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Sample records for acetaminophen

  1. Don't Double Up on Acetaminophen

    Science.gov (United States)

    ... for advice. FDA has an online list of brand names of products containing acetaminophen . back to top ... t Mix For More Information Acetaminophen Information Acetaminophen Awareness Coalition’s Know Your Dose Campaign Using Acetaminophen and ...

  2. Acetaminophen and codeine overdose

    Science.gov (United States)

    ... Comprehensive Study Guide. 7th ed. New York, NY: McGraw-Hill; 2011:chap 180. Ferri FF. Acetaminophen poisoning. ... Comprehensive Study Guide. 7th ed. New York, NY: McGraw-Hill; 2011:chap 184. Kellerman RD. Physical and ...

  3. Acetaminophen for Chronic Pain

    DEFF Research Database (Denmark)

    Ennis, Zandra Nymand; Dideriksen, Dorthe; Vaegter, Henrik Bjarke;

    2016-01-01

    conducted according to PRISMA guidelines. All studies were conducted in patients with hip- or knee osteoarthritis and six out of seven studies had observation periods of less than three months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little......Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first-line treatment in all pain conditions by WHO. We performed a systematic literature review to evaluate the efficacy of acetaminophen when used for chronic pain conditions. Applying three broad search...... evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended. This article is protected by copyright. All rights reserved....

  4. Acetaminophen and Codeine

    Science.gov (United States)

    Acetaminophen and codeine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: dizziness lightheadedness drowsiness upset stomach vomiting constipation stomach pain rash difficulty urinating If you experience either of ...

  5. Acetaminophen: old drug, new warnings.

    Science.gov (United States)

    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. Interventions for paracetamol (acetaminophen) overdose

    DEFF Research Database (Denmark)

    Brok, J; Buckley, N; Gluud, C

    2006-01-01

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

  7. Interventions for paracetamol (acetaminophen) overdoses

    DEFF Research Database (Denmark)

    Brok, J; Buckley, N; Gluud, C

    2002-01-01

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

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

    Science.gov (United States)

    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; pacetaminophen 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.

  9. The treatment of acetaminophen poisoning

    Energy Technology Data Exchange (ETDEWEB)

    Prescott, L.F.; Critchley, J.A.

    1983-01-01

    Acetaminophen has become a very popular over-the-counter analgesic in some countries and as a result it is used increasingly as an agent for self-poisoning. Without treatment only a minority of patients develop severe liver damage and 1 to 2% die in hepatic failure. Until Mitchell and his colleagues discovered the biochemical mechanisms of toxicity in 1973 there was no effective treatment. They showed that the metabolic activation of acetaminophen resulted in the formation of a reactive arylating intermediate, and that hepatic reduced glutathione played an essential protective role by preferential conjugation and inactivation of the metabolite. Early treatment with sulphydryl compounds and glutathione precursors has been dramatically effective in preventing liver damage, renal failure, and death following acetaminophen overdosage. It seems likely that these agents act primarily by stimulating glutathione synthesis. Inhibition of the metabolic activation of acetaminophen is another potential therapeutic approach that has not yet been put to the test clinically. The clinical management of acetaminophen poisoning has been transformed and it is particularly gratifying to have effective treatment based on a well established biochemical mechanism of toxicity. It is likely that effective treatment will be developed for toxicity caused through similar mechanisms by other agents.

  10. Multiple-dose acetaminophen pharmacokinetics.

    Science.gov (United States)

    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

  11. Intravenous paracetamol (acetaminophen).

    Science.gov (United States)

    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

  12. Acetaminophen injection: a review of clinical information.

    Science.gov (United States)

    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

  13. Transcriptomic studies on liver toxicity of acetaminophen.

    Science.gov (United States)

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

    2014-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Laura James

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

  15. Compound list: acetaminophen [Open TG-GATEs

    Lifescience Database Archive (English)

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

  16. Extracorporeal treatment for acetaminophen poisoning

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP). METHODS: After a systematic review...... an overall very low quality of evidence for all recommendations. Clinical data on 135 patients and toxicokinetic data on 54 patients were analyzed. Twenty-three fatalities were reviewed. The workgroup agreed that N-acetylcysteine (NAC) is the mainstay of treatment, and that ECTR is not warranted in most...

  17. The Social Side Effects of Acetaminophen

    Science.gov (United States)

    Mischkowski, Dominik

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

  18. Potentiation of cadmium nephrotoxicity by acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Bernard, A.M.; Russis, R. de; Ouled Amor, A.; Lauwerys, R.R.

    1988-10-01

    The possible interactions between acetaminophen and cadmium (Cd) on the kidney were investigated in female Sprague-Dawley rats. Acetaminophen was administered in the food at an average dose of 900 mg/kg and Cd in drinking water at the concentration of 200 ppm. The treatment with acetaminophen and Cd lasted 2 and 10 months, respectively. No interaction between Cd and acetaminophen was observed during the period of their concomitant administration: the increase in albuminuria caused by Cd and acetaminophen was additive, while the tubular impairment caused by acetaminophen (increased ..beta../sub 2/-microglobulinuria and decreased kidney concentrating ability) was not exacerbated by Cd. None of these treatments affected the glomerular filtration rate. Four months after the end of acetaminophen treatment, the renal changes had almost completely disappeared in the rats which had received the analgesic alone. Those continously exposed to Cd had developed slight tubular damage, as evidenced by an increased urinary excretion of ..beta../sub 2/-microglobulin and ..beta..-N-acetylglucosaminidase. By contrast, rats pretreated with acetaminophen for 2 months and exposed to Cd showed a marked increase in urinary excretion of albumin and ..beta../sub 2/-microglobulin, suggesting an interaction between both treatments. At the end of the study, only the interaction with ..beta../sub 2/-microglobulin excretion was still evident; that with the urinary excretion of ..beta..-N-acetylglucosaminidase and albumin having been masked by the chronic progessive nephrosis affecting most animals at that stage. As acetaminophen had no effect on the renal accumulation of Cd, it may be concluded that pretreatment with this analygesic at a dose causing slight tubular dysfunction renders rat kidney more sensitive to the nephrotoxic action of Cd. This observation may be of clinical relevance for population groups occupationally or environmentally exposed to Cd.

  19. Acetaminophen toxicity with concomitant use of carbamazepine.

    Science.gov (United States)

    Jickling, Glen; Heino, Angela; Ahmed, S Nizam

    2009-12-01

    Acetaminophen is a widely used analgesic that can cause acute liver failure when consumed above a maximum daily dose. Certain patients may be at increased risk of hepatocellular damage even at conventional therapeutic doses. We report a case of a 34-year-old man on carbamazepine for complex partial seizures who developed acute liver and renal failure on less than 2.5 grams a day of acetaminophen. This raises caution that patients on carbamazepine should avoid chronic use of acetaminophen, and if required use at lower doses with vigilant monitoring for signs of liver damage.

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

    Science.gov (United States)

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

    2014-09-01

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

  1. Acetaminophen During Pregnancy May Up Risk of ADHD in Kids

    Science.gov (United States)

    ... 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 ...

  2. Acetaminophen

    Science.gov (United States)

    ... the product. Ask your pharmacist or check the label on the package for a list of ingredients.tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, or herbal products you are taking or ...

  3. Safety of rapid intravenous of infusion acetaminophen.

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2013-06-01

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

  5. Tramadol and acetaminophen tablets for dental pain.

    OpenAIRE

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

    2001-01-01

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

  6. Study of an anaphylactoid reaction to acetaminophen.

    Science.gov (United States)

    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

  7. Acetaminophen-induced cellulitis-like fixed drug eruption

    Directory of Open Access Journals (Sweden)

    Neila Fathallah

    2011-01-01

    Full Text Available Acetaminophen is a widely used analgesic drug. Its adverse reactions are rare but severe. An 89-year-old man developed an indurated edematous and erythematous plaque on his left arm 1 day after acetaminophen ingestion. Cellulitis was suspected and antibiotictherapy was started but there was no improvement of the rash; there was a spectacular extension of the lesion with occurrence of flaccid vesicles and blisters in the affected sites. The diagnosis of generalized-bullous-fixed drug eruption induced by acetaminophen was considered especially with a reported history of a previous milder reaction occurring in the same site. Acetaminophen was withdrawn and the rash improved significantly. According to the Naranjo probability scale, the eruption experienced by the patient was probably due to acetaminophen. Clinicians should be aware of the ability of acetaminophen to induce fixed drug eruption that may clinically take several aspects and may be misdiagnosed.

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

    Science.gov (United States)

    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

  9. Acetaminophen overdose associated with double serum concentration peaks

    Directory of Open Access Journals (Sweden)

    Cristian Papazoglu

    2015-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Judge Bryan S

    2011-03-01

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

  11. N-acetylcysteine overdose after acetaminophen poisoning.

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  13. N-acetylcysteine overdose after acetaminophen poisoning

    OpenAIRE

    Mahmoudi GA; Astaraki P; Mohtashami AZ; Ahadi M

    2015-01-01

    Ghafar Ali Mahmoudi,1 Peyman Astaraki,1 Azita Zafar Mohtashami,1 Maryam Ahadi2 1Faculty of Medicine, Department of Internal Medicine, Lorestan University of Medical Sciences, 2Legal Medicine Research Center of Lorestan, Khorramabad, Iran Abstract: 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 des...

  14. N-acetylcysteine overdose after acetaminophen poisoning

    Directory of Open Access Journals (Sweden)

    Mahmoudi GA

    2015-02-01

    Full Text Available Ghafar Ali Mahmoudi,1 Peyman Astaraki,1 Azita Zafar Mohtashami,1 Maryam Ahadi2 1Faculty of Medicine, Department of Internal Medicine, Lorestan University of Medical Sciences, 2Legal Medicine Research Center of Lorestan, Khorramabad, Iran Abstract: 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. Keywords: N-acetylcysteine, overdose, acetaminophen poisoning, medication error

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

    Science.gov (United States)

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

    2012-02-01

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

  16. Pain management in emergency department: intravenous morphine vs. intravenous acetaminophen

    Directory of Open Access Journals (Sweden)

    Morteza Talebi Doluee

    2015-01-01

    Full Text Available Pain is the most common complaint in emergency department and there are several methods for its control. Among them, pharmaceutical methods are the most effective. Although intravenous morphine has been the most common choice for several years, it has some adverse effects. There are many researches about intravenous acetaminophen as an analgesic agent and it appears that it has good analgesic effects for various types of pain. We searched some electronic resources for clinical trials comparing analgesic effects of intravenous acetaminophen vs. intravenous morphine for acute pain treatment in emergency setting.In two clinical trials, the analgesic effect of intravenous acetaminophen has been compared with intravenous morphine for renal colic. The results revealed no significant difference between analgesic effects of two medications. Another clinical trial revealed that intravenous acetaminophen has acceptable analgesic effects on the post-cesarean section pain when combined with other analgesic medications. One study revealed that administration of intravenous acetaminophen compared to placebo before hysterectomy decreased consumption of morphine via patient-controlled analgesia pump and decreased the side effects. Similarly, another study revealed that the infusion of intravenous acetaminophen vs. placebo after orthopedic surgery decreased the consumption of morphine after the surgery. A clinical trial revealed intravenous acetaminophen provided a level of analgesia comparable to intravenous morphine in isolated limb trauma, while causing less side effects than morphine.It appears that intravenous acetaminophen has good analgesic effects for visceral, traumatic and postoperative pains compare with intravenous morphine.

  17. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

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

    2002-01-01

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

  18. Acetaminophen hepatotoxicity: studies on the mechanism of cysteamine protection

    Energy Technology Data Exchange (ETDEWEB)

    Miller, M.G.; Jollow, D.J.

    1986-03-30

    Inhibition of the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite was investigated as a possible mechanism for cysteamine protection against acetaminophen hepatotoxicity. Studies in isolated hamster hepatocytes indicated that cysteamine competitively inhibited the cytochrome P-450 enzyme system as represented by formation of the acetaminophen-glutathione conjugate. However, cysteamine was not a potent inhibitor of glutathione conjugate formation (Ki = 1.17 mM). Cysteamine also weakly inhibited the glucuronidation of acetaminophen (Ki = 2.44 mM). In vivo studies were in agreement with the results obtained in isolated hepatocytes; cysteamine moderately inhibited both glucuronidation and the cytochrome P-450-dependent formation of acetaminophen mercapturate. The overall elimination rate constant (beta) for acetaminophen was correspondingly decreased. Since cysteamine decreased both beta and the apparent rate constant for mercapturate formation (K'MA), the proportion of the dose of acetaminophen which is converted to the toxic metabolite (K'MA/beta) was not significantly decreased in the presence of cysteamine. Apparently, cysteamine does inhibit the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite, but this effect is not sufficient to explain antidotal protection.

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

    Science.gov (United States)

    Harris, Hope Elaine; Myers, Wade C.

    1997-01-01

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

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

    Science.gov (United States)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-15

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

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

    International Nuclear Information System (INIS)

    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.

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

    Science.gov (United States)

    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

  4. Possible fatal acetaminophen intoxication with atypical clinical presentation.

    Science.gov (United States)

    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

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

    Science.gov (United States)

    Miettinen, Teemu P; Björklund, Mikael

    2014-12-01

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

  6. Acetaminophen-induced cellulitis-like fixed drug eruption

    OpenAIRE

    Neila Fathallah; Chaker Ben Salem; Raoudha Slim; Lobna Boussofara; Najet Ghariani; Kamel Bouraoui

    2011-01-01

    Acetaminophen is a widely used analgesic drug. Its adverse reactions are rare but severe. An 89-year-old man developed an indurated edematous and erythematous plaque on his left arm 1 day after acetaminophen ingestion. Cellulitis was suspected and antibiotictherapy was started but there was no improvement of the rash; there was a spectacular extension of the lesion with occurrence of flaccid vesicles and blisters in the affected sites. The diagnosis of generalized-bullous-fixed drug eruption ...

  7. Toxic epidermal necrolysis induced by acetaminophen: a case report

    OpenAIRE

    M. C. Gupta; Niti Mittal; Nishikant Sharma

    2013-01-01

    Acetaminophen is a very commonly used analgesic and antipyretic drug across various age groups. Although mild to moderate cutaneous reactions have been reported quite frequently, serious reactions like Stevens –Johnson syndrome and Toxic epidermal necrolysis (TEN) are very rare. We report the case of a 10 year old child who had TEN after ingestion of tablet acetaminophen. This case report highlights the need to be critically aware of this rare and serious adverse effect of this commonly ...

  8. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol

    Energy Technology Data Exchange (ETDEWEB)

    Tee, L.B.; Boobis, A.R.; Huggett, A.C.; Davies, D.S.

    1986-04-01

    The toxicity of acetaminophen in freshly isolated hamster hepatocytes was investigated. Cells exposed to 2.5 mM acetaminophen for 90 min, followed by washing to completely remove unbound acetaminophen, and resuspension in fresh buffer, showed a dramatic decrease in viability over the ensuing 4.5 hr by which time only 4% of the cells could still exclude trypan blue. During the initial 90-min incubation, there was a substantial depletion of glutathione, to 19% of control values, covalent binding of (/sup 14/C)acetaminophen to cellular proteins, and evidence of morphological changes consistent with some disturbance of the plasma membrane. During subsequent incubation of these cells, covalent binding did not change nor did lipid peroxidation, despite the decrease in viability that occurred. Subsequent incubation of cells exposed to acetaminophen for 90 min in buffer containing 1.5 mM dithiothreitol (DTT), a disulfide-reducing agent, largely prevented the decrease in cell viability and reversed the morphological changes that occurred during the first 90-min incubation. However, there was no change in lipid peroxidation, glutathione content, or covalent binding. It is concluded that acetaminophen interacted with some critical target in the cell, and that this left unchecked, led eventually to the death of the cell. DTT prevented and reversed this effect. The toxicity of acetaminophen, and its reversal by DTT, appear independent of either covalent binding of acetaminophen or lipid peroxidation. In addition, the effect of DTT was independent of the concentration of glutathione, most probably acting by directly reducing oxidized SH-groups in critical enzymes, possibly membrane-bound ATP-dependent Ca2+ translocases.

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

    Science.gov (United States)

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

    2014-05-01

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

  10. Childhood suicide attempts with acetaminophen in Denmark

    DEFF Research Database (Denmark)

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

    2013-01-01

    Aims: To explore: (1) The relationship between children admitted to our paediatric department as a result of suicide attempts with acetaminophen and their parents and friends. (2) The extent to which the children had attempted to speak to their parents about their problems before their suicide...... attempts. (3) The frequency of self-mutilation among children with suicidal behaviour. (4) The purposes and reasons for childhood suicide attempts. Methods: A retrospective case-control study based on medical records and in-hospital child psychiatric assessments at the Paediatric Department, Hillerød....... There was a significant association between a dissociated parental relationship and 'the feeling of not being heard' (p = 0.004), the discovery of the suicide attempt (p = 0.008), the reasons for the suicide attempt (p = 0.006), academic school problems (p = 0.03), and the child's relationships with friends (p = 0...

  11. Acetaminophen induces apoptosis in rat cortical neurons.

    Directory of Open Access Journals (Sweden)

    Inmaculada Posadas

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

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

    Directory of Open Access Journals (Sweden)

    Ben-Shachar Rotem

    2012-12-01

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

  13. The effect of aging on acetaminophen pharmacokinetics, toxicity and Nrf2 in Fischer 344 rats.

    Science.gov (United States)

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

    2014-04-01

    We investigated the effect of aging on hepatic pharmacokinetics and the degree of hepatotoxicity following a toxic dose of acetaminophen. Young and old male Fischer 344 rats were treated with 800 mg/kg acetaminophen (young n = 8, old n = 5) or saline (young n = 9, old n = 9). Serum measurements showed old rats treated with acetaminophen had significantly lower serum alanine aminotransferase and higher acetaminophen and acetaminophen glucuronide levels and creatinine, compared with acetaminophen treated young rats (p acetaminophen had lower survival than those from old rats (52.4% ± 5.8%, young; 83.6% ± 1.7%, old, p acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age.

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

    Science.gov (United States)

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

    2014-05-01

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

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

    OpenAIRE

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

    2015-01-01

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

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

    Science.gov (United States)

    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

  17. 76 FR 2691 - Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From...

    Science.gov (United States)

    2011-01-14

    ... glutathione levels to bind to the NAPQI and prevent toxicity (Ref. 6). With higher acetaminophen levels and... acetaminophen toxicity, particularly at doses near the current recommended total daily dose of 4,000 mg per day... acetaminophen drugs (final rule, 74 FR 19385, April 29, 2009; and technical amendment, 74 FR 61512, November...

  18. Tramadol and acetaminophen tablets for dental pain.

    Science.gov (United States)

    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

  19. Testing of Candidate Icons to Identify Acetaminophen-Containing Medicines

    Directory of Open Access Journals (Sweden)

    Saul Shiffman

    2016-01-01

    Full Text Available Adding icons on labels of acetaminophen-containing medicines could help users identify the active ingredient and avoid concomitant use of multiple medicines containing acetaminophen. We evaluated five icons for communication effectiveness. Adults (n = 300 were randomized to view a prescription container label or over-the-counter labels with either one or two icons. Participants saw two icon candidates, and reported their interpretation; experts judged whether these reflected critical confusions that might cause harm. Participants rated how effectively each icon communicated key messages. Icons based on abbreviations of “acetaminophen” (“Ac”, “Ace”, “Acm” were rated less confusing and more effective in communicating the active ingredient than icons based on “APAP” or an abstract symbol. Icons did not result in critical confusion when seen on a readable medicine label. Icon implementation on prescription labels was more effective at communicating the warning against concomitant use than implementation on over-the-counter (OTC labels. Adding an icon to a second location on OTC labels did not consistently enhance this communication, but reduced rated effectiveness of acetaminophen ingredient communication among participants with limited health literacy. The abbreviation-based icons seem most suitable for labeling acetaminophen-containing medications to enable users to identify acetaminophen-containing products.

  20. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update.

    Science.gov (United States)

    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

  1. Acetylsalicylic acid and acetaminophen protect against oxidative neurotoxicity.

    Science.gov (United States)

    Maharaj, H; Maharaj, D S; Daya, S

    2006-09-01

    Due to the implication of oxidative stress in neurodegenerative disorders we decided to investigate the antioxidant properties of acetylsalicylic acid and acetaminophen either alone or in combination. The thiobarbituric acid assay (TBA) and the nitroblue tetrazolium (NBT) assay were used to investigate quinolinic acid (QA)-induced: lipid peroxidation and superoxide anion generation in the rat hippocampus, in vivo. The study also shows, using cresyl violet staining, the preservation of structural integrity of neuronal cells following treatment with acetylsalicylic acid and acetaminophen in QA-lesioned rat hippocampus. Furthermore the study sought to determine whether these agents have any effect on endogenous (QA) formation. This study shows that acetylsalicylic acid and acetaminophen inhibit QA-induced superoxide anion generation, lipid peroxidation and cell damage, in vivo, in the rat hippocampus. In addition these agents inhibit the enzyme, 3-hydroxyanthranilic acid oxygenase (3-HAO), responsible for the synthesis of endogenous QA.

