast, treatment at 1.5 and 2.25 h restored hepatic and mitochondrial GSH levels but did not prevent the increase in GSSG formation. Nitrotyrosine adduct formation and liver injury, however, was substantially reduced. GSH treatment at 3 h after AAP was ineffective. Similar results were obtained when these experiments were repeated with glutathione peroxidase-deficient animals. Our data suggest that early GSH treatment (t = 0) prevented cell injury by improving the detoxification of the reactive metabolite of AAP. Delayed GSH treatment enhanced hepatic GSH levels, which scavenged peroxynitrite in a spontaneous reaction. Thus, peroxynitrite is an important mediator of AAP-induced liver cell necrosis. PMID:12388625

  16. Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice.

    PubMed

    Lawson, J A; Fisher, M A; Simmons, C A; Farhood, A; Jaeschke, H

    1999-05-01

    The mechanism of liver cell injury induced by an overdose of the analgesic acetaminophen (AAP) remains controversial. Recently, it was hypothesized that a significant number of hepatocytes die by apoptosis. Since caspases have been implicated as critical signal and effector proteases in apoptosis, we investigated their potential role in the pathophysiology of AAP-induced liver injury. Male C3Heb/FeJ mice were fasted overnight and then treated with 500 mg/kg AAP. Liver injury became apparent at 4 h and was more severe at 6 h (plasma ALT activities: 4110 +/- 320 U/liter; centrilobular necrosis). DNA fragmentation increased parallel to the increase of plasma ALT values. At 6 h there was a 420% increase of DNA fragmentation and a 74-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells located predominantly around central veins. However, the activity of the proapoptotic caspase-3 was not increased at any time after AAP. In contrast, injection of the anti-Fas antibody Jo-2 (positive control) caused a 28-fold increase of caspase-3 activity and severe DNA fragmentation before significant ALT release. Treatment with the caspase inhibitor ZVAD-CHF2 had no effect on AAP toxicity but completely prevented Jo-mediated apoptosis. In contrast, Jo-induced caspase activation and apoptosis could be inhibited by AAP treatment in a time- and dose-dependent manner. We conclude that AAP-induced DNA fragmentation does not involve caspases, suggesting a direct activation of endonucleases through elevated Ca2+ levels. In addition, electrophilic metabolites of AAP may inactivate caspases or their activation pathway. This indicates that AAP metabolism has the potential to inhibit signal transduction mechanisms of receptor-mediated apoptosis. PMID:10222310

  17. Confusion: acetaminophen dosing changes based on NO evidence in adults.

    PubMed

    Krenzelok, Edward P; Royal, Mike A

    2012-06-01

    Acetaminophen (paracetamol) plays a vital role in American health care, with in excess of 25 billion doses being used annually as a nonprescription medication. Over 200 million acetaminophen-containing prescriptions, usually in combination with an opioid, are dispensed annually. While acetaminophen is recognized as a safe and effective analgesic and antipyretic, it is also associated with significant morbidity and mortality (hepatotoxicity) if doses in excess of the therapeutic amount are ingested inappropriately. The maximum daily therapeutic dose of 3900-4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile, and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900-4000 mg to 3000-3250 mg. In 2011, McNeil, the producer of the Tylenol® brand of acetaminophen, voluntarily reduced the maximum daily dose of its 500 mg tablet product to 3000 mg/day, and it has pledged to change the labeling of its 325 mg/tablet product to reflect a maximum of 3250 mg/day. Generic manufacturers have not changed their dosing regimens and they have remained consistent with the established monograph dose. Therefore, confusion will be inevitable as both consumers and health care professionals try to determine the proper therapeutic dose of acetaminophen. Which is the correct dose of acetaminophen: 3000 mg if 500 mg tablets are used, 3250 mg with 325 mg tablets, or 3900 mg when 650 mg arthritis-strength products are used? PMID:22530736

  18. Unintentional overdose and suicide among substance users: a review of overlap and risk factors.

    PubMed

    Bohnert, Amy S B; Roeder, Kathryn; Ilgen, Mark A

    2010-08-01

    Substance use is a risk factor for suicide, suicide attempts, and fatal and non-fatal overdose, but to date, little has been done to integrate the research on suicidal behavior and overdose among substance users. This study reviews the literature on suicide and overdose among substance users with the goal of illuminating the similarities and differences between these two events. A structured review resulted in 15 articles (describing 14 unique studies) published between 1990 and 2010 that examined both overdose and suicide in samples of substance users. There is some evidence that substance users who attempt suicide are more likely to report an overdose and vice versa. This relationship may be partially explained by the fact that overdose is a common method of suicide. The results of the literature review also indicate that substance users with a history of both events may represent a group with particularly poor psychological and social functioning and severe drug-related problems. Further research is needed to understand the overlap of, and differences between, suicide and accidental overdose among individuals who misuse substances, particularly individuals who primarily use substances other than heroin. An improved understanding of the interrelationships between suicide and unintentional overdose among individuals who use alcohol or drugs is necessary to guide the development of effective prevention and intervention approaches. PMID:20430536