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

    Science.gov (United States)

    Herndon, Christopher M; Dankenbring, Dawn M

    2014-06-01

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

  3. Toxic epidermal necrolysis induced by acetaminophen: a case report

    Directory of Open Access Journals (Sweden)

    M. C. Gupta

    2013-12-01

    Full Text Available Acetaminophen is a very commonly used analgesic and antipyretic drug across various age groups. Although mild to moderate cutaneous reactions have been reported quite frequently, serious reactions like Stevens –Johnson syndrome and Toxic epidermal necrolysis (TEN are very rare. We report the case of a 10 year old child who had TEN after ingestion of tablet acetaminophen. This case report highlights the need to be critically aware of this rare and serious adverse effect of this commonly used over the counter drug. [Int J Basic Clin Pharmacol 2013; 2(6.000: 831-832

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

    Science.gov (United States)

    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

  5. Augmentation of acetaminophen analgesia by the antihistamine phenyltoloxamine.

    Science.gov (United States)

    Sunshine, A; Zighelboim, I; De Castro, A; Sorrentino, J V; Smith, D S; Bartizek, R D; Olson, N Z

    1989-07-01

    A double-blind, placebo-controlled, parallel-group study was performed to compare the analgesic activity of the combination of 650 mg acetaminophen plus 60 mg phenyltoloxamine citrate with that of 650 mg acetaminophen alone. Two hundred female inpatients who had severe pain associated with a recent episiotomy procedure were randomly assigned to receive a single dose of one of the two active treatments or a placebo. Analgesia was assessed over a 6-hour period. Treatments were compared on the basis of standard subjective scales for pain intensity and relief, a number of derived variables based on these data and two global measures. For essentially all measures, the two active treatments were significantly superior to the placebo control. The combination was significantly superior to acetaminophen alone for all analgesic measures including SPID, TOTAL, and global ratings. The results of this study demonstrate that 60 mg phenyltoloxamine produces significant augmentation of the analgesic activity of 650 mg acetaminophen in postepisiotomy pain. PMID:2569485

  6. Effect of diethyl ether on the biliary excretion of acetaminophen.

    Science.gov (United States)

    Watkins, J B; Siegers, C P; Klaassen, C D

    1984-10-01

    The biliary and renal excretion of acetaminophen and its metabolites over 8 hr was determined in rats exposed to diethyl ether by inhalation for 1 hr. Additional rats were anesthetized with urethane (1 g/kg ip) while control animals were conscious throughout the experiment (surgery was performed under hexobarbital narcosis: 150 mg/kg ip; 30-min duration). The concentration of UDP-glucuronic acid was decreased 80% in livers from ether-anesthetized rats but was not reduced in urethane-treated animals when compared to that in control rats. The concentration of reduced glutathione was not affected by either urethane or diethyl ether. Basal bile flow was not altered by the anesthetic agents. Bile flow rate after acetaminophen injection (100 mg/kg iv) was increased slightly over basal levels for 2 hr in hexobarbital-treated control rats, was unaltered in urethane-anesthetized animals, and was decreased throughout the 8-hr experiment in rats exposed to diethyl ether for 1 hr. In control and urethane-anesthetized animals, approximately 30-35% of the total acetaminophen dose (100 mg/kg iv) was excreted into bile in 8 hr, while only 16% was excreted in rats anesthetized with diethyl ether. Urinary elimination (60-70% of the dose) was not altered by exposure to ether. Separation of metabolites by reverse-phase high-pressure liquid chromatography showed that ether decreased the biliary elimination of unchanged acetaminophen and its glucuronide, sulfate, and glutathione conjugates by 47, 40, 49, and 73%, respectively, as compared to control rats. Excretion of unchanged acetaminophen and the glutathione conjugate into bile was depressed in urethane-anesthetized animals by 45 and 66%, respectively, whereas elimination of the glucuronide and sulfate conjugates was increased by 27 and 50%, respectively. These results indicate that biliary excretion is influenced by the anesthetic agent and that diethyl ether depresses conjugation with sulfate and glutathione as well as glucuronic

  7. Gastric emptying in rats with acetaminophen-induced hepatitis

    Directory of Open Access Journals (Sweden)

    Hessel G.

    1998-01-01

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

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

    Science.gov (United States)

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

    2015-11-26

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

  9. [Acetaminophen-induced hypothermia, an AIDS related side-effect? About 4 cases].

    Science.gov (United States)

    Denes, Eric; Amaniou, Monique; Rogez, Jean-Philippe; Weinbreck, Pierre; Merle, Louis

    2002-10-01

    Hypothermia is an uncommon side effect of acetaminophen. We report 4 cases of HIV-infected patients who developed hypothermia after intravenous injection of propacetamol (the parenteral formulation of acetaminophen). The mechanism of this hypothermia is unknown. AIDS-induced changes in the metabolism of acetaminophen, could be an explanation. AIDS-associated opportunistic diseases may account for part of the mechanism. These hypothermias occur within 6 hours after the injection, are well tolerated and regress spontaneously. PMID:12486392

  10. Comparing the Efficacy of Intravenous Acetaminophen and Intravenous Meperidine in Pain Relief After Outpatient Urological Surgery

    OpenAIRE

    Kolahdouzan, Khosro; Eydi, Mahmood; Mohammadipour Anvari, Hassan; Golzari, Samad EJ; Abri, Reyhaneh; GHOJAZADEH, Morteza; Ojaghihaghighi, Seyed Hossein

    2014-01-01

    Background: Pain relief after surgery is an essential component of postoperative care. Objectives: The purpose of this study was to compare the efficacy of intravenous acetaminophen and intravenous meperidine in pain relief after outpatient urological surgery. Patients and Methods: In a prospective, randomized, double-blind clinical trial, 100 outpatients of urological surgery were studied in two groups of acetaminophen (A) and meperidine (M). Patients in group A received 1g of acetaminophen ...

  11. Sleep Disruption and Proprioceptive Delirium due to Acetaminophen in a Pediatric Patient

    OpenAIRE

    Carla Carnovale; Marco Pozzi; Andrea Angelo Nisic; Elisa Scrofani; Valentina Perrone; Stefania Antoniazzi; Emilio Clementi; Sonia Radice

    2013-01-01

    We present the case of a 7-year-old boy, who received acetaminophen for the treatment of hyperpyrexia, due to an infection of the superior airways. 13 mg/kg (260 mg) of acetaminophen was administered orally before bedtime, and together with the expected antipyretic effect, the boy experienced sleep disruption and proprioceptive delirium. The symptoms disappeared within one hour. In the following six months, acetaminophen was administered again twice, and the reaction reappeared with similar f...

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

    Science.gov (United States)

    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 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

  13. The effect of acetaminophen administration on its disposition and body stores of sulphate.

    Science.gov (United States)

    Hendrix-Treacy, S; Wallace, S M; Hindmarsh, K W; Wyant, G M; Danilkewich, A

    1986-01-01

    This investigation was designed to investigate the effects of ingestion of multiple therapeutic doses of acetaminophen on the disposition of the drug and on the cosubstrate, sulfate. Nine healthy volunteers and nine outpatients receiving acetaminophen for chronic pain were involved in the study. Volunteers were given a single 650 mg oral dose of acetaminophen. One week later they were given 650 mg of acetaminophen every six hours for five doses. Patients were maintained on their normal treatment and dosage schedules (600 mg every 3 to 8 h) for the study. In healthy volunteers the half-life of acetaminophen after single and multiple dosing was not significantly different. However, the fraction of acetaminophen recovered in the urine as the sulfate conjugate was less and the glucuronide conjugate greater after multiple dosing than after a single of the drug. There was no difference in the percentage recovered as the parent compound between single and multiple dosing. Serum sulfate levels fluctuated over the 6-h period following administration of single and multiple doses of acetaminophen to volunteers. The mean serum sulfate concentration was less after administration of five sequential 650 mg doses of acetaminophen than after a single dose. The renal clearance of inorganic sulfate showed a corresponding decrease. Unexpectedly, patients on chronic acetaminophen therapy exhibited elevated serum sulfate levels (levels higher than the maximum sulfate concentration seen in volunteers). PMID:3732362

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    International Nuclear Information System (INIS)

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

  17. FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF ACETAMINOPHEN

    Directory of Open Access Journals (Sweden)

    Abhay Kumar Mourya et al.

    2012-02-01

    Full Text Available The present research work has been carried out for an optimized formulation of co-processed directly compressible vehicles in the preparation of the Acetaminophen mouth fast dissolving tablets (MFDTs. Acetaminophen was chosen due to its poor compression properties. Di-calcium Phosphate(DCP was incorporated in the neutralized aqueous starch dispersion to prepare co-processed excipient. Co-processed direct compressible DCP and Starch used as co-processed excipient were taken in good formulation ratio such as (25:75 and Cross Povidone used as superdisintegrant. The effects of other superdisintegrants were studied in the best formulation F5. Formulation F5 was found to be optimum compressibility characteristics hardness 3.62±0.40 to 4.68±0.31 kg/cm2 with fast disintegration (10 sec compare to other formulations.

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

    Science.gov (United States)

    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

  19. Toxic epidermal necrolysis caused by acetaminophen featuring almost 100% skin detachment: Acetaminophen is associated with a risk of severe cutaneous adverse reactions.

    Science.gov (United States)

    Watanabe, Hideaki; Kamiyama, Taisuke; Sasaki, Shun; Kobayashi, Kae; Fukuda, Kenichiro; Miyake, Yasufumi; Aruga, Tohru; Sueki, Hirohiko

    2016-03-01

    Toxic epidermal necrolysis (TEN) is an adverse reaction that can be induced by various drugs; the associated mortality rate is 20-25%. A previous report showed a weak association between TEN and acetaminophen. Recently, the US Food and Drug Administration declared that acetaminophen is associated with a risk of serious skin reactions, including TEN. Here, we describe the case of a 43-year-old Japanese woman with TEN caused by acetaminophen. She had poorly controlled ulcerative colitis and was treated with high doses of prednisolone, infliximab, acetaminophen and lansoprazole. Nine days after administrating acetaminophen, targetoid erythematous and bullous lesions appeared on the patient's trunk, palms and the soles of her feet. The skin lesions expanded rapidly; within 3 weeks, skin detachment was detected across nearly 100% of the patient's body. However, no mucosal involvement of the eyes, oral cavity or genitalia was found. We performed lymphocyte transformation tests using various drugs; however, a high stimulation index was obtained only with acetaminophen. The patient recovered following treatment with plasmapheresis, i.v. immunoglobulin therapy, topical medication and supportive therapy. Acetaminophen is included in many prescription and over-the-counter products; thus, clinicians should monitor their patients for severe drug reactions, including TEN. PMID:26362011

  20. Efficacy of Intravenous Acetaminophen after Coronary Artery Bypass Graft Surgery

    OpenAIRE

    Leick AM; Ratliff PD; Shely RN; Lester WC; Short MR

    2015-01-01

    In recent years, a multimodal approach to post-operative pain control consisting of opioid and non-opioid agents administered simultaneously has been used to provide synergistic effects and reduce opioid-related adverse effects. This is a retrospective, cohort study involving coronary artery bypass graft surgery patients who received scheduled intravenous IV acetaminophen 1gm every 6 hours for 4 doses starting at surgery end time with opioids administered as needed versus opioids as monother...

  1. Post hemorrhoidectomy pain control: rectal Diclofenac versus Acetaminophen

    OpenAIRE

    Rahimi M; Makarem J; Maktobi M

    2009-01-01

    "nBackground: Anal surgeries are prevalent, but they didn't perform as outpatient surgeries because of concerns about postoperative pain. The aim of the present study was to compare the effects of rectal acetaminophen and diclofenac on postoperative analgesia after anal surgeries in adult patients. "nMethods: In a randomized, double-blinded, placebo-controlled study 60 ASA class I or II scheduled for haemorrhoidectomy, anal fissure or fistula repair, were randomized (with block...

  2. Post hemorrhoidectomy pain control: rectal Diclofenac versus Acetaminophen

    Directory of Open Access Journals (Sweden)

    Rahimi M

    2009-03-01

    Full Text Available "nBackground: Anal surgeries are prevalent, but they didn't perform as outpatient surgeries because of concerns about postoperative pain. The aim of the present study was to compare the effects of rectal acetaminophen and diclofenac on postoperative analgesia after anal surgeries in adult patients. "nMethods: In a randomized, double-blinded, placebo-controlled study 60 ASA class I or II scheduled for haemorrhoidectomy, anal fissure or fistula repair, were randomized (with block randomization method to receive either a single dose of 650 mg rectal acetaminophen (n=20, 100 mg rectal diclofenac (n=20 or placebo suppositories (n=20 after the operation. The severity of pain, time to first request of analgesic agent after administration of suppositories and complications were compared between three groups. Pain scores were evaluated in patients by Visual Analogue Scale (VAS in 0 (after complete consciousness in recovery, 2, 4, 12 and 24 hours after surgery. The period between administration of the suppositories and the patients' first request to receive analgesic was compared between groups. "nResults: Pain scores were lower significantly in rectal diclofenac than the other groups. The period between administration of the suppositories and the patients' first request to receive analgesic in diclofenac group was 219±73 minutes, was significantly longer compared with placebo (153±47 minutes and acetaminophen (178±64 minutes groups. No complications were reported. "nConclusions: Diclofenac suppository is more effective than acetaminophen suppository in post hemorrhoidectomy pain management.

  3. Efficacy of Intravenous Acetaminophen after Coronary Artery Bypass Graft Surgery

    Directory of Open Access Journals (Sweden)

    Leick AM

    2015-12-01

    Full Text Available In recent years, a multimodal approach to post-operative pain control consisting of opioid and non-opioid agents administered simultaneously has been used to provide synergistic effects and reduce opioid-related adverse effects. This is a retrospective, cohort study involving coronary artery bypass graft surgery patients who received scheduled intravenous IV acetaminophen 1gm every 6 hours for 4 doses starting at surgery end time with opioids administered as needed versus opioids as monotherapy for postoperative pain control. The primary endpoint assessed was total morphine equivalents administered post-operatively in each group with a secondary focus on degree of pain control, total length of stay, ICU length of stay, and time to first bowel movement. The study concludes that the addition of IV acetaminophen to opioids for postoperative pain relief did not produce an opioid sparing effect and paradoxically led to an increase in opioid use. Clinical outcomes including pain control, total length of stay, and ICU length of stay were unaffected by the addition of IV acetaminophen.

  4. Acute interstitial nephritis with acetaminophen and alcohol intoxication

    Directory of Open Access Journals (Sweden)

    Alexopoulou Iakovina

    2011-04-01

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

  5. Acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    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.

  6. Validity of a two-point acetaminophen pharmacokinetic study.

    Science.gov (United States)

    Scavone, J M; Greenblatt, D J; Blyden, G T; Luna, B G; Harmatz, J S

    1990-01-01

    The pharmacokinetics of a single 650-mg intravenous dose of acetaminophen were determined in 82 volunteers using multiple (13 or more) plasma acetaminophen concentrations measured by high pressure liquid chromatography during 24 h after dosage. Kinetic values from the complete study were compared with kinetic estimates based on only two data points: (a) the 2- and 6-h points only; and (b) the 3 and 6-h points only. For elimination half-life, values from the complete study (mean 2.42 h) were highly correlated (r = 0.87 and 0.84) with methods a and b (means 2.41 and 2.43 h), with regression slopes of 1.00 and 0.99, respectively. For clearance, the complete study values (mean 312 ml/min) were highly correlated (r = 0.97 and 0.97) with method a and b values, but both two-point methods significantly overestimated clearance (means 350 and 355 ml/min) by an average of 13 and 14%, respectively. Results for volume of distribution were similar to those for clearance. Although acetaminophen elimination half-life can be estimated with reasonable precision using a two-point blood-sampling procedure, clearance and volume of distribution values using the two-point method overestimate the actual values. PMID:2305419

  7. Fennel and raspberry leaf as possible inhibitors of acetaminophen oxidation.

    Science.gov (United States)

    Langhammer, Astrid Jordet; Nilsen, Odd Georg

    2014-10-01

    In addition to CYP2E1, several CYP isoenzymes, notably CYP1A2, 2D6, and 3A4, are suggested to contribute in acetaminophen oxidation and formation of the hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). The in vitro CYP2E1 inhibitory potentials of fennel and raspberry leaf, herbs previously found to inhibit CYP1A2, 2D6, and 3A4 activities in vitro, were investigated. Extracts from commercially available herbal products were incubated with recombinant cDNA-expressed human CYP2E1. A validated LC/MS/MS methodology was applied for determination of 6-hydroxychlorzoxazone formation with disulfiram used as a positive inhibitory control. CYP2E1 IC50 inhibition constants were found to be 23 ± 4 and 27 ± 5 µg/ml for fennel and raspberry leaf, respectively, constants significantly lower than those presented in the literature for other herbal extracts. Together with previous findings, the presented in vitro data for CYP2E1 inhibition suggest that fennel and raspberry leaf have a significant potential of inhibiting all the major metabolic pathways for acetaminophen oxidation and NAPQI formation. Both herbs should be further investigated for their in vivo ability of inhibiting acetaminophen oxidation and NAPQI formation.

  8. Developmental exposure to acetaminophen does not induce hyperactivity in zebrafish larvae.

    Science.gov (United States)

    Reuter, Isabel; Knaup, Sabine; Romanos, Marcel; Lesch, Klaus-Peter; Drepper, Carsten; Lillesaar, Christina

    2016-08-01

    First line pain relief medication during pregnancy relies nearly entirely on the over-the-counter analgesic acetaminophen, which is generally considered safe to use during gestation. However, recent epidemiological studies suggest a risk of developing attention-deficit/hyperactivity disorder (ADHD)-like symptoms in children if mothers use acetaminophen during pregnancy. Currently, there are no experimental proofs that prenatal acetaminophen exposure causes developmental brain alterations of progeny. Exposure to high acetaminophen concentrations causes liver toxicity, which is well investigated in different model organisms. However, sub-liver-toxic concentrations have not been experimentally investigated with respect to ADHD endophenotypes such as hyperactivity. We used zebrafish to investigate the potential impact of acetaminophen exposure on locomotor activity levels, and compared it to the established zebrafish Latrophilin 3 (Lphn3) ADHD-model. We determined the sub-liver-toxic concentration of acetaminophen in zebrafish larvae and treated wild-type and lphn3.1 knockdown larvae with increasing concentrations of acetaminophen. We were able to confirm that lphn3.1 knockdown alone causes hyperactivity, strengthening the implication of Lphn3 dysfunction as an ADHD risk factor. Neither acute nor chronic exposure to acetaminophen at sub-liver-toxic concentrations in wild-type or lphn3.1 knock-downs increases locomotor activity levels. Together our findings show that embryonic to larval exposure to acetaminophen does not cause hyperactivity in zebrafish larvae. Furthermore, there are no additive and/or synergistic effects of acetaminophen exposure in a susceptible background induced by knock-down of lphn3.1. Our experimental study suggests that there is, at least in zebrafish larvae, no direct link between embryonic acetaminophen exposure and hyperactivity. Further work is necessary to clarify this issue in humans. PMID:27116683

  9. The potential interaction between oral anticoagulants and acetaminophen in everyday practice

    NARCIS (Netherlands)

    van den Bemt, PMLA; Geven, LM; Kuitert, NA; Risselada, A; Brouwers, JRBJ

    2002-01-01

    Objective: The drug-drug interaction between oral anticoagulants (especially warfarin) and acetaminophen has been described, but evidence is conflicting and evidence for a similar interaction between acenocoumarol or phenprocoumon and acetaminophen is limited. Therefore, a study was performed to det

  10. [Impact factors and degradation mechanism for the ozonation of acetaminophen in aqueous solution].

    Science.gov (United States)

    Cao, Fei; Yuan, Shou-Jun; Zhang, Meng-Tao; Wang, Wei; Hu, Zhen-Hu

    2014-11-01

    The effect and mechanism of O3 on the degradation of acetaminophen in aqueous solution were studied by the batch experiment. The results showed that acetaminophen could be degraded effectively by ozone and degradation of acetaminophen fitted well with the pseudo-first-order kinetics model (R2 > 0.992). The degradation of acetaminophen was promoted with the increase of pH, the concentration of bicarbonate and ozone. The results of gas chromatography-mass spectrometry (GC-MS) and ion chromatography analysis showed that degradation products such as hydroquinone and a series of carboxylic acids were firstly formed during ozonation of acetaminophen. Then, the products were further oxidized. The degradation pathways of acetaminophen were also discussed by the identified products. The result of TOC showed that the mineralization of acetaminophen was ultimately lower. When the initial concentration of acetaminophen was 20 mg x L(-1) and the concentration of ozone was 9.10 mg x L(-1), the mineralization was only 16.42% after 130 min.

  11. Fetal growth and adverse birth outcomes in women receiving prescriptions for acetaminophen during pregnancy

    DEFF Research Database (Denmark)

    Thulstrup, Ane Marie; Sørensen, Henrik Toft; Nielsen, Gunnar Lauge;

    1999-01-01

    We studied the association between acetaminophen exposure during pregnancy and the prevalence of congenital abnormalities and fetal growth. Our study included 123 women who had received a prescription of acetaminophen during pregnancy and/or 30 days before conception and 13,329 controls who did n...

  12. Postoperative pain relief with pentazocine and acetaminophen: comparison with other analgesic combinations and placebo.

    Science.gov (United States)

    Petti, A

    1985-01-01

    A single-blind, parallel-group study was carried out to evaluate the efficacy and safety of an analgesic combining 650 mg of acetaminophen and 25 mg of pentazocine in 129 patients with moderate postoperative pain. Comparisons were made with a combination containing acetaminophen (300 mg) and codeine (30 mg), a combination containing acetaminophen (650 mg) and propoxyphene napsylate (100 mg), and a placebo. A nurse observer queried patients at regular intervals over a six-hour period concerning the intensity of pain and the degree of pain relief. The scores obtained were used in the calculation of standard measures of analgesic efficacy. Acetaminophen/pentazocine proved to be significantly superior to placebo and equivalent to the other active analgesic combinations. No side effects were reported with acetaminophen/pentazocine, acetaminophen/propoxyphene napsylate, or placebo. One mild side effect was questionably associated with acetaminophen/codeine. This study demonstrates that the combination of acetaminophen and pentazocine is as safe and effective in controlling postoperative pain of moderate severity as other commonly used analgesics. PMID:2870808

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  15. Fulminate Hepatic Failure in a 5 Year Old Female after Inappropriate Acetaminophen Treatment

    Directory of Open Access Journals (Sweden)

    Irena Kasmi

    2015-09-01

    CONCLUSION: Healthcare providers should considered probable acetaminophen toxicity in any child who has received the drug and presented with liver failure. When there is a high index of suspicion of acetaminophen toxicity NAC should be initiated and continued until there are no signs of hepatic dysfunction.

  16. Bromfenac sodium, acetaminophen/oxycodone, ibuprofen, and placebo for relief of postoperative pain.

    Science.gov (United States)

    Johnson, G H; Van Wagoner, J D; Brown, J; Cooper, S A

    1997-01-01

    The objective of this double-masked, parallel-group, multicenter, inpatient study was to compare bromfenac with an acetaminophen/oxycodone combination and ibuprofen in patients who had pain due to abdominal gynecologic surgery. In the 8-hour, single-dose phase, 238 patients received single oral doses of bromfenac (50 or 100 mg), acetaminophen 650 mg/oxycodone 10 mg, ibuprofen 400 mg, or placebo. In the multiple-dose phase, 204 patients received bromfenac, acetaminophen/oxycodone, or ibuprofen for up to 5 days. In the single-dose phase, both bromfenac doses produced peak analgesic responses equivalent to acetaminophen/oxycodone, but the responses to bromfenac were longer lasting. Bromfenac produced significantly better overall (8-hour) analgesic summed scores than acetaminophen/oxycodone. Ibuprofen was less efficacious than the other analgesics. The remedication rate was lower in both bromfenac groups than in the other treatment groups. The acetaminophen/oxycodone group reported more somnolence and vomiting. Single doses of bromfenac provided analgesia at least equivalent to that of the acetaminophen/oxycodone combination, with a longer duration of action. Both doses of bromfenac and acetaminophen/oxycodone were superior to ibuprofen in this study. PMID:9220215

  17. Impact of Intraoperative Acetaminophen Administration on Postoperative Opioid Consumption in Patients Undergoing Hip or Knee Replacement

    Science.gov (United States)

    Vaughan, Cathy; McGee, Ann

    2014-01-01

    Abstract Background: Opioid utilization for acute pain has been associated with numerous adverse events, potentially resulting in longer inpatient stays and increased costs. Objective: To examine the effect of intravenous (IV) acetaminophen administered intraoperatively on postoperative opioid consumption in adult subjects who underwent hip or knee replacement. Methods: This retrospective cohort study evaluated postoperative opioid consumption in 176 randomly selected adult subjects who underwent hip or knee replacement at Duke University Hospital (DUH). Eighty-eight subjects received a single, intraoperative, 1 g dose of IV acetaminophen. The other subjects did not receive any IV acetaminophen. This study evaluated mean opioid consumption (in oral morphine equivalents) during the 24-hour postoperative period in the 2 groups. Other endpoints included length of stay in the postanesthesia care unit (PACU), incidence of oversedation, need for acute opioid reversal, and adjunctive analgesic utilization. Results: Subjects who were given a single dose of intraoperative acetaminophen received an average of 149.3 mg of oral morphine equivalents during the 24 hours following surgery compared to 147.2 mg in participants who were not exposed to IV acetaminophen (P = .904). The difference in average length of PACU stay between the IV acetaminophen group (163 minutes) and those subjects not exposed to IV acetaminophen (169 minutes) was not statistically significant (P = .588). No subjects in the study experienced oversedation or required acute opioid reversal. Conclusion: There was not a statistically significant difference in postoperative opioid consumption between patients receiving and not receiving IV acetaminophen intraoperatively. PMID:25673891

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

    Science.gov (United States)

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

    2011-05-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-15

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

  20. Association of prenatal exposure to acetaminophen and coffee with childhood asthma

    DEFF Research Database (Denmark)

    Liu, Xiaoqin; Liew, Zeyan; Olsen, Jørn;

    2016-01-01

    PurposeSome studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma......, and whether such a potential association could be modified by maternal coffee consumption. MethodsWe included 63 652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire...... and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards...

  1. Analgesic effect of acetaminophen, phenyltoloxamine and their combination in postoperative oral surgery pain.

    Science.gov (United States)

    Forbes, J A; Barkaszi, B A; Ragland, R N; Hankle, J J

    1984-01-01

    In this factorial study, 148 outpatients with pain after oral surgery were randomly assigned, on a double-blind basis, a single oral dose of acetaminophen 650 mg, phenyltoloxamine 60 mg, a combination of acetaminophen 650 mg with phenyltoloxamine 60 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 6 hours after medication. Measures of total and peak analgesia were derived from these subjective reports. The acetaminophen effect was significant for every measure of total and peak analgesia. The phenyltoloxamine effect was not significant for any measure of analgesia. Although efficacy was lower for the acetaminophen-phenyltoloxamine combination than for acetaminophen alone, for every variable, the contrast for interaction was not statistically significant. The results of this study differ from those of previous studies in patients with headache and musculoskeletal pain. All adverse effects were transitory and consistent with the known pharmacologic profiles of the study medications or the backup analgesic. PMID:6483639

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

    Directory of Open Access Journals (Sweden)

    Josh eFoster

    2016-03-01

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

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

    Science.gov (United States)

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

    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. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

    Science.gov (United States)

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  5. Implications of Sensorineural Hearing Loss With Hydrocodone/Acetaminophen Abuse.

    Science.gov (United States)

    Novac, Andrei; Iosif, Anamaria M; Groysman, Regina; Bota, Robert G

    2015-01-01

    Sensorineural hearing loss is an infrequently recognized side effect of pain medication abuse. Chronic pain patients treated with opiates develop different degrees of tolerance to pain medications. In many cases, the tolerance becomes the gateway to a variety of cycles of overuse and unmasking of significant psychiatric morbidity and mortality. An individualized approach utilizing combined treatment modalities (including nonopiate pharmaceuticals) is expected to become the norm. Patients can now be provided with multidisciplinary care that addresses an individual's psychiatric, social, and medical needs, which requires close cooperation between physicians of varying specialties. This report describes a patient who experienced hearing loss from hydrocodone/acetaminophen abuse. PMID:26835162

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

    Science.gov (United States)

    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.

  7. Activation of LXR Increases Acetaminophen Clearance and Prevents Its Toxicity

    OpenAIRE

    Saini, Simrat P. S.; Zhang, Bin; Niu, Yongdong; Jiang, Mengxi; Gao, Jie; Zhai, Yonggong; Lee, Jung Hoon; Uppal, Hirdesh; Tian, Hui; Tortorici, Michael A.; Poloyac, Samuel M.; Qin, Wenxin; Venkataramanan, Raman; Xie, Wen

    2011-01-01

    Overdose of acetaminophen (APAP), the active ingredient of Tylenol, is the leading cause of drug-induced acute liver failure in the US. As such, it is necessary to develop novel strategies to prevent or manage APAP toxicity. In this report, we revealed a novel function of the liver X receptor (LXR) in preventing APAP-induced hepatotoxicity. Activation of LXR in transgenic mice or by an LXR agonist conferred resistance to the hepatotoxicity of APAP, whereas the effect of LXR agonist on APAP to...

  8. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years.

    Directory of Open Access Journals (Sweden)

    John M D Thompson

    Full Text Available OBJECTIVE: Our aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children. METHODS: Participants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress. RESULTS: Acetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11 if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners' Parent Rating Scale-Revised. CONCLUSIONS: These findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen.

  9. Pharmacist and Physician Interpretation of Abbreviations for Acetaminophen Intended for Use in a Consumer Icon

    Directory of Open Access Journals (Sweden)

    Saul Shiffman

    2015-10-01

    Full Text Available Concomitant use of multiple acetaminophen medications is associated with overdose. To help patients identify acetaminophen medications and thus avoid concomitant use, an icon with an abbreviation for “acetaminophen” has been proposed for all acetaminophen medications. This study assessed pharmacists’ and physicians’ use and interpretation of abbreviations for “acetaminophen”, to identify abbreviations with other meanings that might cause confusion. Physicians (n = 150 reported use and interpretation of candidate abbreviations Ac and Acm. Pharmacists (n = 150 interpretations of prescription orders using the candidate abbreviations APAP, Ac, Ace and Acm in typed, handwritten or spoken form, were judged for critical confusions likely to cause patient harm. Critical confusion was rare, except for omission by pharmacists of the acetaminophen dose for Hydrocodone/APAP prescriptions (10%. Ac was in common use to indicate “before meals”, and was interpreted as such, but some physicians (8% said they use Ac to indicate anticoagulant drugs. Most pharmacists (54% interpreted Ace as acetaminophen, and none interpreted it as referring to ACE-inhibitors. Acm was rarely used in prescriptions, had no common interfering meanings, and was often (63% interpreted as acetaminophen, especially when prescribed in combination with an opiate (85%. The data validated concerns about abbreviations in prescribing: all abbreviations resulted in some misinterpretations. However, Acm was rarely misinterpreted, was readily associated with “acetaminophen”, and seemed appropriate for use in a graphic icon to help consumers/patients identify acetaminophen medications.

  10. Prophylactic and Therapeutic Potential of Acetyl-L-carnitine against Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Alotaibi, Salman A; Alanazi, Abdulrazaq; Bakheet, Saleh A; Alharbi, Naif O; Nagi, Mahmoud N

    2016-01-01

    Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen-induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N-acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N-acetylcystiene in the treatment of acetaminophen toxicity.

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

    Directory of Open Access Journals (Sweden)

    Esmaeil Biazar

    2010-03-01

    Full Text Available Esmaeil Biazar1, S Mahdi Rezayat2, Naser Montazeri1, Khalil Pourshamsian1, Reza Zeinali3, Azadeh Asefnejad3, Mehdi Rahimi3, Mohammadmajid Zadehzare3, Mehran Mahmoudi3, Rohollah Mazinani3, Mehdi Ziaei31Department of Chemistry, Islamic Azad University, Tonekabon Branch, Mazandaran, Iran; 2Department of Pharmacology, School of Medicine, Tehran University of Medical Science, Tehran, Iran; 3Biomedical Engineering, Islamic Azad University, Research and Science Branch, Tehran, IranAbstract: Acetaminophen, a pain-reliever, is one of the most widely used medications in the world. Acetaminophen with normal dosage is considered a nontoxic drug for therapeutic applications, but when taken at overdose levels it produces liver damage in human and various animal species. By a high energy mechanically activated method, we produced acetaminophen in a nanometer crystalline size (24 nm. Forty-eight hours after injection of crystalline particles with normal and reduced size of our drug, the effect of liver toxicity was compared by determination of liver transferase enzymes such as alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase (ALT. These enzymes were examined by routine colorimetric methods using commercial kits and pathologic investigations. Statistical analysis and pathological figures indicated that ALT delivery and toxicity in reduced size acetaminophen was significantly reduced when compared with normal size acetaminophen. Pathology figures exhibited reduced necrosis effects, especially the confluent necrosis, in the central part of the lobule in the reduced size acetaminophen samples when compared with the normal samples.Keywords: acetaminophen, size reduction, pathological and enzymatic investigations, toxicity

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

    Science.gov (United States)

    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

  13. Plasma concentrations after high-dose (45 mg.kg-1) rectal acetaminophen in children.

    Science.gov (United States)

    Montgomery, C J; McCormack, J P; Reichert, C C; Marsland, C P

    1995-11-01

    Although the recommended dose of rectal acetaminophen (25-30 mg.kg-1) is twice that for oral administration (10-15 mg.kg-1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route. We measured venous plasma acetaminophen concentrations resulting from 45 mg.kg-1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined using a TDxFLx fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 +/- 39 mumol.L-1 (13 +/- 6 micrograms.ml-1) and the time of peak plasma concentration was 198 +/- 70 min (mean +/- SD). At 420 min, the mean plasma concentration was 46 +/- 18 mumol.L-1 (7.0 +/- 0.9 micrograms.ml-1). No plasma concentrations associated with toxicity (> 800 mumol.L-1) were identified. A 45 mg.kg-1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10-15 mg.kg-1 of oral acetaminophen at three hours after suppository insertion. It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children. PMID:8590508

  14. Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis Associated with Acetaminophen Use during Viral Infections

    Science.gov (United States)

    Ban, Ga-Young; Ahn, Seun-Joo; Yoo, Hye-Soo; Park, Hae-Sim

    2016-01-01

    An association between drug treatment for viral infections and severe cutaneous adverse reactions has been noted. We investigated six patients diagnosed with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) after being prescribed acetaminophen for suspected viral illnesses. Multiplex analysis was performed to measure cytokine levels in sera before and after treatment. IL-2Rα levels significantly decreased during the convalescence phase. Although acetaminophen is relatively safe, the drug can trigger SJS/TEN in patients with suspected viral infections. T-cells and monocytes may be key components of the link between viral infection and acetaminophen-induced SJS/TEN. PMID:27574505

  15. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated with Acetaminophen Use during Viral Infections.

    Science.gov (United States)

    Ban, Ga-Young; Ahn, Seun-Joo; Yoo, Hye-Soo; Park, Hae-Sim; Ye, Young-Min

    2016-08-01

    An association between drug treatment for viral infections and severe cutaneous adverse reactions has been noted. We investigated six patients diagnosed with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) after being prescribed acetaminophen for suspected viral illnesses. Multiplex analysis was performed to measure cytokine levels in sera before and after treatment. IL-2Rα levels significantly decreased during the convalescence phase. Although acetaminophen is relatively safe, the drug can trigger SJS/TEN in patients with suspected viral infections. T-cells and monocytes may be key components of the link between viral infection and acetaminophen-induced SJS/TEN. PMID:27574505

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

    Science.gov (United States)

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

    2015-01-29

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

  17. Formulation and Characterization of Acetaminophen Nanoparticles in Orally Disintegrating Films

    Science.gov (United States)

    AI-Nemrawi, Nusaiba K.

    The purpose of this study is to prepare acetaminophen loaded nanoparticles to be cast directly, while still in the emulsion form, into Orally Disintegrating Films (ODF). By casting the nanoparticles in the films, we expected to keep the particles in a stable form where the nanoparticles would be away from each other to prevent their aggregation. Once the films are applied on the buccal mucosa, they are supposed to dissolve within seconds, releasing the nanoparticles. Then the nanoparticles could be directly absorbed through the mucosa to the blood stream and deliver acetaminophen there. The oral cavity mucosa is one of the most attractive sites for systemic drug delivery due to its high permeability and blood supply. Furthermore, it is robust and shows short recovery times after stress or damage, and the drug bypasses first pass effect and avoids presystemic elimination in the GI tract. Nanoencapsulation increases drug efficacy, specificity, tolerability and therapeutic index. These Nanocapsules have several advantages in the protection of premature degradation and interaction with the biological environment, enhancement of absorption into a selected tissue, bioavailability, retention time and improvement of intracellular penetration. The most important characteristics of nanoparticles are their size, encapsulation efficiency (EE), zeta potential (surface charge), and the drug release profiles. Unfortunately, nanoparticles tend to precipitate or aggregate into larger particles within a short time after preparation or during storage. Some solutions for this problem were mentioned in literature including lyophilization and spray drying. These methods are usually expensive and give partial solutions that might have secondary problems; such as low re-dispersion efficacy of the lyophilized NPs. Furthermore, most of the formulations of NPs are invasive or topical. Few formulas are available to be given orally. Fast disintegrating films (ODFs) are rapidly gaining interest

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

    Science.gov (United States)

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

    2016-12-01

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

  19. Sleep Disruption and Proprioceptive Delirium due to Acetaminophen in a Pediatric Patient

    Directory of Open Access Journals (Sweden)

    Carla Carnovale

    2013-01-01

    Full Text Available We present the case of a 7-year-old boy, who received acetaminophen for the treatment of hyperpyrexia, due to an infection of the superior airways. 13 mg/kg (260 mg of acetaminophen was administered orally before bedtime, and together with the expected antipyretic effect, the boy experienced sleep disruption and proprioceptive delirium. The symptoms disappeared within one hour. In the following six months, acetaminophen was administered again twice, and the reaction reappeared with similar features. Potential alternative explanations were excluded, and analysis with the Naranjo algorithm indicated a “probable” relationship between acetaminophen and this adverse reaction. We discuss the potential mechanisms involved, comprising imbalances in prostaglandin levels, alterations of dopamine, and cannabinoid and serotonin signalings.

  20. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood

    DEFF Research Database (Denmark)

    Liew, Zeyan; Ritz, Beate; Virk, Jasveer;

    2015-01-01

    Acetaminophen (paracetamol) is the most commonly used pain and fever medication during pregnancy. Previously, a positive ecological correlation between acetaminophen use and autism spectrum disorders (ASD) has been reported but evidence from larger studies based on prospective data is lacking. We...... followed 64,322 children and mothers enrolled in the Danish National Birth Cohort (DNBC; 1996-2002) for average 12.7 years to investigate whether acetaminophen use in pregnancy is associated with increased risk of ASD in the offspring. Information on acetaminophen use was collected prospectively from three...... computer-assisted telephone interviews. We used records from the Danish hospital and psychiatric registries to identify diagnoses of ASD. At the end of follow up, 1,027 (1.6%) children were diagnosed with ASD, 345 (0.5%) with infantile autism. We found that 31% of ASD (26% of infantile autism) have also...

  1. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    Directory of Open Access Journals (Sweden)

    Maria Goretti R. Queiroz

    2008-10-01

    Full Text Available Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae leaf essential oil (EOCz was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o. acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT, serum glutamate oxaloacetate transaminase (GOT activities, that were significantly (p<0.01 elevated in the acetaminophen alone treated animals. Histopathological examinations of liver tissue corroborated well with the biochemical changes. Hepatic steatosis, hydropic degeneration and necrosis were observed in the acetaminophen treated group, while these were completely absent in the standard and EOCz treated groups. In conclusion, these data suggest that the Croton zehntneri essential oil can prevent hepatic injuries from acetaminophen-induced hepatotoxicity in mice.

  2. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

    DEFF Research Database (Denmark)

    van den Driesche, Sander; Macdonald, Joni; Anderson, Richard A;

    2015-01-01

    Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons...

  3. Effects of prednisone, aspirin, and acetaminophen on an in vivo biologic response to interferon in humans.

    Science.gov (United States)

    Witter, F R; Woods, A S; Griffin, M D; Smith, C R; Nadler, P; Lietman, P S

    1988-08-01

    In healthy volunteers receiving a single intramuscular dose of 18 X 10(6) U interferon alone or after 24 hours of an 8-day course of prednisone (40 mg/day), aspirin (650 mg every 4 hours), or acetaminophen (650 mg every 4 hours), the magnitude of the biologic response to interferon was quantified by measuring the time course of the induction of 2'-5'-oligoadenylate synthetase and resistance to vesicular stomatitis virus infection in human peripheral blood mononuclear cells. Prednisone decreased the AUC of 2'-5'-oligoadenylate synthetase activity (p less than 0.05), whereas administration of aspirin or acetaminophen did not affect this biologic response. No measurable effect was seen during administration of prednisone, aspirin, or acetaminophen on the duration or intensity of vesicular stomatitis virus yield reduction. The side effects seen with interferon administration at the dose tested were not altered in a clinically meaningful manner by prednisone, aspirin, or acetaminophen. PMID:2456175

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  5. Acetaminophen Use: An Unusual Cause of Drug-Induced Pulmonary Eosinophilia.