  19. 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

  20. Baclofen overdose from possible intrinsic malfunction of SynchroMed II pump.

    PubMed

    Davanzo, Justin R; Rizk, Elias

    2015-08-01

    This is a case report illustrating an overdose of baclofen in a 10-year-old boy due to a likely malfunction of a SynchroMed II pump. This ultimately necessitated a pump replacement. One-year follow-up showed no further incidents of baclofen overdose, with multiple pump refills. PMID:25978532

  1. 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. PMID:27126739

  2. MODULATION OF ACETAMINOPHEN-INDUCED HEPATOTOXICITY BY THE XENOBIOTIC RECEPTOR CAR

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR-...

  3. 76 FR 2691 - Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-14

    ... acetaminophen drugs (final rule, 74 FR 19385, April 29, 2009; and technical amendment, 74 FR 61512, November 25... is produced when acetaminophen is broken down by the body (Ref. 5). With low doses of acetaminophen... Syndrome, chronic alcoholism, acute excess alcohol use, and use of anticonvulsant or...

  4. Overdose prevention for prisoners in New York: a novel program and collaboration.

    PubMed

    Zucker, Howard; Annucci, Anthony J; Stancliff, Sharon; Catania, Holly

    2015-01-01

    This is a brief report on the establishment of a new program in New York State prisons to prepare prisoners to avoid the increased risks of drug overdose death associated with the transition to the community by training them in overdose prevention and making available naloxone, a medication that quickly reverses the effects of an opioid overdose, to all prisoners as they re-enter the community. It is a milestone collaboration in the USA between public health, the correctional system, and a community-based harm reduction program in response to the growth of heroin and opioid analgesic use and related morbidity and mortality, working together to get naloxone into the hands of the people at high risk of overdosing and/or of witnessing an opioid overdose. PMID:26541987

  5. 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

  6. Characteristics of inmates witnessing overdose events in prison: implications for prevention in the correctional setting

    PubMed Central

    Albizu-García, Carmen E; Hernández-Viver, Adriana; Feal, Jacqueline; Rodríguez-Orengo, José F

    2009-01-01

    Background Although prevention of opiate overdose has been gaining attention as a harm reduction measure with community drug users, there is scarce information about drug overdose in prison. In correctional institutions without a drug free environment, awareness of overdose events is an important public health concern. This study explores the frequency with which inmates in a state penitentiary system report having witnessed drug overdose events in prison. It also explores whether participants who have witnessed an overdose in prison and know someone who died from an overdose in prison significantly differ from those that do not in selected sociodemographic variables and drug use history to identify a target population for prevention interventions. Methods Data comes from a cross-sectional survey of sentenced inmates in the state prisons of Puerto Rico. A complex probabilistic, multistage sampling design was used. A total of 1,179 individuals participated for an 89% response rate. Results Factors associated with witnessing an overdose event in prison include: male sex, age 25 or older, drug use during current incarceration, and drug injection in prison. Factors associated with knowing someone who died from an overdose in prison include: male sex, age between 25–35, previous incarcerations, and drug use during current incarceration. Conclusion Witnessing a drug overdose is a frequent occurrence within the prison system. The likelihood of witnessing an overdose is greater with being male, polydrug use and drug injection in prison. Findings signal an urgent public health challenge that requires prompt interventions to reduce this drug related harm within the correctional system, including adequate access to medication with opiate agonists. PMID:19589157

  7. Associations Between Childhood Trauma and Non-Fatal Overdose Among People Who Inject Drugs

    PubMed Central

    Lake, Stephanie; Hayashi, Kanna; Milloy, M-J; Wood, Evan; Dong, Huiru; Montaner, Julio; Kerr, Thomas