    Science.gov (United States)

    Saint-Pierre, Mathieu D; Moran-Mendoza, Onofre

    2016-01-01

    Pulmonary eosinophilia (PE) can be found in very diverse pathological processes. Several medications have also been associated with this entity. Acetaminophen is a medication commonly used in multiple different drug formulations, many of which are available without a prescription. It has however been associated with pulmonary eosinophilia (eosinophilic pneumonia) in a few cases in Japan. We describe the case of a 68-year-old Caucasian female who presented with new persistent dry cough and dyspnea on exertion after she started using up to 4 grams of acetaminophen on a daily basis. Chest imaging revealed peripheral lower lung zone ground glass and reticular opacities, and increased eosinophils were present on bronchoalveolar lavage (BAL). The patient's symptoms markedly improved upon acetaminophen cessation, and significantly decreased eosinophils were seen on repeat BAL. To our knowledge, this is the first case of likely acetaminophen-induced pulmonary eosinophilia reported outside Japan. PMID:27445539

  6. Sleep Disruption and Proprioceptive Delirium due to Acetaminophen in a Pediatric Patient

    Science.gov (United States)

    Carnovale, Carla; Pozzi, Marco; Nisic, Andrea Angelo; Scrofani, Elisa; Perrone, Valentina; Antoniazzi, Stefania; Radice, Sonia

    2013-01-01

    We present the case of a 7-year-old boy, who received acetaminophen for the treatment of hyperpyrexia, due to an infection of the superior airways. 13 mg/kg (260 mg) of acetaminophen was administered orally before bedtime, and together with the expected antipyretic effect, the boy experienced sleep disruption and proprioceptive delirium. The symptoms disappeared within one hour. In the following six months, acetaminophen was administered again twice, and the reaction reappeared with similar features. Potential alternative explanations were excluded, and analysis with the Naranjo algorithm indicated a “probable” relationship between acetaminophen and this adverse reaction. We discuss the potential mechanisms involved, comprising imbalances in prostaglandin levels, alterations of dopamine, and cannabinoid and serotonin signalings. PMID:23573447

  7. Protective Effect of Acacia nilotica (L.) against Acetaminophen-Induced Hepatocellular Damage in Wistar Rats

    OpenAIRE

    Kannan, Narayanan; Sakthivel, Kunnathur Murugesan; Guruvayoorappan, Chandrasekaran

    2013-01-01

    The potential biological functions of A. nilotica have long been described in traditional system of medicine. However, the protective effect of A. nilotica on acetaminophen-induced hepatotoxicity is still unknown. The present study attempted to investigate the protective effect of A. nilotica against acetaminophen-induced hepatic damage in Wistar rats. The biochemical liver functional tests Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline phosphatase (ALP), total bilirubin, ...

  8. The Effect of Polymer Content on the Non-Newtonian Behavior of Acetaminophen Suspension

    OpenAIRE

    Eskandar Moghimipour; Maryam Kouchak; Anayatollah Salimi; Saeed Bahrampour; Somayeh Handali

    2013-01-01

    Acetaminophen is used as an analgesic and antipyretic agent. The aim of the study was evaluation of the effect of different polymers on rheological behavior of acetaminophen suspension. In order to achieve controlled flocculation, sodium chloride was added. Then structural vehicles such as carboxymethyl cellulose (CMC), polyvinyl pyrrolidone (PVP), tragacanth, and magnesium aluminum silicate (Veegum) were evaluated individually and in combination. Physical stability parameters such as sedimen...

  9. Pre emptive analgesia for reducing pain after cholecystectomy: Oral tramadol vs. acetaminophen codeine

    Directory of Open Access Journals (Sweden)

    Sayyed Morteza Heidari Tabaei Zavareh

    2013-01-01

    Conclusion: The findings of current study indicated that in lower dose of tramadol (50 mg and acetaminophen/codeine (325 mg/10 mg the analgesic effect of tramadol is better and its side effects are higher than acetaminophen/codeine, which limit its use for mentioned purpose. It seems that administration of each of studied agents it depends on patients′ tolerance and decision of the physician.

  10. Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid

    OpenAIRE

    Silverman, S. L.; Kriegman, A.; Goncalves, J.; Kianifard, F; Carlson, T.; Leary, E.

    2010-01-01

    Summary A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms. Introduction Transient symptoms including myalgia and pyrexia have been reported post-infus...

  11. Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation.

    Science.gov (United States)

    Abernethy, D R; Greenblatt, D J; Ameer, B; Shader, R I

    1985-08-01

    Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:4020675

  12. Nootropic activity of acetaminophen against colchicine induced cognitive impairment in rats

    OpenAIRE

    Pitchaimani, Vigneshwaran; Arumugam, Somasundaram; Thandavarayan, Rajarajan A.; Thiyagarajan, Manisenthilkumar K.; Aiyalu, Rajasekaran; Sreedhar, Remya; Nakamura,Takashi; Watanabe, Kenichi

    2012-01-01

    Alzheimer’s disease is a devastating neurodegenerative disorder, the most common among the dementing illnesses. Acetaminophen has gaining importance in neurodegenerative diseases by attenuating the dopaminergic neurodegeneration in Caenorhabditis elegans model, decreasing the chemokines and the cytokines and increasing the anti apoptotic protein such as Bcl-2 in neuronal cell culture. The low concentration acetaminophen improved the facilitation to find the hidden platform in Morris Water Maz...

  13. Alterations in the Rat Serum Proteome During Liver Injury from Acetaminophen Exposure

    OpenAIRE

    Merrick, B. Alex; Bruno, Maribel E.; Madenspacher, Jennifer H.; Wetmore, Barbara A.; Foley, Julie; Pieper, Rembert; Zhao, Ming; Makusky, Anthony J.; McGrath, Andrew M.; ZHOU, JEFF X.; Taylor, John; Tomer, Kenneth B.

    2006-01-01

    Changes in the serum proteome were identified during early, fulminant and recovery phases of liver injury from acetaminophen in the rat. Male F344 rats received a single, non-injury dose or a high, injury-producing dose of acetaminophen for evaluation at 6 hr to 120 hr. Two-dimensional gel electrophoresis of immunodepleted serum separated about 800 stained proteins per sample from which differentially expressed proteins were identified by mass spectrometry. Serum ALT/AST levels and histopatho...

  14. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism

    DEFF Research Database (Denmark)

    Jensen, Morten Søndergaard; Rebordosa, Cristina; Thulstrup, Ane Marie;

    2010-01-01

    Cyclooxygenase (COX) inhibitors-acetaminophen, ibuprofen and acetylsalicylic acid-have endocrine-disruptive properties in the rainbow trout. In humans, aspirin blocks the androgen response to human chorionic gonadotropin (hCG), and, because hCG-stimulated androgen production in utero is crucial...... for normal testicular descent, exposure to COX inhibitors at vulnerable times during gestation may impair testicular descent. We examined whether prenatal exposure to acetaminophen, ibuprofen, and acetylsalicylic acid was associated with increased occurrence of cryptorchidism....

  15. Comparison of oral nalbuphine, acetaminophen, and their combination in postoperative pain.

    Science.gov (United States)

    Jain, A K; Ryan, J R; McMahon, F G; Smith, G

    1986-03-01

    This double-blind, randomized, parallel, placebo-controlled study evaluated the analgesic effects of single oral doses of 30 mg nalbuphine, 650 mg acetaminophen, and the contribution of each to the efficacy of their combination in 128 hospitalized patients with postoperative pain. Subjective reports of patients evaluated each hour for 6 hours were used as indices of analgesic response. Both nalbuphine and acetaminophen were significantly superior to placebo for most measures of total and peak analgesia. The interaction contrast between nalbuphine and acetaminophen was not significant for any analgesic measurements, indicating an additive effect of the components. The combination was the most effective treatment, followed by nalbuphine, acetaminophen, and placebo. Effects of the combination were significantly different from those of acetaminophen at 4, 5, and 6 hours and from those of placebo at 1 to 6 hours. There was no significant difference in the frequency or intensity of side effects among the groups. The combination of nalbuphine and acetaminophen appears to be a therapeutically useful combination. PMID:3512149

  16. Treatment of mild to moderate pain of acute soft tissue injury: diflunisal vs acetaminophen with codeine.

    Science.gov (United States)

    Muncie, H L; King, D E; DeForge, B

    1986-08-01

    Acute soft tissue injuries create pain and limitation of function. Treatment requires analgesia and time for full recovery. Acetaminophen with codeine (650 mg plus 60 mg, respectively, every 4 to 6 hours) is used frequently as the analgesic of choice. Diflunisal (1,000 mg initially then 500 mg twice a day) vs acetaminophen with codeine was prospectively studied in the treatment of acute mild to moderate pain from soft tissue injuries. Thirty-five patients with acute strains, sprains, or low back pain were randomized to treatment (17 acetaminophen with codeine vs 18 diflunisal). Both groups were similar in the amount of pain and type of injury at initiation of therapy. Patient pain rating went from 3.3 +/- 0.6 to 1.6 +/- 1.5 for acetaminophen with codeine and from 3.3 +/- 0.6 to 1.3 +/- 1.1 for diflunisal. However, 65 percent of acetaminophen with codeine patients experienced side effects, with 35 percent of these patients stopping the medication because of intolerable side effects. In the diflunisal group, 28 percent of the patients experienced side effects and 5 percent had to stop the medication early. Diflunisal was found to be an effective analgesic in mild to moderate pain of acute soft tissue injuries, and caused fewer and more tolerable side effects than did acetaminophen with codeine. PMID:2942630

  17. Impact of Educational Levels and Health Literacy on Community Acetaminophen Knowledge.

    Science.gov (United States)

    Ip, Eric J; Tang, Terrill T-L; Cheng, Vincent; Yu, Junhua; Cheongsiatmoy, Derren S

    2015-12-01

    Patient understanding of acetaminophen is important for its safe and appropriate self-use. A cross-sectional survey was conducted in the San Francisco Bay Area to determine the impact of educational level, patient health literacy score, and other demographic characteristics on acetaminophen knowledge. A 17-item, in-person, paper-and-pen questionnaire containing questions about demographics and acetaminophen knowledge was administered to 311 adults outside 5 local grocery stores in varying socioeconomic communities. Knowledge assessed was whether Tylenol-McNeil contains acetaminophen, maximum daily dose, and primary organ affected by toxicity. Participant health literacy was evaluated using the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF) test. Of the 300 who successfully completed the study, only 3.8% of all subjects were able to answer all 3 acetaminophen knowledge questions correctly regardless of educational level or health literacy score. This reaffirms that a lack of appropriate acetaminophen knowledge remains present in the general population, and further efforts to educate patients will be needed to prevent adverse events.

  18. Hepatoprotective effect of coenzyme Q10 in rats with acetaminophen toxicity.

    Science.gov (United States)

    Fouad, Amr A; Jresat, Iyad

    2012-03-01

    The potential protective effect of coenzyme Q10 against acute liver injury induced by a single dose of acetaminophen (700 mg/kg, p.o.) was investigated in rats. Coenzyme Q10 treatment was given as two i.p. injections, 10 mg/kg each, at 1 and 12 h following acetaminophen administration. Coenzyme Q10 significantly reduced the levels of serum aminotransferases, suppressed lipid peroxidation, prevented the decreases of reduced glutathione and catalase activity, decreased the elevations of tumor necrosis factor-α and nitric oxide as well as attenuating the reductions of selenium and zinc ions in liver tissue resulting from acetaminophen administration. Histopathological liver tissue damage mediated by acetaminophen was ameliorated by coenzyme Q10. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the acetaminophen-induced overexpression of inducible nitric oxide synthase, nuclear factor-κB, caspase-3 and p53 in liver tissue. It was concluded that coenzyme Q10 protects rat liver against acute acetaminophen hepatotoxicity, most probably through its antioxidant, anti-inflammatory and antiapoptotic effects.

  19. "Nifedipine in the treatment of liver toxicity induced by Acetaminophen overdose in mice "

    Directory of Open Access Journals (Sweden)

    Kalantari H

    2000-11-01

    Full Text Available Acetaminophen is an analgesic and antipyretic drug, which is widely used by public and poisoning with this drug, is common. One of the most important adverse effects of acetaminophen poisoning is centrilobullar necrosis in hepatic cells, which depends on activity of microsomal cytochrome P-450 (CYP enzymes. The aim of this investigation was to find out the protective effect of nifedipine against liver toxicity caused by acetaminophen overdose (700 mg/kg as calcium channel blocker. In this study doses of 5, 50, 100, 250, 500 mg/kg of nifedipine were administered to mice orally one hour before acetaminophen administration. The negative control group receive normal saline. The positive control group was administered with acetaminophen at a dose of 700 mg/kg one hour after nifedipine administration. After 24 hours, enzyme activity (ALT, AST, histopathological examination and liver weight were compared with the control groups. The results revealed that nifedipine at dose of 500 mg/kg was the most effective and protected damage from acetaminophen toxicity.

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

    Science.gov (United States)

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

    2010-04-07

    Acetaminophen, a pain-reliever, is one of the most widely used medications in the world. Acetaminophen with normal dosage is considered a nontoxic drug for therapeutic applications, but when taken at overdose levels it produces liver damage in human and various animal species. By a high energy mechanically activated method, we produced acetaminophen in a nanometer crystalline size (24 nm). Forty-eight hours after injection of crystalline particles with normal and reduced size of our drug, the effect of liver toxicity was compared by determination of liver transferase enzymes such as alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase (ALT). These enzymes were examined by routine colorimetric methods using commercial kits and pathologic investigations. Statistical analysis and pathological figures indicated that ALT delivery and toxicity in reduced size acetaminophen was significantly reduced when compared with normal size acetaminophen. Pathology figures exhibited reduced necrosis effects, especially the confluent necrosis, in the central part of the lobule in the reduced size acetaminophen samples when compared with the normal samples.

  1. Circadian rhythm of serum sulfate levels in man and acetaminophen pharmacokinetics.

    Science.gov (United States)

    Hoffman, D A; Wallace, S M; Verbeeck, R K

    1990-01-01

    The circadian variation of serum inorganic sulfate levels was studied in healthy volunteers. The effect of subchronic acetaminophen administration (650 mg q.i.d. for 4 days) on serum inorganic sulfate levels was investigated and the possible role of fluctuating serum inorganic sulfate levels on the pharmacokinetics of acetaminophen was evaluated. During a 24 h cycle, serum inorganic sulfate levels were lowest in the morning (11.00 h) and typically increased in the afternoon to reach a maximum in the early evening (19.00 h). Average 24 h serum concentrations were 360 microM and the difference between minimum and maximum levels was on average 25.8%. Subchronic administration of acetaminophen (650 mg q.i.d. for 4 days) significantly reduced serum inorganic sulfate levels to a 24 h average of 253 microM. The circadian rhythm, however, was not affected and the difference between minimum (12.00 h) and maximum (18.50 h) serum concentrations was 31.3%. Subchronic acetaminophen administration lead to a significant decrease in the renal excretion (-51%) and renal clearance (-33%) of inorganic sulfate. No significant differences were found in the disposition kinetics of acetaminophen and its glucuronide and sulfate conjugates during two consecutive dosing intervals (08.00-14.00 h, 14.00-20.00 h) on Day 4 of the acetaminophen regimen. PMID:2253663

  2. Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults

    DEFF Research Database (Denmark)

    Carroll, C C; Dickinson, J M; LeMoine, J K;

    2011-01-01

    Millions of older individuals consume acetaminophen or ibuprofen daily and these same individuals are encouraged to participate in resistance training. Several in vitro studies suggest that cyclooxygenase-inhibiting drugs can alter tendon metabolism and may influence adaptations to resistance...... group, and this response was not influenced with ibuprofen consumption. Mean tendon CSA increased with training in the acetaminophen group (3%, P .... These responses were generally uninfluenced by ibuprofen consumption. In the acetaminophen group, tendon deformation and strain increased 20% (P

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-06-30

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

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  6. Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats.

    Directory of Open Access Journals (Sweden)

    Julio R Chavez

    Full Text Available It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC.Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg, morphine (3 mg/kg, tramadol (10 mg/kg, acetaminophen (300 mg/kg + morphine (3 mg/kg, and acetaminophen (300 mg/kg + tramadol (10 mg/kg.The control and acetaminophen groups did not present statistically significant differences (p = 0.98. The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% ± 0.04%, 0.99% ± 0.009%, 0.97% ± 0.02%, and 0.99% ± 0.01%, respectively.The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane.

  7. Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats

    Science.gov (United States)

    Chavez, Julio R.; Ibancovichi, José A.; Sanchez-Aparicio, Pedro; Acevedo-Arcique, Carlos M.; Moran-Muñoz, Rafael; Recillas-Morales, Sergio

    2015-01-01

    Background It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC) of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC. Methods Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg), morphine (3 mg/kg), tramadol (10 mg/kg), acetaminophen (300 mg/kg) + morphine (3 mg/kg), and acetaminophen (300 mg/kg) + tramadol (10 mg/kg). Results The control and acetaminophen groups did not present statistically significant differences (p = 0.98). The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% ± 0.04%, 0.99% ± 0.009%, 0.97% ± 0.02%, and 0.99% ± 0.01%, respectively. Conclusions The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane. PMID:26605541

  8. Potentiation in the intact rat of the hepatotoxicity of acetaminophen by 1,3-bis(2-chloroethyl)-1-nitrosourea.

    Science.gov (United States)

    Nakae, D; Oakes, J W; Farber, J L

    1988-12-01

    Studies of the killing of cultured hepatocytes by acetaminophen indicate that the cells are injured by an oxidative stress that accompanies the metabolism of the toxin (J. L. Farber et al. (1988) Arch. Biochem. Biophys. 267, 640-650). The present report documents that the essential features of the killing of cultured hepatocytes by acetaminophen are reproduced in the intact animal. Male rats had no evidence of liver necrosis 24 h after administration of up to 1000 mg/kg of acetaminophen. Induction of mixed function oxidase activity by 3-methylcholanthrene increased the hepatotoxicity of acetaminophen. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the hepatotoxicity of acetaminophen in male rats induced with 3-methylcholanthrene. Whereas the pretreatment with BCNU reduced the GSH content by 40%, a comparable depletion of GSH by diethylmaleate did not potentiate the toxicity of acetaminophen. The antioxidant diphenylphenylenediamine (25 mg/kg) and the ferric iron chelator deferoxamine (1000 mg/kg) prevented the liver necrosis produced by 500 mg/kg acetaminophen in rats pretreated with BCNU. Neither protective agent prevented the fall in GSH produced by acetaminophen. It is concluded the conditions of the irreversible injury of cultured hepatocytes by acetaminophen previously reported are not necessarily different from those that obtain in the intact rat with this toxin. PMID:3214175

  9. Preparation and electrochemical application of a new biosensor based on plant tissue/polypyrrole for determination of acetaminophen

    Indian Academy of Sciences (India)

    Gholamhossein Rounaghi; Roya Mohammadzadeh Kakhki

    2012-10-01

    Banana tissue containing polyphenol oxidase was incorporated into polypyrrole matrix to make a biosensor for the analysis of acetaminophen (ACT). The electrocatalytic behaviour of oxidized acetaminophen was studied at the surface of the biosensor, using various electrochemical methods. The advantages of this biosensor for the determination of acetaminophen are excellent catalytic activity, good detection limit and high exchange current density. The electrochemical and structural properties of the electrode were assessed using cyclic voltammetry, differential voltammetry, chronoamperometric techniques. The analytical properties (sensitivity, p) of this biosensor increased with plant tissue loading. Also this new biosensor was successfully applied for determination of acetaminophen in biologic samples.

  10. Formulation and Characterization of Acetaminophen Nanoparticles in Orally Disintegrating Films

    Science.gov (United States)

    AI-Nemrawi, Nusaiba K.

    The purpose of this study is to prepare acetaminophen loaded nanoparticles to be cast directly, while still in the emulsion form, into Orally Disintegrating Films (ODF). By casting the nanoparticles in the films, we expected to keep the particles in a stable form where the nanoparticles would be away from each other to prevent their aggregation. Once the films are applied on the buccal mucosa, they are supposed to dissolve within seconds, releasing the nanoparticles. Then the nanoparticles could be directly absorbed through the mucosa to the blood stream and deliver acetaminophen there. The oral cavity mucosa is one of the most attractive sites for systemic drug delivery due to its high permeability and blood supply. Furthermore, it is robust and shows short recovery times after stress or damage, and the drug bypasses first pass effect and avoids presystemic elimination in the GI tract. Nanoencapsulation increases drug efficacy, specificity, tolerability and therapeutic index. These Nanocapsules have several advantages in the protection of premature degradation and interaction with the biological environment, enhancement of absorption into a selected tissue, bioavailability, retention time and improvement of intracellular penetration. The most important characteristics of nanoparticles are their size, encapsulation efficiency (EE), zeta potential (surface charge), and the drug release profiles. Unfortunately, nanoparticles tend to precipitate or aggregate into larger particles within a short time after preparation or during storage. Some solutions for this problem were mentioned in literature including lyophilization and spray drying. These methods are usually expensive and give partial solutions that might have secondary problems; such as low re-dispersion efficacy of the lyophilized NPs. Furthermore, most of the formulations of NPs are invasive or topical. Few formulas are available to be given orally. Fast disintegrating films (ODFs) are rapidly gaining interest

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

    Directory of Open Access Journals (Sweden)

    Gholamreza Faridaalaee

    2015-05-01

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

  12. Comparison of Acetaminophen with or without Codeine to Ibuprofen on the Postoperative Pain of Pediatric Tonsillectomy

    Directory of Open Access Journals (Sweden)

    2011-04-01

    Full Text Available Introduction: Management of pain in children is often inadequate and numerous clinical practice guidelines and policy statements have been published on the subject of pediatric pain. Tonsillectomy is among the most frequent otorhinolaryngologic surgeries, especially in the pediatric age group and after tonsillectomy the patients usually suffer from mild to severe pain for three postoperative days which may limit activity level and intake, leading to dehydration and a prolonged hospital stay. In this study acetaminophen, acetaminophen codeine and ibuprofen have been compared in a single study. Materials and Methods: A randomized, prospective, double-blind study was conducted at the Tabriz pediatric hospital. Patients were selected randomly from the hospitalized patients undergoing tonsillectomy suffering from recurrent tonsillitis or adenotonsillar hypertrophy and assigned to one of three groups (acetaminophen (ACT-acetaminophen codeine (ACT/C-ibuprofen (IBU according to a predetermined randomization code. All the operations were taken place under same conditions by the same surgeon. Objective pain score used for pain assessment and adverse drug reactions were collected on checklists and analyzed using SPSS software. Results: Chi square test results revealed a significant difference between ACT ACT/C IBU groups. Neither acetaminophen nor Ibuprofen at the doses given was able to provide sufficient analgesia. The rate of bleeding in all groups did not show any significant difference according to Pearson-chi-square test (P=0.22. The incidence of anorexia in ACT, ACT/C and IBU groups was 15.7, 7.8 and 25.8 percent, respectively, which showed a significant difference by chi-square test (P=0.045. Conclusion: According to our study it can be concluded that acetaminophen codeine posses more analgesic effect than acetaminophen and ibuprofen in post tonsillectomy pain management in pediatric patients.

  13. Effect of antipyrine coadministration on the kinetics of acetaminophen and lidocaine.

    Science.gov (United States)

    Blyden, G T; Greenblatt, D J; LeDuc, B W; Scavone, J M

    1988-01-01

    Pharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received: 1, antipyrine 1.0 g intravenously (i.v.); 2, acetaminophen 650 mg i.v.; 3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously. Between Trials 1 and 3, antipyrine elimination t1/2 (17.2 vs 17.4 h), clearance (0.44 vs 0.43 ml.min-1.kg-1) and 24-h recovery of antipyrine and metabolites (313 vs 293 mg) did not differ significantly. Between Trials 2 and 3, acetaminophen VZ was reduced (1.14 vs 1.00 l.kg-1), t1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml.min-1.kg-1), and fractional urinary recovery of acetaminophen glucuronide reduced. Eight additional subjects received 50 mg of lidocaine hydrochloride i.v. in the control state, and on a second occasion immediately after antipyrine 1.0 g given i.v. The two trials did not differ significantly in lidocaine VZ (2.6 vs 2.7 l.kg-1), t1/2 (2.0 vs 2.4 h) or clearance (15.0 vs 13.5 ml.min-1.kg-1). Although acetaminophen does not alter antipyrine kinetics, acute administration of antipyrine appears to impair acetaminophen clearance, possibly via inhibition of glucuronide formation. However, antipyrine has no significant effect on the kinetics of a single i.v. dose of lidocaine. PMID:3197750

  14. Cooperativity in CYP2E1 metabolism of acetaminophen and styrene mixtures.

    Science.gov (United States)

    Hartman, Jessica H; Letzig, Lynda G; Roberts, Dean W; James, Laura P; Fifer, E Kim; Miller, Grover P

    2015-10-01

    Risk assessment for exposure to mixtures of drugs and pollutants relies heavily on in vitro characterization of their bioactivation and/or metabolism individually and extrapolation to mixtures assuming no interaction. Herein, we demonstrated that in vitro CYP2E1 metabolic activation of acetaminophen and styrene mixtures could not be explained through the Michaelis-Menten mechanism or any models relying on that premise. As a baseline for mixture studies with styrene, steady-state analysis of acetaminophen oxidation revealed a biphasic kinetic profile that was best described by negative cooperativity (Hill coefficient=0.72). The best-fit mechanism for this relationship involved two binding sites with differing affinities (Ks=830μM and Kss=32mM). Introduction of styrene inhibited that reaction less than predicted by simple competition and thus provided evidence for a cooperative mechanism within the mixture. Likewise, acetaminophen acted through a mixed-type inhibition mechanism to impact styrene epoxidation. In this case, acetaminophen competed with styrene for CYP2E1 (Ki=830μM and Ksi=180μM for catalytic and effector sites, respectively) and resulted in cooperative impacts on binding and catalysis. Based on modeling of in vivo clearance, cooperative interactions between acetaminophen and styrene resulted in profoundly increased styrene activation at low styrene exposure levels and therapeutic acetaminophen levels. Current Michaelis-Menten based toxicological models for mixtures such as styrene and acetaminophen would fail to detect this concentration-dependent relationship. Hence, future studies must assess the role of alternate CYP2E1 mechanisms in bioactivation of compounds to improve the accuracy of interpretations and predictions of toxicity.

  15. Supra-additive effects of tramadol and acetaminophen in a human pain model.

    Science.gov (United States)

    Filitz, Jörg; Ihmsen, Harald; Günther, Werner; Tröster, Andreas; Schwilden, Helmut; Schüttler, Jürgen; Koppert, Wolfgang

    2008-06-01

    The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics. PMID:17709207

  16. Effect of acetaminophen on the leukocyte-labeling efficiency of indium oxine In 111

    Energy Technology Data Exchange (ETDEWEB)

    Augustine, S.C.; Schmelter, R.F.; Nelson, K.L.; Petersen, R.J.; Qualfe, M.A.

    1983-11-01

    The effect of acetaminophen on the labeling efficiency of leukocytes with indium oxine In 111 was studied. A blood sample was obtained from eight healthy men before and after they received acetaminophen 650 mg every four hours for 24 hours. After dividing the plasma from each sample into three portions, leukocytes were separated and labeled with indium oxine In 111. In an in vitro study, 200 ml of blood was obtained from one of the men, and the plasma was separated into four portions. Acetaminophen in 95% ethanol was added to three of the plasma fractions to produce acetaminophen concentrations of 4, 20, and 100 micrograms/ml; ethanol was added to the fourth fraction as a control. Each plasma fraction was then subdivided into three aliquots, and leukocytes were labeled as in the in vivo study. Mean leukocyte labeling efficiencies in both studies were calculated from the ratios of leukocyte radioactivity to initial radioactivity in the samples, expressed as percentages. Leukocyte labeling efficiencies before acetaminophen administration ranged from 79 to 85%; after administration, labeling efficiencies ranged from 70 to 87%. No significant differences in mean labeling efficiency before and after acetaminophen administration were noted in any of the subjects. Leukocyte labeling efficiencies in all in vitro plasma fractions were reduced, ranging from 54 to 63%, but no significant differences in labeling efficiency between any of the plasma fractions were found. Using the labeling procedures in this study, exposure of leukocytes from healthy men to acetaminophen in vivo or in vitro does not affect labeling efficiency with indium oxine In 111.

  17. TRPV1 in brain is involved in acetaminophen-induced antinociception.

    Directory of Open Access Journals (Sweden)

    Christophe Mallet

    Full Text Available BACKGROUND: Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404 by fatty acid amide hydrolase (FAAH in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV(1 in vitro. Pharmacological activation of TRPV(1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV(1 in the brain contributes to the analgesic effect of acetaminophen. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV(1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E(2 (PGE(2 and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV(1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV(1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test. CONCLUSIONS: This study shows that TRPV(1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV(1 in the brain.

  18. ANALGESIC EFFICACY OF INTRAVENOUS VERSUS RECTAL ACETAMINOPHEN AFTER ADENO TONSILLECTOMY IN CHILDREN

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    Geeta

    2015-03-01

    Full Text Available INTRODUCTION: Doses of acetaminophen 15mg/ kg intravenous and 40 mg / kg rectally produce similar effect - site concentrations. However, the clinical effectiveness of these routes has not been compared. The aim of this study was to compare the efficacy of analgesia (in terms of duration of analgesia and effect on pain intensity in children following adenotonsillectomy after acetaminophen either 15 mg/ kg IV or 40 mg/ kg rectally . METHODS: Fifty children, aged between 5 and 14 yr s. , undergoing elective adenotonsillectomy were randomly allocated into two groups. Group IV received 15mg/kg intravenous acetaminophen and Group PR received 40mg/kg rectal aceta minophen. Blood pressure, heart rate, respiratory rate and oxygen saturation were continuously monitored. Postoperative pain was assessed by visual analogue scale (VAS and rescue analgesia provided if scores were 4 or greater. The primary outcome measure was time to first rescue analgesia. RESULTS: The time to first rescue analgesia was significantly longer in children receiving rectal acetaminophen (8.96 ± 3.46 compared with those receiving IV acetaminophen (6.00 ± 1.63 ( P - value 0.000. Only one child in IV Group required rescue analgesia within first 6 hours with differences between the groups being most prominent in the period from 6 to 10 hours. Vitals did not show any difference in both groups peri - operatively. Postoperative pain assessment by VAS a t various time intervals showed no significant difference between the groups. CONCLUSIONS: Rectal acetaminophen 40 mg/ kg provides longer analgesia for moderately painful procedures when compared with 15 mg/ kg acetaminophen IV. However, efficacy of intrav enous paracetamol has no superiority to rectal administration.

  19. Biliary excretion of acetaminophen-glutathione as an index of toxic activation of acetaminophen: effect of chemicals that alter acetaminophen hepatotoxicity

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    Madhu, C.; Gregus, Z.; Klaassen, C.D.

    1989-03-01

    Acetaminophen (AA) is converted, presumably by cytochrome P-450, to an electrophile which is conjugated with glutathione (GS). AA-GS is excreted into bile, therefore the biliary excretion rate of AA-GS may reflect the rate of activation of AA in vivo. In order to test this hypothesis, the effect of agents capable of altering the activation of AA including cytochrome P-450 inducers and inhibitors, cobaltous chloride which decreases the amount of P-450, prostaglandin synthetase inhibitors (indomethacin and naproxen), antioxidants (butylated hydroxyanisole, alpha-tocopherol, ascorbic acid and ascorbic acid palmitate) and other chemicals known to decrease AA hepatotoxicity (dimethylsulfoxide and cysteamine), on the biliary excretion of AA-GS was studied in hamsters, the species most sensitive to AA-induced hepatotoxicity. The biliary excretion of AA-GS increased linearly up to 1 mmol/kg of AA i.v., but at higher dosages exhibited saturation kinetics. Dosages above 0.5 mmol/kg lowered hepatic GS concentration. Of the cytochrome P-450 inducers, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased the biliary excretion of AA-GS (2.9- and 3.2-fold, respectively) whereas ethanol and isoniazid did not affect it, and pregnenolone-16 alpha-carbonitrile tended to decrease it (43%). Phenobarbital tended to increase the biliary excretion of AA-GS, but not in a statistically significant manner. Several cytochrome P-450 inhibitors (metyrapone, 8-methoxypsoralen, 2-(4,6-dichloro-biphenyloxy) ethylamine, alpha-naphthoflavone and cimetidine) decreased the biliary excretion of AA-GS, although SKF 525-A and piperonyl butoxide did not. Cobaltous chloride decreased dramatically the biliary excretion of AA-GS.

  20. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

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    KuKanich, Butch

    2010-01-01

    The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after IV codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs.

  1. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein

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    Kopylchuk G.P.

    2015-09-01

    Full Text Available Background. Acetaminophen is known as inducer of acute hepatotoxicity. Extrahepatic manifestations of acetaminophen toxicity are poorly understood in particular its nephrotoxicity. Objective. The purpose of this study was the morphological characteristic of rat kidneys under the conditions of acetaminophen-induced nephrotoxicity on the background of alimentary deprivation of protein. Methods. Аfter administration of the toxic dose of acetaminophen and maintenance of rats on a different regimen of protein nutrition their kidneys were sectioned and stained with hematoxylin and eosin according to a standard technique. Results. It was estimated, that in rats maintained during long period of time under the conditions of alimentary deprivation of protein, and in rats injected with toxic dose of acetaminophen morphological changes of kidney were not observed. Administration of acetaminophen on the background of previous protein deficiency causes the pathological changes of kidney morphology with papillary necrosis as a key sign. Conclusion. Alimentary deprivation of protein in case of acetaminophen injection is the critical factor for the impairment of structural integrity of kidney tissue with its subsequent dysfunction. Citation: Kopylchuk GP, Voloshchuk ON, Buchkovskaia IM, Davydenko IS. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein]. Morphologia. 2015;9(3:28-30. Russian.

  2. Protective Effect of Acacia nilotica (L. against Acetaminophen-Induced Hepatocellular Damage in Wistar Rats

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    Narayanan Kannan

    2013-01-01

    Full Text Available The potential biological functions of A. nilotica have long been described in traditional system of medicine. However, the protective effect of A. nilotica on acetaminophen-induced hepatotoxicity is still unknown. The present study attempted to investigate the protective effect of A. nilotica against acetaminophen-induced hepatic damage in Wistar rats. The biochemical liver functional tests Alanine transaminase (ALT, Aspartate transaminase (AST, Alkaline phosphatase (ALP, total bilirubin, total protein, oxidative stress test (Lipid peroxidation, antioxidant parameter glutathione (GSH, and histopathological changes were examined. Our results show that the pretreatment with A. nilotica (250 mg/kg·bw orally revealed attenuation of serum activities of ALT, AST, ALP, liver weight, and total bilirubin levels that were enhanced by administration of acetaminophen. Further, pretreatment with extract elevated the total protein and GSH level and decreased the level of LPO. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by acetaminophen. The present study undoubtedly provides a proof that hepatoprotective action of A. nilotica extract may rely on its effect on reducing the oxidative stress in acetaminophen-induced hepatic damage in rat model.

  3. Piperine, an active ingredient of black pepper attenuates acetaminophen-induced hepatotoxicity in mice

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    Evan Prince Sabina; Annie Deborah Harris Souriyan; Deborah Jackline; Mahaboob Khan Rasool

    2010-01-01

    Objective: To explore the hepatoprotective and antioxidant effects of piperine against acetaminophen-induced hepatotoxicity in mice. Methods: In mice, hepatotoxicity was induced by a single dose of acetaminophen (900 mg/kg b.w. i.p.). Piperine (25 mg/kg b.w. i.p.) and standard drug silymarin (25 mg/kg b.w. i.p.) were given to mice, 30 min after the single injection of acetaminophen. After 4 h, the mice were decapitated. Activities of liver marker enzymes [(aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP)] and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase and glutathione) were determined in liver homogenate of control and experimental mice. Results: Acetaminophen induction (900 mg/kg b.w. i.p.) significantly increased the levels of liver marker enzymes, TNF-α, and lipid peroxidation, and caused the depletion of antioxidant status. Piperine and silymarin treatment to acetaminophen challenged mice resulted in decreased liver marker enzymes activity, TNF-α and lipid peroxidation levels with increase in antioxidant status. Conclusions: The results clearly demonstrate that piperine shows promising hepatoprotective effect as comparable to standard drug silymarin.

  4. Preventive and curative effects of Acalypha indica on acetaminophen-induced hepatotoxicity

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    M Mathew

    2011-01-01

    Full Text Available Effect of ethanol extract of the leaves of Acalypha indica (Euphorbiaceae was investigated against acetaminophen-induced hepatic damage. Acetaminophen (paracetamol at the rate of 1 g/kg produced liver damage in rats as manifested by the significant (P<0.001 rise in serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT and alkaline phosphatase (ALP, compared to respective control values. Treatment of rats with acetaminophen led to a marked increase in lipid peroxidation as measured by malondialdehyde (MDA. This was associated with a significant reduction in superoxide dismutase (SOD and glutathione (GSH contents. Pretreatment of animals with the plant extract (100 mg/kg orally once daily for 5 days prevented (P<0.01 the acetaminophen-induced rise in serum transaminases (AST and ALT and ALP. Post treatment with five successive doses of the extract (100 mg/kg restricted the hepatic damage induced by the above said Paracetamol (P<0.001. Histological changes around the hepatic central vein were recovered by administration of the drug. Thus, it is evident that these biochemical and histological alterations resulting from acetaminophen administration were inhibited by pre and post treatment with A. indica leaf extract. One notable study of the study was the spontaneous recovery of liver damage within a week after stopping paracetamol. These results indicate that the crude ethanol extract of A. indica exhibits hepatoprotective action through antioxidant effect and validates the traditional use of the plant in hepatic dysfunction.

  5. Rapid onset of Stevens-Johnson syndrome and toxic epidermal necrolysis after ingestion of acetaminophen.

    Science.gov (United States)

    Kim, Eun-Jin; Lim, Hyun; Park, So Young; Kim, Sujeong; Yoon, Sun-Young; Bae, Yun-Jeong; Kwon, Hyouk-Soo; Cho, You Sook; Moon, Hee-Bom; Kim, Tae-Bum

    2014-01-01

    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but life-threatening, severe cutaneous adverse reactions most frequently caused by exposure to drugs. Several reports have associated the use of acetaminophen with the risk of SJS or TEN. A typical interval from the beginning of drug therapy to the onset of an adverse reaction is 1-3 weeks. A 43-year-old woman and a 60-year-old man developed skin lesions within 3 days after administration of acetaminophen for a 3-day period. Rapid identification of the symptoms of SJS and TEN caused by ingestion of acetaminophen enabled prompt withdrawal of the culprit drug. After administration of intravenous immunoglobulin G, both patients recovered fully and were discharged. These two cases of rapidly developed SJS/TEN after ingestion of acetaminophen highlight the possibility that these complications can develop within only a few days following ingestion of over-the-counter medications such as acetaminophen. PMID:24527413

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

    Science.gov (United States)

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

    2015-12-01

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

  7. The protective role of Gongronema latifolium in acetaminophen induced hepatic toxicity in Wistar rats

    Institute of Scientific and Technical Information of China (English)

    Nnodim Johnkennedy; Emejulu Adamma

    2011-01-01

    Objective: To evaluate the protective effect of leaf extract of Gongronema latifolium (G. latifolium) against acute acetaminophen induced hepatic toxicity in Wistar rats. Methods:Thirty six Wistar rats were divided into 6 groups with 6 rats in each group. Animals in group 1 and 2 were administered with 600 mg/kg b.w. of acetaminophen only and acetaminophen plus 100 mg/kg b.w. of caffeine by oral gavages, respectively. Experimental groups 3 and 4 were treated as in group 1 but in addition received 200 and 400 mg/kg b.w., respectively of the leaf extract of G. latifolium by oral gavages. The experimental groups 5 and 6 were treated as in group 2 and in addition received 200 and 400 mg/kg b.w. of leaf extract of G. latifolium, respectively. The treatment lasted for 14 days. Results: The results obtained showed that the serum glutamic-oxalacetic transaminease (AST), glutamic-pyruvic transaminase (ALT) and alkaline phosphatase (ALP) levels had a greater increase in group 2 than in group 1 but dropped marginally in groups 3 and 4. However, in groups 5 and 6, AST, ALT and ALP were significantly reduced (P<0.05). Similarly, serum protein levels were significantly increased in groups 3, 4, 5 and 6 when compared with group 1 and 2. Conclusions: It can be concluded that extract of G. latifolium offers protection against acetaminophen and caffeinated acetaminophen toxicity in Wistar rats.

  8. Satkara (Citrus macroptera Fruit Protects against Acetaminophen-Induced Hepatorenal Toxicity in Rats

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    Sudip Paul

    2016-01-01

    Full Text Available Although Citrus macroptera (Rutaceae, an indigenous fruit in Bangladesh, has long been used in folk medicine, however, there is a lack of information concerning its protective effects against oxidative damage. The protective effects of an ethanol extract of Citrus macroptera (EECM against acetaminophen-induced hepatotoxicity and nephrotoxicity were investigated in rats. Rats (treatment groups were pretreated with EECM at doses of 250, 500, and 1000 mg/kg, respectively, orally for 30 days followed by acetaminophen administration. Silymarin (100 mg/kg was administered as a standard drug over a similar treatment period. Our findings indicated that oral administration of acetaminophen induced severe hepatic and renal injuries associated with oxidative stress, as observed by 2-fold higher lipid peroxidation (TBARS compared to control. Pretreatment with EECM prior to acetaminophen administration significantly improved all investigated biochemical parameters, that is, transaminase activities, alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transferase activities and total bilirubin, total cholesterol, triglyceride and creatinine, urea, uric acid, sodium, potassium and chloride ions, and TBARS levels. These findings were confirmed by histopathological examinations. The improvement was prominent in the group that received 1000 mg/kg EECM. These findings suggested that C. macroptera fruit could protect against acetaminophen-induced hepatonephrotoxicity, which might be via the inhibition of lipid peroxidation.