    2015-01-01

    Introduction Although people who inject drugs (IDU) remain at a high risk of accidental overdose, interventions that address overdose remain limited. Accordingly there is a continuing need to identify psychological and social factors that shape overdose risk. Despite being reported frequently among IDU, childhood trauma has received little attention as a potential risk factor for overdose. This study aims to evaluate relationships between non-fatal overdose and five forms of childhood maltreatment among a cohort of IDU in Vancouver, Canada. Methods Data was obtained from two prospective cohorts of IDU between December 2005 and May 2013. Multivariate generalized estimating equations (GEE) were used to explore relationships between five forms of childhood trauma and non-fatal overdose, adjusting for potential confounders. Results During the study period, 1697 IDU, including 552 (32.5%) women, were followed. At baseline, 1136 (67.0%) participants reported at least one form of childhood trauma, while 4–9% reported a non-fatal overdose at each semi-annual follow-up. In multivariate analyses, physical [adjusted odds ratio (AOR): 1.36, 95% confidence interval (CI): 1.08–1.71], sexual (AOR: 1.48, CI: 1.17–1.87), and emotional abuse (AOR: 1.54, CI: 1.22–1.93) and physical neglect (AOR: 1.28, CI: 1.01–1.62) were independently associated with non-fatal overdose (all p < 0.05). Conclusions Childhood trauma was common among participants, and reporting an experience of trauma was positively associated with non-fatal overdose. These findings highlight the need to provide intensive overdose prevention to trauma survivors and to incorporate screening for childhood trauma into health and social programs tailored to IDU. PMID:25588793

  8. Fatal Insulin Overdoses: Case Report and Update on Testing Methodology.

    PubMed

    Sunderland, Nick; Wong, Sophia; Lee, Carol K

    2016-01-01

    Suicidal insulin overdoses are an under-recognized and uncommon cause of death, often relying on scene and nonspecific autopsy findings. Here, we present a case report of a fatal exogenous insulin overdose in a patient with type 1 diabetes. In our case, there were no contributory autopsy findings; however, serum analog aspart insulin levels were c. 10× the predicted therapeutic upper limit (4000, reference 6.6-55 uU/mL), which correlated with scene findings. This was specifically determined by a newly developed immunocapture liquid chromatography-tandem mass spectrometry assay, able to discriminate between various synthetic insulin analogs. Total insulin levels by immunoassay were highly elevated on the Siemens Advia Centaur, but not the Roche platforms (4741 vs. 5.2 uU/mL, respectively), showing variable sensitivity of detection within the same analog depending on assay. We discuss the prevalence and features to look for at autopsy in these types of cases. Additionally, analytical options for testing insulin levels, including new methodologies, guidance on collection of samples, as well as an outline of available historical reference range data are discussed. PMID:26399839

  9. 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

  10. [Case of catecholamine-resistant shock caused by drug overdose].

    PubMed

    Sato, Rui; Shimizu, Keiki; Taguchi, Shigemasa; Sekii, Hajime; Yokote, Ryo; Kiyota, Kazuya

    2007-01-01

    A 27-year-old man with schizophrenia took an overdose of a psychotic agent. He became unconscious and had severe hypotension. Although he was diagnosed as having distributive shock caused by drug overdose and treated by hydration and catecholamine, the shock status was lasting. The use of vasopressin changed the situation dramatically. After the injection of vasopressin at maximum dose, 0.1 U/min, the dose of vasopressin could be tapered. He recovered from shock and was discharged on the third day without sequelae. There are an increasing number of reports that indicate that vasopressin is effective for distributive shock, especially catecholamine-resistant septic shock. It seems that the appropriate dose of vasopressin is under 0.04U/min considering the deterioration of cardiac function although the maximum dose of vasopressin was O.1U/min in this case. For that reason, monitoring by pulmonary artery catheter is recommended. The side effects of vasopressin should be discussed for appropriate use. PMID:17319503

  11. 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

  12. 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. PMID:25271657

  13. A rapid quantitative determination of acetaminophen in plasma.

    PubMed

    O'Connell, S E; Zurzola, F J

    1982-11-01

    A simple method is described for the rapid, quantitative analysis of acetaminophen in plasma. The nonconjugated acetaminophen present in the plasma following drug administration is determined after plasma protein precipitation by high-pressure liquid chromatography (HPLC) at a wavelength of 240 nm. Acetaminophen (I) is detectable at levels as low as 0.1 microgram/ml. Mean recoveries of 94% with a coefficient of variation of 3% were obtained for plasma standards whose concentrations ranged from 0 to 32 microgram/ml. Interassay variability of the slope of the standard curve had a coefficient of variation of 2.7%. Application and verification of this method by comparison with another procedure run simultaneously during several human bioavailability studies are described. PMID:7175728

  14. Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose.

    PubMed

    Allen, Kirstie M; Crawford, Veronica B; Conaglen, John V; Elston, Marianne S

    2015-11-01

    There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment. We report a levothyroxine (15,800 mcg) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid-stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT4), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT3) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery. Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis. PMID:25824846

  15. Opioid Agonist Treatments and Heroin Overdose Deaths in Baltimore, Maryland, 1995–2009

    PubMed Central

    Gryczynski, Jan; O’Grady, Kevin E.; Sharfstein, Joshua M.; Warren, Gregory; Olsen, Yngvild; Mitchell, Shannon G.; Jaffe, Jerome H.