  9. Acetaminophen fails to inhibit ethanol-induced subjective effects in human volunteers.

    Science.gov (United States)

    Pickworth, W B; Klein, S A; George, F R; Henningfield, J E

    1992-01-01

    In animals, ethanol causes some of its CNS effects by releasing prostaglandins (PG); this is demonstrated by reports that prostaglandin synthetase inhibitors (PGSIs) diminish ethanol-induced effects. However, use of animals in these studies has precluded testing for subjective effects. We studied the interaction of ethanol and acetaminophen, a PGSI, in a double-blind crossover experiment. Six adult males were given no drug or acetaminophen (0, 325, 650, 1300 or 1950 mg) 75 min before ethanol (total dose = 0.625 g/kg; five divided doses). Physiologic, subjective and performance measures were collected. Compared to the no drug condition, ethanol significantly increased ratings of drug "liking," "drunk," "sluggish" and "drug strength" and decreased ratings of "sober." Ethanol increased heart rate and acetaminophen did not diminish or enhance this effect. The failure to antagonize ethanol-induced subjective and physiologic effects by acetaminophen in humans may be due to species differences or inadequate dosage of the PGSI. It is also possible that subjective and certain physiologic effects of ethanol in humans are not mediated by prostaglandin-dependent neural processes. Nevertheless, the finding that at greater than typical analgesic doses, acetaminophen failed to prevent subjective effects of ethanol is of clinical significance. PMID:1539069

  10. Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in postoperative oral surgery pain.

    Science.gov (United States)

    Forbes, J A; Butterworth, G A; Burchfield, W H; Beaver, W T

    1990-01-01

    One-hundred twenty-eight outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, to receive oral doses of ketorolac tromethamine 10 mg, aspirin 650 mg, a combination of acetaminophen 600 mg plus codeine 60 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. All active medications were significantly superior to placebo. The acetaminophen-codeine combination was significantly superior to aspirin for peak analgesia. Ketorolac was significantly superior to aspirin for every measure of total and peak analgesia, and significantly superior to acetaminophen-codeine for measures of total effect. The analgesic effect of ketorolac was significant by hour 1 and persisted for 6 hours. Repeat-dose data also suggested that ketorolac 10 mg was superior to aspirin 650 mg and acetaminophen-codeine on the day of surgery. Differences among the active medications were trivial for the postoperative days 1-6 analyses. The frequency of adverse effects was over 4 times greater for acetaminophen-codeine than for ketorolac or aspirin. PMID:2082317

  11. The immunological and histopathological changes of Tramadol, Tramadol/Acetaminophen and Acetaminophen in male Albino rats "Comparative study"

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    Hanan Mostafa Rabei

    2011-10-01

    Full Text Available Tramadol is a synthetic opioid analgesic. It is commonly prescribed for moderate to severe pain, becoming abused more popular among teens in most countries. Paracetamol as anti-inflammatory drugs (acetaminophen (APAP is widely used as an analgesic and antipyretic agent. Meanwhile, tramadol/acetaminophen (tramacet is effective in acute or chronic moderate-to-moderately severe pain. In comparative study, the current investigation threw the light on the effect of over doses of tramadol and/or APAP on the immune function and hepatocytes in adult male Sprague-Dawley rats. Material and methods: Treated rats received oral doses of each drug for 15 consecutive days and after last treatment, they kept three days later for withdrawal studies. The rats were divided into four treatment groups, in the first group, rats received saline and used as control. The second, third and fourth groups treated with tramadol (45 mg/kg, tramadol/APAP (45/450 mg/kg, APAP (450 mg/kg respectively, once a-day at the first week and ending with 90, 90/900, 900 mg/kg at the second week. Rats were sacrificed at the end of the first, second weeks and three days of last treatment. Results: Daily doses of tramadol and /or APAP exposure in rats decreased the cellularity of spleen. Moreover, phagocytic and killing of S. aureus by PMN and macrophage cells caused a highly significant decrease in treated groups. IFN- was reduced in a statistically different treated group of rats. Serum IL-10 was unaffected by any of the treatment regimens but increased only in tramadol/APAP treated rats. Spleen histology exhibited mild pathological alteration with different injures between treated groups. Splenic white pulp accompanied by ill deformed which reflected the reduction of white pulp zones, thickened vasculature in the splenic net work, fibrous trabeculae become prominent feature, where splenic red pulp occupied large areas of the splenic network with predominant edema and megakaryocytes. On

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

    Science.gov (United States)

    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

  13. Pharmacogenomics of Acetaminophen in Pediatric Populations: a Moving Target

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    Wanqing eLiu

    2014-10-01

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

  14. Carbon Based Electrodes Modified with Horseradish Peroxidase Immobilized in Conducting Polymers for Acetaminophen Analysis

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    Cecilia Cristea

    2013-04-01

    Full Text Available The development and optimization of new biosensors with horseradish peroxidase immobilized in carbon nanotubes-polyethyleneimine or polypyrrole nanocomposite film at the surface of two types of transducer is described. The amperometric detection of acetaminophen was carried out at −0.2 V versus Ag/AgCl using carbon based-screen printed electrodes (SPEs and glassy carbon electrodes (GCEs as transducers. The electroanalytical parameters of the biosensors are highly dependent on their configuration and on the dimensions of the carbon nanotubes. The best limit of detection obtained for acetaminophen was 1.36 ± 0.013 μM and the linear range 9.99–79.01 μM for the HRP-SWCNT/PEI in GCE configuration. The biosensors were successfully applied for the detection of acetaminophen in several drug formulations.

  15. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

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    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

  16. Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

    Science.gov (United States)

    Schreiter, Thomas; Sowa, Jan-Peter; Schlattjan, Martin; Treckmann, Jürgen; Paul, Andreas; Strucksberg, Karl-Heinz; Baba, Hideo A.; Odenthal, Margarete; Gieseler, Robert K.; Gerken, Guido; Arteel, Gavin E.; Canbay, Ali

    2016-01-01

    Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients. PMID:27550092

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

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    Abeer Hanafy

    2016-01-01

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

  18. Double-blind parallel comparison of ketoprofen (Orudis), acetaminophen plus codeine, and placebo in postoperative pain.

    Science.gov (United States)

    Turek, M D; Baird, W M

    1988-12-01

    One hundred sixty-one patients with postoperative pain were treated at a single center in a double-blind, randomized, parallel study designed to compare the efficacy and safety of single oral doses of ketoprofen (50 and 150 mg), an acetaminophen (650 mg) plus codeine (60 mg) combination, and placebo. From 1 through 4 hours after administration of the study drugs, the mean summed pain intensity difference (SPID) and time-weighted total pain relief (TOPAR) scores for the three active treatments generally were significantly (P less than 0.05) higher than those for placebo but not significantly different from each other. At the 6-hour evaluation, the ketoprofen groups, but not the acetaminophen-codeine group, had higher (P less than 0.05) mean SPID and TOPAR scores than the placebo group, as a result of a shorter duration of pain relief in the acetaminophen-codeine group. The 6-hour TOPAR scores were significantly (P less than 0.05) higher for both ketoprofen groups than for the acetaminophen-codeine group; the ketoprofen 150 mg group also had significantly (P less than 0.05) higher mean 6-hour SPID and global subjective assessment scores. As a result of a higher frequency of somnolence, there was a significantly (P less than 0.05) greater incidence of central nervous system adverse drug reactions among patients treated with acetaminophen plus codeine than among those treated with 150 mg of ketoprofen. These results indicate that the analgesic efficacy of both 50 and 150 mg doses of ketoprofen equals that of acetaminophen 650 mg plus codeine 60 mg and the duration of the analgesic effect of ketoprofen is significantly longer. PMID:3072354

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

    Science.gov (United States)

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

    2014-09-01

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

  20. Acute liver failure following cleft palate repair: a case of therapeutic acetaminophen toxicity.

    Science.gov (United States)

    Iorio, Matthew L; Cheerharan, Meera; Kaufman, Stuart S; Reece-Stremtan, Sarah; Boyajian, Michael

    2013-11-01

    Background : Acetaminophen is a widely used analgesic and antipyretic agent in the pediatric population. While the hepatotoxic effects of the drug have been well recognized in cases of acute overdose and chronic supratherapeutic doses, the toxic effects of acetaminophen are rarely documented in cases where therapeutic guidelines are followed. Case : An 8-month-old boy underwent cleft palate repair and placement of bilateral myringotomy tubes. His anesthetic course was uneventful, consisting of maintenance with desflurane and fentanyl. He received acetaminophen for routine postoperative pain management and was tolerating liquids and discharged home on postoperative day 1. On day 3, the child was profoundly lethargic with multiple episodes of emesis and was taken to the emergency department. He suffered a 45-second tonic-clonic seizure in transport to the regional children's medical center, and initial laboratory results demonstrated acute hepatitis with AST 24,424 U/L, ALT 12,885 U/L, total bilirubin 3.1 mg/dL, and a serum acetaminophen level of 83 μg/mL. Aggressive supportive measures including blood products and periprocedural fresh frozen plasma, piperacillin/tazobactam, and intravenous infusions of N-acetylcysteine, sodium phenylacetate and sodium benzoate, carnitine, and citrulline were administered. His metabolic acidosis and acute hepatitis began to correct by day 4, and he was discharged home without further surgical intervention on day 15. Conclusion : Although acetaminophen is an effective and commonly used analgesic in pediatric practice, hepatotoxicity is a potentially devastating complication. This report challenges the appropriateness of existing guidelines for acetaminophen administration and emphasizes the importance of close follow-up and hydration after even relatively minor surgery.

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

    Energy Technology Data Exchange (ETDEWEB)

    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya; Okada, Norihiko; Yoshida, Saori; Yamamoto, Junya; Ohkubo, Rika [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Abiko, Yumi [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Yamada, Hidenori [Jobu Hospital for Respiratory Diseases, Maebashi 371-0048 (Japan); Akahoshi, Noriyuki [Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543 (Japan); Kasahara, Tadashi [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Kumagai, Yoshito [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Ishii, Isao, E-mail: isao-ishii@umin.ac.jp [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan)

    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

  2. Rapid onset of Stevens-Johnson syndrome and toxic epidermal necrolysis after ingestion of acetaminophen

    OpenAIRE

    Kim, Eun-Jin; Lim, Hyun; Park, So Young; Kim, Sujeong; Yoon, Sun-Young; Bae, Yun-Jeong; Kwon, Hyouk-Soo; Cho, You Sook; Moon, Hee-Bom; Kim, Tae-Bum

    2014-01-01

    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but life-threatening, severe cutaneous adverse reactions most frequently caused by exposure to drugs. Several reports have associated the use of acetaminophen with the risk of SJS or TEN. A typical interval from the beginning of drug therapy to the onset of an adverse reaction is 1-3 weeks. A 43-year-old woman and a 60-year-old man developed skin lesions within 3 days after administration of acetaminophen for a 3-da...

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

    Directory of Open Access Journals (Sweden)

    Fakhreddin Taghaddosi-Nejad

    2012-11-01

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

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

    Science.gov (United States)

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

    2016-01-28

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

  5. Acetaminophen induces human neuroblastoma cell death through NFKB activation.

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    Inmaculada Posadas

    Full Text Available Neuroblastoma resistance to apoptosis may contribute to the aggressive behavior of this tumor. Therefore, it would be relevant to activate endogenous cellular death mechanisms as a way to improve neuroblastoma therapy. We used the neuroblastoma SH-SY5Y cell line as a model to study the mechanisms involved in acetaminophen (AAP-mediated toxicity by measuring CYP2E1 enzymatic activity, NFkB p65 subunit activation and translocation to the nucleus, Bax accumulation into the mitochondria, cytochrome c release and caspase activation. AAP activates the intrinsic death pathway in the SH-SY5Y human neuroblastoma cell line. AAP metabolism is partially responsible for this activation, because blockade of the cytochrome CYP2E1 significantly reduced but did not totally prevent, AAP-induced SH-SY5Y cell death. AAP also induced NFkB p65 activation by phosphorylation and its translocation to the nucleus, where NFkB p65 increased IL-1β production. This increase contributed to neuroblastoma cell death through a mechanism involving Bax accumulation into the mitochondria, cytochrome c release and caspase3 activation. Blockade of NFkB translocation to the nucleus by the peptide SN50 prevented AAP-mediated cell death and IL-1β production. Moreover, overexpression of the antiapoptotic protein Bcl-x(L did not decrease AAP-mediated IL-1β production, but prevented both AAP and IL-1β-mediated cell death. We also confirmed the AAP toxic actions on SK-N-MC neuroepithelioma and U87MG glioblastoma cell lines. The results presented here suggest that AAP activates the intrinsic death pathway in neuroblastoma cells through a mechanism involving NFkB and IL-1β.

  6. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    Directory of Open Access Journals (Sweden)

    Miriam S. N. Hohmann

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Soundharrajan Ilavenil

    2016-01-01

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

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

    Science.gov (United States)

    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

  9. Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin.

    Science.gov (United States)

    Schwartz, Jules I; Musser, Bret J; Tanaka, Wesley K; Taggart, William V; Mehta, Anish; Gottesdiener, Keith M; Greenberg, Howard E

    2015-09-01

    This double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI-M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI-M excretion following single and multiple doses (P = .004 vs placebo). PGI-M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx-M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx-M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx-M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX-1 and COX-2 following a single dose, but acetaminophen was a less potent COX-1 inhibitor than indomethacin. PMID:27137142

  10. Acetaminophen increases the risk of arsenic-mediated development of hepatic damage in rats by enhancing redox-signaling mechanism.

    Science.gov (United States)

    Majhi, Chhaya Rani; Khan, Saleem; Leo, Marie Dennis Marcus; Prawez, Shahid; Kumar, Amit; Sankar, Palanisamy; Telang, Avinash Gopal; Sarkar, Souvendra Nath

    2014-02-01

    We evaluated whether the commonly used analgesic-antipyretic drug acetaminophen can modify the arsenic-induced hepatic oxidative stress and also whether withdrawal of acetaminophen administration during the course of long-term arsenic exposure can increase susceptibility of liver to arsenic toxicity. Acetaminophen was co-administered orally to rats for 3 days following 28 days of arsenic pre-exposure (Phase-I) and thereafter, acetaminophen was withdrawn, but arsenic exposure was continued for another 28 days (Phase-II). Arsenic increased lipid peroxidation and reactive oxygen species (ROS) generation, depleted glutathione (GSH), and decreased superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR) activities. Acetaminophen caused exacerbation of arsenic-mediated lipid peroxidation and ROS generation and further enhancement of serum alanine aminotransferase and aspartate aminotransferase activities. In Phase-I, acetaminophen caused further GSH depletion and reduction in SOD, catalase, GPx and GR activities, but in Phase-II, only GPx and GR activities were more affected. Arsenic did not alter basal and inducible nitric oxide synthase (iNOS)-mediated NO production, but decreased constitutive NOS (cNOS)-mediated NO release. Arsenic reduced expression of endothelial NOS (eNOS) and iNOS genes. Acetaminophen up-regulated eNOS and iNOS expression and NO production in Phase-I, but reversed these effects in Phase-II. Results reveal that acetaminophen increased the risk of arsenic-mediated hepatic oxidative damage. Withdrawal of acetaminophen administration also increased susceptibility of liver to hepatotoxicity. Both ROS and NO appeared to mediate lipid peroxidation in Phase-I, whereas only ROS appeared responsible for peroxidative damage in Phase-II.

  11. 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

    OpenAIRE

    Franke RM; Morton T; Devarakonda K

    2015-01-01

    Ryan M Franke, Terri Morton, Krishna Devarakonda Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA Abstract: 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 crosso...

  12. Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol.

    Science.gov (United States)

    Lee, Yung-Pin; Liao, Jian-Tong; Cheng, Ya-Wen; Wu, Ting-Lun; Lee, Shou-Lun; Liu, Jong-Kang; Yin, Shih-Jiun

    2013-11-01

    Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mM NAD(+). Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (Kis) ranging from 0.90 mM (ADH2) to 20 mM (ADH1A), and the intercept inhibition constants (Kii) ranging from 1.4 mM (ADH1C allozymes) to 19 mM (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (Kis = 3.0 mM and Kii = 2.2 mM), but competitive inhibition for ALDH1A1 (Kis = 0.96 mM). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2-0.5 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 μm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12-26%) and ADH2 (14-28%) in the liver and small intestine, ADH4 (15-31%) in the stomach, and ALDH1A1 (16-33%) and ALDH2 (8.3-19%) in all 3 tissues. The

  13. Improvement of Physico-mechanical Properties of Partially Amorphous Acetaminophen Developed from Hydroalcoholic Solution Using Spray Drying Technique

    OpenAIRE

    Fatemeh Sadeghi; Mansour Torab; Mostafa Khattab; Alireza Homayouni; Hadi Afrasiabi Garekani

    2013-01-01

      Objective(s): This study was performed aiming to investigate the effect of particle engineering via spray drying of hydroalcoholic solution on solid states and physico-mechanical properties of acetaminophen.   Materials and Methods: Spray drying of hydroalcoholic solution (25% v/v ethanol/water) of acetaminophen (5% w/v) in the presence of small amounts of polyninylpyrrolidone K30 (PVP) (0, 1.25, 2.5 and 5% w/w based on acetaminophen weight) was carried out. The properties of spray dried pa...

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

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    Khan Hira

    2016-01-01

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

  15. Hepatoprotective potential of threesargassum species from Karachi coast against carbon tetrachloride and acetaminophen intoxication

    Institute of Scientific and Technical Information of China (English)

    Khan Hira; Viqar Sultana; Jehan Ara; Syed Ehteshamul-Haque; Mohammad Athar

    2016-01-01

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

  16. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    OpenAIRE

    Maria Goretti R. Queiroz; José Henrique L. Cardoso; Adriana R. Tomé; Roberto C. P. Lima Jr.; Jamile M. Ferreira; Daniel F. Sousa; Felipe C. Lima; Campos, Adriana R.

    2008-01-01

    Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae) leaf essential oil (EOCz) was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o.) acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT), serum glutamate oxaloacetate transaminase (GOT) activities, that were significantly (p

  17. Effect of Tramadol/Acetaminophen on Motivation in Patients with Chronic Low Back Pain.

    Science.gov (United States)

    Tetsunaga, Tomoko; Tetsunaga, Tomonori; Tanaka, Masato; Nishida, Keiichiro; Takei, Yoshitaka; Ozaki, Toshifumi

    2016-01-01

    Background. The contribution of apathy, frequently recognized in individuals with neurodegenerative diseases, to chronic low back pain (LBP) remains unclear. Objectives. To investigate levels of apathy and clinical outcomes in patients with chronic LBP treated with tramadol-acetaminophen. Methods. A retrospective case-control study involving 73 patients with chronic LBP (23 male, 50 female; mean age 71 years) treated with tramadol-acetaminophen (n = 36) and celecoxib (n = 37) was performed. All patients were assessed using the self-reported questionnaires. A mediation model was constructed using a bootstrapping method to evaluate the mediating effects of pain relief after treatment. Results. A total of 35 (55.6%) patients met the criteria for apathy. A four-week treatment regimen in the tramadol group conferred significant improvements in the Apathy scale and numerical rating scale but not in the Rolland-Morris Disability Questionnaire, Pain Disability Assessment Scale, or Pain Catastrophizing Scale. The depression component of the Hospital Anxiety and Depression Scale was lower in the tramadol group than in the celecoxib group. The mediation analysis found that the impact of tramadol-acetaminophen on the change in apathy was not mediated by the pain relief. Conclusions. Tramadol-acetaminophen was effective at reducing chronic LBP and conferred a prophylactic motivational effect in patients with chronic LBP. PMID:27445626

  18. In vivo antioxidant activity of bark extract of Bixa orellana L. against acetaminophen- induced oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Smilin Bell Aseervatham G; Shamna R; Sangeetha B; Sasikumar JM

    2012-01-01

    Objective: To evaluate the in vivo activity of bark extract of Bixa orellana L. (B. orellana) against acetaminophen induced oxidative stress. Methods: In the present study, antioxidant activity ofB. orellana was evaluated by using normal and acetaminophen induced oxidative stressed rats at the dose of 100 mg/kg and 200 mg/kg p.o. oraly daily for 20 days. The animal's body weight was checked before and after treatment. Different biochemical parameters such as serum glutamate pyruvate transaminases, serum glutamate oxalo transaminases, alkaline phosphatase, total bilirubin, cholesterol, protein, lactate dehydrogenase, superoxide dismutase, catalase, ascorbic acid, lipid peroxide was performed. Histopathological analysis of the control and the hepatotoxicity induced rats were performed. Results: It was observed that the B. orellana bark extract showed significant protective activity against acetaminophen induced damage at 200 mg/kg dose level, while the 100 mg/kg dose showed moderate activity. Conclusions: From the result obtained in the present study suggest that B. orellana bark extract elicit protective activity through antioxidant activity on acetaminophen induced hepatic damage in rats.

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kappelle L Jaap

    2008-11-01

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

  1. AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver

    NARCIS (Netherlands)

    Hadi, Mackenzie; Dragovic, Sanja; van Swelm, Rachel; Herpers, Bram; van de Water, Bob; Russel, Frans G. M.; Commandeur, Jan N. M.; Groothuis, Geny M. M.

    2013-01-01

    N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic regioisomer of the well-known hepatotoxicant acetaminophen (APAP). However, so far, AMAP has only been shown to be non-toxic in mice and hamsters. To investigate whether AMAP could also be used as non-toxic analog of APAP in rat

  2. Effect of Tramadol/Acetaminophen on Motivation in Patients with Chronic Low Back Pain.

    Science.gov (United States)

    Tetsunaga, Tomoko; Tetsunaga, Tomonori; Tanaka, Masato; Nishida, Keiichiro; Takei, Yoshitaka; Ozaki, Toshifumi

    2016-01-01

    Background. The contribution of apathy, frequently recognized in individuals with neurodegenerative diseases, to chronic low back pain (LBP) remains unclear. Objectives. To investigate levels of apathy and clinical outcomes in patients with chronic LBP treated with tramadol-acetaminophen. Methods. A retrospective case-control study involving 73 patients with chronic LBP (23 male, 50 female; mean age 71 years) treated with tramadol-acetaminophen (n = 36) and celecoxib (n = 37) was performed. All patients were assessed using the self-reported questionnaires. A mediation model was constructed using a bootstrapping method to evaluate the mediating effects of pain relief after treatment. Results. A total of 35 (55.6%) patients met the criteria for apathy. A four-week treatment regimen in the tramadol group conferred significant improvements in the Apathy scale and numerical rating scale but not in the Rolland-Morris Disability Questionnaire, Pain Disability Assessment Scale, or Pain Catastrophizing Scale. The depression component of the Hospital Anxiety and Depression Scale was lower in the tramadol group than in the celecoxib group. The mediation analysis found that the impact of tramadol-acetaminophen on the change in apathy was not mediated by the pain relief. Conclusions. Tramadol-acetaminophen was effective at reducing chronic LBP and conferred a prophylactic motivational effect in patients with chronic LBP.

  3. A Biomedical Application of Activated Carbon Adsorption: An Experiment Using Acetaminophen and N-Acetylcysteine.

    Science.gov (United States)

    Rybolt, Thomas R.; And Others

    1988-01-01

    Illustrates an interesting biomedical application of adsorption from solution and demonstrates some of the factors that influence the in vivo adsorption of drug molecules onto activated charcoal. Uses acetaminophen and N-acetylcysteine for the determination. Suggests several related experiments. (MVL)

  4. Effect of pretreatment with acetaminophen-propoxyphene for oral surgery pain.

    Science.gov (United States)

    Liashek, P; Desjardins, P J; Triplett, R G

    1987-02-01

    To determine the effect of pretreatment and multiple doses on postsurgical pain, a study of the relative analgesic efficacy of placebo, acetaminophen 650 mg, and propoxyphene napsylate 100 mg alone and in combination was conducted. Forty-five patients undergoing surgical removal of impacted third molar teeth under local anesthesia were randomly allocated to the four treatment regimens under double-blind conditions. The first oral dose was administered one hour preoperatively and the second dose when the pain became moderate or severe, following the dissipation of the local anesthesia. Pain intensity and pain relief were assessed using standard verbal descriptor scales at 30 minutes and hourly for four hours after the postoperative dose. Measures of total effect, peak effect and duration of their effect were derived from these descriptors. Acetaminophen was no better than placebo. For peak and total effects, propoxyphene alone and the propoxyphene-acetaminophen combination were substantially superior to both placebo and acetaminophen alone. Duration of analgesia was also significantly longer with both propoxyphene-containing treatments. No side effects were reported. The results suggest that pretreatment with a narcotic agonist markedly improves postoperative analgesia. PMID:3468226

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

    Science.gov (United States)

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

    2014-09-01

    Acetaminophen is globally one of the most prescribed drugs due to its antipyretic and analgesic properties. However, it is highly toxic when the dosage surpasses the detoxification capability of an exposed organism, with involvement of an already described oxidative stress pathway. To address the issue of the ecotoxicity of acetaminophen, we performed acute exposures of two aquatic plant species, Lemna gibba and Lemna minor, to this compound. The selected biomarkers were number of fronds, biomass, chlorophyll content, lipid peroxidation (TBARS assay), and proline content. Our results showed marked differences between the two species. Acetaminophen caused a significant decrease in the number of fronds (EC50 = 446.6 mg/L), and the establishment of a dose-dependent peroxidative damage in L. minor, but not in L. gibba. No effects were reported in both species for the indicative parameters chlorophyll content and total biomass. However, the proline content in L. gibba was substantially reduced. The overall conclusions point to the occurrence of an oxidative stress scenario more prominent for L. minor. However, the mechanisms that allowed L. gibba to cope with acetaminophen exposure were distinct from those reported for L. minor, with the likely involvement of proline as antioxidant. PMID:24888614

  6. Antioxidant and hepatoprotective potential of Pouteria campechiana on acetaminophen-induced hepatic toxicity in rats.

    Science.gov (United States)

    Aseervatham, G Smilin Bell; Sivasudha, T; Sasikumar, J M; Christabel, P Hephzibah; Jeyadevi, R; Ananth, D Arul

    2014-03-01

    Pouteria campechiana (Kunth) Baehni. is used as a remedy for coronary trouble, liver disorders, epilepsy, skin disease, and ulcer. Therefore, the present study aims to investigate the antioxidant and hepatoprotective effect of polyphenolic-rich P. campechiana fruit extract against acetaminophen-intoxicated rats. Total phenolic and flavonoid contents of egg fruit were estimated followed by the determination of antioxidant activities. Treatment with P. campechiana fruit extract effectively scavenged the free radicals in a concentration-dependent manner within the range of the given concentrations in all antioxidant models. The presence of polyphenolic compounds were confirmed by high-performance thin-layer chromatography (HPTLC). The animals were treated with acetaminophen (250 mg/kg body weight; p.o.) thrice at the interval of every 5 days after the administration of P. campechiana aqueous extract and silymarin (50 mg/kg). Acetaminophen treatment was found to trigger an oxidative stress in liver, leading to an increase of serum marker enzymes. However, treatment with P. campechiana fruit extract significantly reduced the elevated liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) and increased the antioxidant enzymes (viz., superoxide dismutase and catalase) and glutathione indicating the effect of the extract in restoring the normal functional ability of hepatocytes. These results strongly suggest that P. campechiana fruit extract has strong antioxidant and significant hepatoprotective effect against acetaminophen-induced hepatotoxicity.

  7. Cats Have Nine Lives, but Only One Liver: The Effects of Acetaminophen

    Science.gov (United States)

    Dewprashad, Brahmadeo

    2009-01-01

    This case recounts the story of a student who gave her cat half of a Tylenol tablet not knowing its potential harmful effects. The cat survives, but the incident motivates the student to learn more about the reaction mechanism underlying the liver toxicity of acetaminophen. The case outlines three possible reaction schemes that would explain the…

  8. Effect of acetaminophen on fetal acid-base balance in chorioamnionitis.

    Science.gov (United States)

    Kirshon, B; Moise, K J; Wasserstrum, N

    1989-12-01

    The effect of antipyretic treatment with acetaminophen on fetal status was examined in eight laboring women febrile with chorioamnionitis. After a fetal heart rate tracing and scalp blood gas level were obtained near maximum maternal fever, a 650-mg acetaminophen suppository was administered. If the temperature remained greater than 101 degrees F, the dose was repeated in one to two hours. The fetal heart rate tracing was analyzed again after the mother's fever was reduced by acetaminophen. All patients delivered within four hours of the first dose. Umbilical artery blood gases were obtained at delivery. Significant improvements in the bicarbonate concentration and base deficit were noted at the time of delivery as compared to the scalp gas at the height of the maternal fever. The fetal heart rate tracings at the height of the maternal fever, characterized by tachycardia, poor variability and late decelerations, changed to a normal heart rate pattern without decelerations when the mother's fever was reduced. Hence, in the laboring gravida with chorioamnionitis, reducing maternal fever with acetaminophen improves fetal status and thereby may reduce the probability of cesarean section for fetal distress. PMID:2621737

  9. Differential effect of cigarette smoking on antipyrine oxidation versus acetaminophen conjugation.

    Science.gov (United States)

    Scavone, J M; Greenblatt, D J; LeDuc, B W; Blyden, G T; Luna, B G; Harmatz, J S

    1990-01-01

    The effect of cigarette smoking on drug oxidation and conjugation was studied using antipyrine and acetaminophen as marker compounds. For the antipyrine study, healthy cigarette smokers (n = 30) and nonsmoking controls (n = 53) received a single 1.0-gram intravenous dose of antipyrine. For the acetaminophen study, 14 smokers and 15 nonsmokers received a 650-mg intravenous dose of acetaminophen. The clearance of antipyrine was significantly increased (0.93 vs. 0.60 ml/min/kg, p less than 0.0001) and elimination half-life was correspondingly reduced (8.9 vs. 13.0 h, p less than 0.0001) in smokers compared to nonsmoking controls. Total recovery of antipyrine and metabolites excreted in urine did not differ between groups, but there was a significantly increased fractional clearance of antipyrine via formation of 4-hydroxyantipyrine and 3-hydroxymethyl metabolites in smokers. Fractional clearance via formation of norantipyrine did not differ significantly between groups. Comparison of acetaminophen kinetics between smokers and nonsmokers indicated no significant differences in elimination half-life, clearance or volume of distribution. Thus, cigarette smoking is more likely to induce drug oxidation rather than drug conjugation. However, not all oxidative pathways are equally influenced; induction effects of smoking are highly substrate selective and pathway specific. PMID:2345775

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

    NARCIS (Netherlands)

    Swelm, R.P.L. van; Laarakkers, J.M.M.; Blous, L.; Peters, J.G.P.; Blaney Davidson, E.N.; Kraan, P.M. van der; Swinkels, D.W.; Masereeuw, R.; Russel, F.G.M.

    2012-01-01

    Acetaminophen (APAP), a major cause of acute liver injury in the Western world, is mediated by metabolism and oxidative stress. Recent studies have suggested a role for iron in potentiating APAP-induced liver injury although its regulatory mechanism is not completely understood. The current study wa

  11. Effect of corn silk extract on acetaminophen induced renal damage in mice

    International Nuclear Information System (INIS)

    To evaluate the protective role of Corn Silk extract on Acetaminophen induced nephrotoxicity in albino mice. Study Design: Laboratory based randomized controlled trials. Place and Duration of Study: The study was carried out in experimental research laboratory University of Health Sciences and Anatomy department, Lahore. The study duration was one year from February 2012 to February 2013. Material and Methods: Twenty seven male albino mice, 6-8 weeks old weighing 30 + 5 gm, were used; these animals were randomly divided into three groups having nine mice in each group. Group A served as control and was given 16.6ml/kg normal saline intraperitoneally on first day of experiment and was sacrificed on 10th day of the experiment. Group B was treated with acetaminophen 600 mg/kg dissolved in 16.6 ml of normal saline intraperitoneally on 1st day of experiment and was sacrificed after 48 hours. Group C was given acetaminophen at a dose of 600 mg/kg intraperitoneally on first day of experiment and then corn silk extract was given by oral route at a dose of 400 mg/kg for next 8 days. The animals were sacrificed on 10th day of the experiment, the kidneys were removed; 3mm three tissue pieces were fixed in 10% formaline; processed and stained with H and E for histological study. Results: It was observed on microscopic examination that Corn silk extract reduced deleterious effects of acetaminophen on tubules of kidney as evidenced by reduction of tubular vacuolation and necrosis, absence of protein casts, vascular congestion and inflammation. Conclusion: It is concluded from current results that corn silk extract protects acetaminophen induced nephrotoxicity. (author)

  12. Enhanced photoactivity of graphene/titanium dioxide nanotubes for removal of Acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Hong; Liang, Xiao [School of Environment and Architecture, University of Shanghai for Science and Technology, Shanghai 200093 (China); Zhang, Qian [Graduate Institute of Environmental Engineering, National Taiwan University, 10617, Taiwan (China); Chang, Chang-Tang, E-mail: ctchang@niu.edu.tw [Department of Environmental Engineering, National I-Lan University, 26047, Taiwan (China)

    2015-01-01

    Highlights: • TiO{sub 2} and graphite oxide were used as precursors of titanium dioxide nanotubes and graphene respectively. Titanium dioxide nanotube and graphene (GR-TNT) nanocomposites were synthesized through a simple hydrothermal method. • And its application to removal acetaminophen, degradation efficiency is more than 96%. • The photocatalytic degradation results indicated that the sample with 5% GO in GR-TNT nanocomposites for 3 h had the highest degradation rate. • The degradation intermediates of acetaminophen by the composites were invested by GC-MS and the possible pathways were invested. - Abstract: Acetaminophen is commonly used as an antipyretic or analgesics agent and poses threat to human health. In this research, TiO{sub 2} and graphite oxide were used as precursors of titanium dioxide nanotubes and graphene respectively. Titanium dioxide nanotube and graphene (GR-TNT) nanocomposites were synthesized through a hydrothermal method. FT-IR, UV-Vis, XRD, and TGA were used to characterize the catalysts. The acetaminophen degradation rate can reach up to 96% under UV light irradiation for 3 h and with the 5% GR-TNT dosage of 0.1 g L{sup −1}. Further experiments were done to probe the mechanism of the photocatalytic reaction catalyzed by the GR-TNT composite. EDTA (hole scavengers) and t-BuOH (radical scavengers) were used to detect the main active oxidative species in the system. The results showed that the holes are the main oxidation species in the photocatalytic process. This study provides a new prospect for acetaminophen degradation by using high efficiency catalysts.

  13. Acetaminophen structure-toxicity studies: In vivo covalent binding of a nonhepatotoxic analog, 3-hydroxyacetanilide

    Energy Technology Data Exchange (ETDEWEB)

    Roberts, S.A.; Price, V.F.; Jollow, D.J. (Medical Univ. of South Carolina, Charleston (USA))

    1990-09-01

    High doses of 3-hydroxyacetanilide (3HAA), a structural isomer of acetaminophen, do not produce hepatocellular necrosis in normal male hamsters or in those sensitized to acetaminophen-induced liver damage by pretreatment with a combination of 3-methylcholanthrene, borneol, and diethyl maleate. Although 3HAA was not hepatotoxic, the administration of acetyl-labeled (3H or 14C)3HAA (400 mg/kg, ip) produced levels of covalently bound radiolabel that were similar to those observed after an equimolar, hepatotoxic dose of (G-3H)acetaminophen. The covalent nature of 3HAA binding was demonstrated by retention of the binding after repetitive organic solvent extraction following protease digestion. Hepatic and renal covalent binding after 3HAA was approximately linear with both dose and time. In addition, 3HAA produced only a modest depletion of hepatic glutathione, suggesting the lack of a glutathione threshold. 3-Methylcholanthrene pretreatment increased and pretreatment with cobalt chloride and piperonyl butoxide decreased the hepatic covalent binding of 3HAA, indicating the involvement of cytochrome P450 in the formation of the 3HAA reactive metabolite. The administration of multiple doses or a single dose of (ring-3H)3HAA to hamsters pretreated with a combination of 3-methylcholanthrene, borneol, and diethyl maleate produced hepatic levels of 3HAA covalent binding that were in excess of those observed after a single, hepatotoxic acetaminophen dose. These data suggest that the nature and/or the intracellular processing of the reactive metabolites of acetaminophen and 3HAA are different. These data also demonstrate that absolute levels of covalently bound xenobiotic metabolites cannot be utilized as absolute predictors of cytotoxic potential.

  14. Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Trabert, Britton; Ness, Roberta B; Lo-Ciganic, Wei-Hsuan;

    2014-01-01

    BACKGROUND: Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS: We analyzed pooled data from 12 ...

  15. Effect of Momordica charantia (bitter melon on serum glucose level and various protein parameters in acetaminophen intoxicated rabbits

    Directory of Open Access Journals (Sweden)

    Kanwal Zahra

    2012-02-01

    Full Text Available Aim: Liver function tests, including total plasma proteins, albumin, bilirubin and glucose were analyzed to find out the hepatocurative and hepatoprotective effects of Momordica charantia. Method: The study was divided into two categories. In first category, the livers of rabbits were intoxicated with acetaminophen, and then Momordica fruit extract was given to observe its hepatocurative effects. Results: The results indicated significant changes in concentrations of the parameters in acetaminophen-challenged rabbits. In the second category, treatment was started by giving Momordica fruit extract dose orally for 10 days and 15 days to two groups of rabbits, respectively. Then, livers of rabbits were damaged with acetaminophen and hepatoprotective effects of Momordica were observed. Conclusion: The results showed that the animals treated with Momordica fruit extract experienced less liver damage due to acetaminophen intoxication, indicating that Momordica has hepatoprotective properties. [J Intercult Ethnopharmacol 2012; 1(1.000: 7-12

  16. Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults

    DEFF Research Database (Denmark)

    Carroll, Chad C; Dickinson, Jared M; Lemoine, Jennifer K;

    2011-01-01

    Millions of older individuals consume acetaminophen or ibuprofen daily and these same individuals are encouraged to participate in resistance training. Several in vitro studies suggest that cyclooxygenase-inhibiting drugs can alter tendon metabolism and may influence adaptations to resistance...

  17. Impact of intravenous acetaminophen therapy on the necessity of cervical spine imaging in patients with cervical spine trauma

    Institute of Scientific and Technical Information of China (English)

    Koorosh Ahmadi; Amir Masoud Hashemian; Elham Pishbin; Mahdi Sharif-Alhoseini; Vafa Rahimi-Movaghar

    2014-01-01

    Objective:We evaluated a new hypothesis of acetaminophen therapy to reduce the necessity of imaging in patients with probable traumatic cervical spine injury.Methods:Patients with acute blunt trauma to the neck and just posterior midline cervical tenderness received acetaminophen (15 mg/kg) intravenously after cervical spine immobilization.Then,all the patients underwent plain radiography and computerized tomography of the cervical spine.The outcome measure was the presence of traumatic cervical spine injury.Sixty minutes after acetaminophen infusion,posterior midline cervical tendemess was reassessed.Results:Of 1 309 patients,41 had traumatic cervical spine injuries based on imaging.Sixty minutes after infusion,posterior midline cervical tenderness was eliminated in 1 041 patients,none of whom had abnormal imaging.Conclusion:Patients with cervical spine trauma do not need imaging if posterior midline cervical tendemess is eliminated after acetaminophen infusion.This analgesia could be considered as a diagnostic and therapeutic intervention.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-15

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

  19. A randomized placebo-controlled trial of acetaminophen for prevention of post-vaccination fever in infants.

    Directory of Open Access Journals (Sweden)

    Lisa A Jackson

    Full Text Available BACKGROUND: Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States. METHODS: Children six weeks through nine months of age were randomized 1:1 to receive up to five doses of acetaminophen (10-15 mg per kg or placebo following routine vaccinations. The primary outcome was a rectal temperature ≥38°C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo. RESULTS: A temperature ≥38°C was recorded for 14% (25/176 of children randomized to acetaminophen compared with 22% (37/176 of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40-1.01. Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24% (RR, 0.42; 95% CI, 0.25-0.70 or to have the treatment assignment unblinded (3% vs 9% (RR, 0.31; 95% CI, 0.11-0.83 than those randomized to placebo. In age-stratified analyses, among children ≥24 weeks of age, there was a significantly lower risk of temperature ≥38°C in the acetaminophen group (13% vs. 25%; p = 0.03. CONCLUSION: The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness. TRIAL REGISTRATION: Clinicaltrials.gov NCT00325819.

  20. Role of Protective Effect of L-Carnitine against Acute Acetaminophen Induced Hepatic Toxicity in Adult Albino Rats

    OpenAIRE

    Zeinab M. Gebaly* and Gamal M. Aboul Hassan

    2012-01-01

    Background: Acetaminophen, a widely used analgesic and antipyretic is known to cause hepatic injury in humans and experimental animals when administered in high doses. It was reported that toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. L-carnitine is a cofactor in the transfer of long-chain fatty acid allowing to the beta-oxidation of fatty acid in the mitochondria. It is a known antioxidant with protective effects against lipid peroxidati...

  1. Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity

    OpenAIRE

    Kim, Yoon-Jeong; Lim, Kyung-Hwan; Kim, Mi-Young; Jo, Eun-Jung; Lee, Suh-Young; Lee, Seung-Eun; Yang, Min-Suk; Song, Woo-Jung; Kang, Hye-Ryun; Park, Heung-Woo; Chang, Yoon-Seok; Cho, Sang-Heon; Min, Kyung-Up; Kim, Sae-Hoon

    2013-01-01

    Purpose Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance. Methods We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral prov...

  2. Effects of Acetaminophen on Oxidant and Irritant Respiratory Tract Responses to Environmental Tobacco Smoke in Female Mice

    OpenAIRE

    Smith, Gregory J.; Cichocki, Joseph A.; Doughty, Bennett J.; Manautou, Jose E.; Jordt, Sven-Eric; Morris, John B.

    2015-01-01

    Background: Although it is known that acetaminophen causes oxidative injury in the liver, it is not known whether it causes oxidative stress in the respiratory tract. If so, this widely used analgesic may potentiate the adverse effects of oxidant air pollutants. Objectives: The goal of this study was to determine if acetaminophen induces respiratory tract oxidative stress and/or potentiates the oxidative stress and irritant responses to an inhaled oxidant: environmental tobacco smoke (ETS). M...