    2013-01-01

    Objectives. We examined the association between the expansion of methadone and buprenorphine treatment and the prevalence of heroin overdose deaths in Baltimore, Maryland from 1995 to 2009. Methods. We conducted a longitudinal time series analysis of archival data using linear regression with the Newey–West method to correct SEs for heteroscedasticity and autocorrelation, adjusting for average heroin purity. Results. Overdose deaths attributed to heroin ranged from a high of 312 in 1999 to a low of 106 in 2008. While mean heroin purity rose sharply (1995–1999), the increasing number of patients treated with methadone was not associated with a change in the number of overdose deaths, but starting in 2000 expansion of opioid agonist treatment was associated with a decline in overdose deaths. Adjusting for heroin purity and the number of methadone patients, there was a statistically significant inverse relationship between heroin overdose deaths and patients treated with buprenorphine (P = .002). Conclusions. Increased access to opioid agonist treatment was associated with a reduction in heroin overdose deaths. Implementing policies that support evidence-based medication treatment of opiate dependence may decrease heroin overdose deaths. PMID:23488511

  16. 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

  17. The analgesic efficacy of flurbiprofen compared to acetaminophen with codeine.

    PubMed

    Cooper, S A; Kupperman, A

    1991-01-01

    In a single-dose, parallel group, randomized block treatment allocation study, the relative analgesic efficacy of flurbiprofen, a nonsteroidal antiinflammatory drug, was compared to acetaminophen 650 mg with codeine 60 mg, zomepirac sodium 100 mg, and placebo. A total of 226 post-surgical dental patients (146 females and 80 males) participated in the study. Flurbiprofen in 50 mg and 100 mg dosages demonstrated effective analgesic activity with the 100 mg dosage being at least as effective as the acetaminophen/codeine combination. The results of this study support previous work on flurbiprofen. PMID:1930699

  18. The pharmacokinetics of sertraline in overdose and the effect of activated charcoal

    PubMed Central

    Cooper, Joyce M; Duffull, Stephen B; Saiao, Ana S; Isbister, Geoffrey K

    2015-01-01

    Aims To investigate the pharmacokinetics (PK) of sertraline in overdose and the effect of single dose activated charcoal (SDAC). Methods Patients presenting to a toxicology unit with sertraline overdoses had demographic and clinical information recorded, and serial serum collected for measurement of sertraline concentrations. Monolix® version 4.2 was used to develop a population PK model of sertraline overdose and the effect of SDAC. Uncertainty in dose time was accounted for by shifting dose time using lag time with between subject variability (BSV). BSV on relative fraction absorbed was used to model uncertainty in dose. Results There were 77 timed sertraline concentrations measured in 28 patients with sertraline overdoses with a median dose of 1550 mg (250–5000 mg). SDAC was given to seven patients between 1.5 and 4 h post-overdose. A one compartment model with lag time of 1 h and first order input and elimination adequately described the data. Including BSV on both lag time and relative fraction absorbed improved the model. The population PK parameter estimates for absorption rate constant, volume of distribution and clearance were 0.895 h−1, 5340 l and 130 l h−1, respectively. The calculated half-life of sertraline following overdose was 28 h (IQR 19.4−30.6h). When given up to 4 h post-overdose, SDAC significantly increased the clearance of sertraline by a factor of 1.9, decreased the area under the curve and decreased the maximum plasma concentration (Cmax). Conclusions Sertraline had linear kinetics in overdose with parameter values similar to those in therapeutic use. SDAC is effective in increasing clearance when given 1.5 to 4 h post-overdose. PMID:25155462

  19. Preventing Opiate Overdose Deaths: Examining Objections to Take-Home Naloxone

    PubMed Central

    Bazazi, Alexander R.; Zaller, Nickolas D.; Fu, Jeannia J.; Rich, Josiah D.

    2010-01-01

    Opiate overdose persists as a major public health problem, contributing to significant morbidity and mortality among opiate users globally. Opiate overdose can be reversed by the timely administration of naloxone. Programs that distribute naloxone to opiate users and their acquaintances have been successfully implemented in a number of cities around the world and have shown that non-medical personnel are able to administer naloxone to reverse opiate overdoses and save lives. Objections to distributing naloxone to non-medical personnel persist despite a lack of scientific evidence. Here we respond to some common objections to naloxone distribution and their implications. PMID:21099064

  20. 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