  3. Role of Protective Effect of L-Carnitine against Acute Acetaminophen Induced Hepatic Toxicity in Adult Albino Rats

    Directory of Open Access Journals (Sweden)

    Zeinab M. Gebaly* and Gamal M. Aboul Hassan

    2012-10-01

    Full Text Available Background: Acetaminophen, a widely used analgesic and antipyretic is known to cause hepatic injury in humans and experimental animals when administered in high doses. It was reported that toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. L-carnitine is a cofactor in the transfer of long-chain fatty acid allowing to the beta-oxidation of fatty acid in the mitochondria. It is a known antioxidant with protective effects against lipid peroxidation. This study aimed to investigate the possible beneficial effect of L-carnitine as an antioxidant agent against acetaminophen induced hepatic toxicity in rats. Material and Methods: Four rat groups (N=7 in each group. Group I is the control, group II received 500 mg/kg/ body weight of L-carnitine for 7 days by oral route, group III received 640/kg/ bw of acetaminophen by oral route, group IV acute acetaminophen group pretreated with L-carnitine for 7 days by gastric tube gavage tube. The liver of all rats were removed for investigation using light and electro microscopic studies. Results: Acetaminophen caused massive centrilobular necrosis and massive degenerative changes. The electron-microscopic study showed few mitochondria, increased fat droplets and scanty smooth endoplasmic reticulum (SER, rough endoplasmic reticulum (RER.These changes were reduced by L-carnitine pretreatment. Conclusion: those results suggest that acetaminophen results damage in the liver as an acute effect and L-carnitine ameliorated the adverse effects of acetaminophen via its antioxidant role

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

    Energy Technology Data Exchange (ETDEWEB)

    McGill, Mitchell R.; Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Norris, Hye-Ryun K.; Slawson, Matthew H. [Center for Human Toxicology, University of Utah, Salt Lake City, UT (United States); Bajt, Mary Lynn; Xie, Yuchao; Williams, C. David [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Wilkins, Diana G.; Rollins, Douglas E. [Center for Human Toxicology, University of Utah, Salt Lake City, UT (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    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

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

    Science.gov (United States)

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

    2016-06-01

    Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; Pchildren (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.

  6. Targeted metabolomic study indicating glycyrrhizin’s protection against acetaminophen-induced liver damage through reversing fatty acid metabolism.

    Science.gov (United States)

    Yu, Jian; Jiang, Yang-Shen; Jiang, Yuan; Peng, Yan-Fang; Sun, Zhuang; Dai, Xiao-Nan; Cao, Qiu-Ting; Sun, Ying-Ming; Han, Jing-Chun; Gao, Ya-Jie

    2014-06-01

    The present study aimed to give a short report on a possible mechanism of glycyrrhizin to acetaminophen-induced liver toxicity. Seven-day intraperitoneal administration of glycyrrhizin (400 mg/kg/day) to 2- to 3-month-old male C57BL/6N mice (mean weight 27 g) significantly prevents acetaminophen-induced liver damage, as indicated by the activity of alanine transaminase and aspartate aminotransferase. Metabolomics analysis and principal component analysis (PCA) using ultra-fast liquid chromatography coupled to triple time-of-flight mass spectrometer were performed. PCA separated well the control, glycyrrhizin-treated, acetaminophen-treated, and glycyrrhizin+acetaminophen-treated groups. Long-chain acylcarnitines were listed as the top ions that contribute to this good separation, which include oleoylcarnitine, palmitoylcarnitine, palmitoleoylcarnitine, and myristoylcarnitine. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by acetaminophen administration. In conclusion, this metabolomic study indicates a significant glycyrrhizin protection effect against acetaminophen-induced liver damage through reversing fatty acid metabolism.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2011-12-01

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

  9. Improvement of Physico-mechanical Properties of Partially Amorphous Acetaminophen Developed from Hydroalcoholic Solution Using Spray Drying Technique

    Directory of Open Access Journals (Sweden)

    Fatemeh Sadeghi

    2013-10-01

    Full Text Available   Objective(s: This study was performed aiming to investigate the effect of particle engineering via spray drying of hydroalcoholic solution on solid states and physico-mechanical properties of acetaminophen.   Materials and Methods: Spray drying of hydroalcoholic solution (25% v/v ethanol/water of acetaminophen (5% w/v in the presence of small amounts of polyninylpyrrolidone K30 (PVP (0, 1.25, 2.5 and 5% w/w based on acetaminophen weight was carried out. The properties of spray dried particles namely morphology, surface characteristics, particle size, crystallinity, dissolution rate and compactibility were evaluated. Results: Spray drying process significantly changed the morphology of acetaminophen crystals from acicular (rod shape to spherical microparticle. Differential scanning calorimetery (DSC and x-ray powder diffraction (XRPD studies ruled out any polymorphism in spray dried samples, however, a major reduction in crystallinity up to 65%, especially for those containing 5% w/w PVP was observed. Spray dried acetaminophen particles especially those obtained in the presence of PVP exhibited an obvious improvement of the dissolution and compaction properties. Tablets produced from spray dried samples exhibited excellent crushing strengths and no tendency to cap. Conclusions: The findings of this study revealed that spray drying of acetaminophen from hydroalcoholic solution in the presence of small amount of PVP produced partially amorphous particles with improved dissolution and excellent compaction properties.

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

    Science.gov (United States)

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

    2009-08-01

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

  11. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility.

    Science.gov (United States)

    Lopes, Renato D; Horowitz, John D; Garcia, David A; Crowther, Mark A; Hylek, Elaine M

    2011-12-01

    Ms TS is a 66-year-old woman who receives warfarin for prevention of systemic embolization in the setting of hypertension, diabetes, and atrial fibrillation. She had a transient ischemic attack about 4 years ago when she was receiving aspirin. Her INR control was excellent; however, over the past few months it has become erratic, and her average dose required to maintain an INR of 2.0 to 3.0 appears to have decreased. She has had back pain over this same period and has been taking acetaminophen at doses at large as 650 mg four times daily, with her dose varying based on her symptoms. You recall a potential interaction and wonder if (1) her acetaminophen use is contributing to her loss of INR control, and (2) does this interaction place her at increased risk of warfarin-related complications? PMID:21911832

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

    Science.gov (United States)

    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

  13. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

    OpenAIRE

    Henderson, Colin J.; Wolf, C. Roland; Kitteringham, Neil; Powell, Helen; Otto, Diana; Park, B. Kevin

    2000-01-01

    Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in ...

  14. Simultaneous Spectrophotometric Determination of Four Components including Acetaminophen by Taget Factor Analysis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    UV Spectrophotometric Target Factor Analysis (TFA) was used for the simultaneous determination of four components (acetaminophen, guuaifenesin, caffeine, Chlorphenamine maleate) in cough syrup. The computer program of TFA is based on VC++ language. The difficulty of overlapping of absorption spectra of four compounds was overcome by this procedure. The experimental results show that the average recovery of each component is all in the range from 98.9% to 106.8% and each component obtains satisfactory results without any pre-separation.

  15. Activation of the Farnesoid X Receptor Provides Protection against Acetaminophen-Induced Hepatic Toxicity

    OpenAIRE

    Lee, Florence Ying; de Aguiar Vallim, Thomas Quad; Chong, Hansook Kim; Zhang, Yanqiao; Liu, Yaping; Jones, Stacey A.; Osborne, Timothy F.; Edwards, Peter A.

    2010-01-01

    The nuclear receptor, farnesoid X receptor (FXR, NR1H4), is known to regulate cholesterol, bile acid, lipoprotein, and glucose metabolism. In the current study, we provide evidence to support a role for FXR in hepatoprotection from acetaminophen (APAP)-induced toxicity. Pharmacological activation of FXR induces the expression of several genes involved in phase II and phase III xenobiotic metabolism in wild-type, but not Fxr−/− mice. We used chromatin immunoprecipitation-based genome-wide resp...

  16. Carbon Based Electrodes Modified with Horseradish Peroxidase Immobilized in Conducting Polymers for Acetaminophen Analysis

    OpenAIRE

    Cecilia Cristea; Robert Sandulescu; Anca Florea; Mihaela Tertis

    2013-01-01

    The development and optimization of new biosensors with horseradish peroxidase immobilized in carbon nanotubes-polyethyleneimine or polypyrrole nanocomposite film at the surface of two types of transducer is described. The amperometric detection of acetaminophen was carried out at −0.2 V versus Ag/AgCl using carbon based-screen printed electrodes (SPEs) and glassy carbon electrodes (GCEs) as transducers. The electroanalytical parameters of the biosensors are highly dependent on their configur...

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

    OpenAIRE

    Yang Runkuan; Zhang Shutian; Kajander Henri; Zhu Shengtao; Koskinen Marja-Leena; Tenhunen Jyrki

    2011-01-01

    Abstract Background Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Liver regeneration is a vital process for survival after a toxic insult. Since hepatocytes are mostly in a quiescent state (G0), the regeneration process requires the priming of hepatocytes by cytokines such as TNF-α and IL-6. Ringer's lactate solution (RLS) has been shown to increase serum TNF-α and IL-6 in patients and experimental animals; in addition, RLS also provides lactate, which can be used as an a...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Godrat Akhavanakbari

    2013-01-01

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

  20. Paracetamol/Acetaminophen (Single Administration) for Perineal Pain in the Early Postpartum Period

    OpenAIRE

    Chou, D; Abalos, E.; Gyte, G M; Gulmezoglu, A. M.

    2010-01-01

    BACKGROUND: Perineal pain is a common but poorly studied adverse outcome following childbirth. Pain may result from perineal trauma due to bruising, spontaneous tears, surgical incisions (episiotomies), or in association with operative births (ventouse or forceps assisted births). OBJECTIVES: To determine the efficacy of a single administration of paracetamol (acetaminophen) systemic drugs used in the relief of acute postpartum perineal pain SEARCH STRATEGY: We searched the Cochrane Pregnancy...

  1. Can intravenous acetaminophen reduce the needs to more opioids to control pain in intubated patients?

    Directory of Open Access Journals (Sweden)

    Babak Mahshidfar

    2016-01-01

    Full Text Available Aims: To evaluate the effect of intravenous (IV acetaminophen on reducing the need for morphine sulfate in intubated patients admitted to the Intensive Care Unit (ICU. Settings and Design: Current study was done as a clinical trial on the patients supported by mechanical ventilator. Subjects and Methods: Behavioral pain scale (BPS scoring system was used to measure pain in the patients. All of the patients received 1 g, IV acetaminophen, every 6 h during the 1 st and 3 rd days of admission and placebo during the 2 nd and 4 th days. Total dose of morphine sulfate needed, its complications, and the BPS scores at the end of every 6 h interval were compared. Results: Totally forty patients were enrolled. The mean pain scores were significantly lower in the 2 nd and 4 th days (4.33 and 3.66, respectively; mean: 4.0 in which the patients had received just morphine sulfate compared to the 1 st and 3 rd days (7.36 and 3.93, respectively; mean: 5.65 in which the patients had received acetaminophen in addition to morphine sulfate too (P < 0.001. Cumulative dose of morphine sulfate used, was significantly higher in the 1 st and 3 rd days (8.92 and 3.15 mg, respectively; 12.07 mg in total compared to the 2 nd and 4 th days (6.47 mg and 3.22 mg, respectively; 9.7 mg in total (P = 0.035. Conclusion: In our study, IV acetaminophen had no effect on decreasing the BPSs and need of morphine sulfate in intubated patients admitted to ICU.

  2. Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

    OpenAIRE

    Borlak, Jürgen; Chatterji, Bijon; Londhe, Kishor B; Watkins, Paul B

    2013-01-01

    Background Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (...

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

    OpenAIRE

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

    2014-01-01

    Honey, a supersaturated natural product of honey bees, contains complex compounds with antioxidant properties and therefore has a wide a range of applications in both traditional and modern medicine. In the present study, the protective effects of Sundarban honey from Bangladesh against acetaminophen- (APAP-) induced hepatotoxicity and nephrotoxicity in experimental rats were investigated. Adult male Wistar rats were pretreated with honey (5 g/kg) for 4 weeks, followed by the induction of hep...

  4. Utilization of Cellulose from Luffa cylindrica Fiber as Binder in Acetaminophen Tablets

    Directory of Open Access Journals (Sweden)

    John Carlo O. Macuja

    2015-01-01

    Full Text Available Cellulose is an important pharmaceutical excipient. This study aimed to produce cellulose from the fiber of Luffa cylindrica as an effective binder in the formulation of acetaminophen tablets. This study was divided into three phases, namely, (I preparation of cellulose from Luffa cylindrica, (II determination of the powder properties of the LC-cellulose, and (III production and evaluation of acetaminophen of the tablets produced using LC-cellulose as binder. The percentage yield of LC-cellulose was 61%. The values of the powder properties of LC-cellulose produced show fair and passable flow properties and are within the specifications of a powdered pharmaceutical excipient. The mean tablet hardness and disintegration time of the LC-cellulose tablets have a significant difference in the mean tablet hardness and disintegration time of the tablets without binder; thus the cellulose produced improved the suitability of acetaminophen in the dry compression process. However, the tablet properties of the tablets produced using LC-cellulose as binder do not conform to the specifications of the US pharmacopeia; thus the study of additional methods and excipients is recommended.

  5. Antioxidant and Hepatoprotective Properties of Tofu (Curdle Soymilk against Acetaminophen-Induced Liver Damage in Rats

    Directory of Open Access Journals (Sweden)

    Ndatsu Yakubu

    2013-01-01

    Full Text Available The antioxidant and hepatoprotective properties of tofu using acetaminophen to induce liver damage in albino rats were evaluated. Tofus were prepared using calcium chloride, alum, and steep water as coagulants. The polyphenols of tofu were extracted and their antioxidant properties were determined. The weight gain and feed intake of the rats were measured. The analysis of serum alanine aminotransferase (ALT, alkaline phosphatase (ALP, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH activities and the concentrations of albumin, total protein, cholesterol, and bilirubin were analyzed. The result reveals that the antioxidant property of both soluble and bound polyphenolic extracts was significantly higher in all tofus, but the steep water coagulated tofu was recorded higher. Rats fed with various tofus and acetaminophen had their serum ALP, ALT, AST, and LDH activities; total cholesterol; and bilirubin levels significantly (P<0.05 reduced, and total protein and albumin concentrations increased when compared with basal diet and acetaminophen administered group. Therefore, all tofus curdled with various coagulants could be used to prevent liver damage caused by oxidative stress.

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

    Directory of Open Access Journals (Sweden)

    Bekhit MH

    2015-10-01

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

  7. One-step electrodeposition of graphene loaded nickel oxides nanoparticles for acetaminophen detection.

    Science.gov (United States)

    Liu, Gui-Ting; Chen, Hui-Fen; Lin, Guo-Ming; Ye, Ping-ping; Wang, Xiao-Ping; Jiao, Ying-Zhi; Guo, Xiao-Yu; Wen, Ying; Yang, Hai-Feng

    2014-06-15

    An electrochemical sensor of acetaminophen (AP) based on electrochemically reduced graphene (ERG) loaded nickel oxides (Ni2O3-NiO) nanoparticles coated onto glassy carbon electrode (ERG/Ni2O3-NiO/GCE) was prepared by a one-step electrodeposition process. The as-prepared electrode was characterized by scanning electron microscopy, X-ray photoelectron spectroscopy and Raman spectroscopy. The electrocatalytic properties of ERG/Ni2O3-NiO modified glassy carbon electrode toward the oxidation of acetaminophen were analyzed via cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The electrodes of Ni2O3-NiO/GCE, ERG/GCE, and Ni2O3-NiO deposited ERG/GCE were fabricated for the comparison and the catalytic mechanism understanding. The studies showed that the one-step prepared ERG/Ni2O3-NiO/GCE displayed the highest electro-catalytic activity, attributing to the synergetic effect derived from the unique composite structure and physical properties of nickel oxides nanoparticles and graphene. The low detection limit of 0.02 μM (S/N=3) with the wide linear detection range from 0.04 μM to 100 μM (R=0.998) was obtained. The resulting sensor was successfully used to detect acetaminophen in commercial pharmaceutical tablets and urine samples.

  8. Enhanced photoactivity of graphene/titanium dioxide nanotubes for removal of Acetaminophen

    Science.gov (United States)

    Tao, Hong; Liang, Xiao; Zhang, Qian; Chang, Chang-Tang

    2015-01-01

    Acetaminophen is commonly used as an antipyretic or analgesics agent and poses threat to human health. In this research, TiO2 and graphite oxide were used as precursors of titanium dioxide nanotubes and graphene respectively. Titanium dioxide nanotube and graphene (GR-TNT) nanocomposites were synthesized through a hydrothermal method. FT-IR, UV-Vis, XRD, and TGA were used to characterize the catalysts. The acetaminophen degradation rate can reach up to 96% under UV light irradiation for 3 h and with the 5% GR-TNT dosage of 0.1 g L-1. Further experiments were done to probe the mechanism of the photocatalytic reaction catalyzed by the GR-TNT composite. EDTA (hole scavengers) and t-BuOH (radical scavengers) were used to detect the main active oxidative species in the system. The results showed that the holes are the main oxidation species in the photocatalytic process. This study provides a new prospect for acetaminophen degradation by using high efficiency catalysts.

  9. Zirconyl acetaminophen phosphate: A nanoscaled analgetic with very high drug load.

    Science.gov (United States)

    Heck, Joachim G; Feldmann, Claus

    2016-11-01

    Drug release belongs to the most challenging aspects of nanoparticles addressing molecular biology and medicine. Besides targeted delivery, obvious challenges are related to high drug load and continuous slow drug release. Based on our recently developed concept of inorganic-organic hybrid nanoparticles (IOH-NP), we here present [ZrO](2+)[AAP](2-) IOH-NPs containing the analgetic phosphate prodrug acetaminophen phosphate for drug release. [ZrO](2+)[AAP](2-) combines an uncomplex synthesis in water with a high prodrug load of 68wt.%. [ZrO](2+)[AAP](2-) nanoparticles exhibit a diameter of 37(11)nm and can be readily obtained as colloidally highly stable suspension in water. The chemical composition is studied in detail based on infrared spectroscopy, energy-dispersive X-ray analysis, thermogravimetry and elemental analysis. Moreover, the release of acetaminophen from [ZrO](2+)[AAP](2-) is studied by means of model experiments indicating the carbon content of the nanoparticles and, in alternative, the fluorescence of labeled nanoparticles. Both data show a continuous release of 80wt.% of the analgetic acetaminophen on a time scale up to 48h. PMID:27451036

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Science.gov (United States)

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

    2015-12-01

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

  12. Use of acetylcysteine for non-acetaminophen-induced acute liver failure.

    Science.gov (United States)

    Sales, Ibrahim; Dzierba, Amy L; Smithburger, Pamela L; Rowe, Deanna; Kane-Gill, Sandra L

    2013-01-01

    The purpose of this review was to evaluate the effectiveness of acetylcysteine in the treatment of acute liver failure not related to acetaminophen. A search of MEDLINE April 2003 through May 2012 using the Pub Med database was conducted using the keywords acetylcysteine and non-acetaminophen-induced acute liver failure or acetylcysteine and liver failure. All human case reports, case series, and research articles that discussed the use of acetylcysteine for non-acetaminophen induced liver failure were evaluated. A total of 263 articles were identified during this broad search with 11 articles included for review in this article; eight case reports, two retrospective trials, and one prospective, randomized, double-blind multicenter study. In conclusion, the data suggest marginal benefit of IV acetylcysteine in NAI-ALF with coma grades I-II; however, the routine use of acetylcysteine cannot be recommended. It may be considered in non-transplant centers while awaiting referral or when transplantation is not an option. Further studies are necessary to determine optimal dosing, duration, and criteria for patient selection.

  13. Ibuprofen versus Acetaminophen in Controlling Postoperative Impacted Third Molar Tooth Extraction Pain

    International Nuclear Information System (INIS)

    Objectives: To compare the efficacy of ibuprofen and acetaminophen in reducing postoperative third molar extraction pain in patients reporting to Armed Forces Institute of Dentistry. Study design: Randomized controlled trial. Place and duration of study: The study was carried out on patients who presented for surgical removal of impacted teeth at Armed Forces Institute of Dentistry Rawalpindi (AFID) from February 2008 to March 2--9 at the Department of Oral Surgery, Armed Forces Institute of Dentistry Rawalpindi. Patients and methods: One hundred and forty patients requiring surgical removal of mandibular impacted teeth were equally divided into two groups. Surgical extraction of third molar tooth was performed under local anesthesia. Patients in group A were given ibuprofen and in group B were given acetaminophen at 6 hourly intervals. First dose was given 3 hours postoperatively. Each patient rated pain on a visual analog scale at baseline and then at 12, 24, 48 and 72 hours postoperatively. Results: There was statistically significant difference (p=0.025) during first 12 hours with ibuprofen group showing better efficacy but afterwards there was no significant difference in the efficacy of both drugs. Conclusions: Ibuprofen is more effective in controlling severe third molar extraction pain as compared to acetaminophen but has similar efficacy in controlling moderate pain. (author)

  14. Some physicochemical properties of acetaminophen pediatric suspensions formulated with okra gums obtained from different extraction processes as suspending agent

    Directory of Open Access Journals (Sweden)

    Ikoni Ogaji

    2011-01-01

    Full Text Available The purpose of this work was to evaluate the effect of the extraction process and the potential of okra gum as a suspending agent in pharmaceutical oral formulations containing acetaminophen as a model drug. Clarified mucilage of dried okra was either extracted directly with ethanol 96% (F1 or was first treated with base (F2, acid (F3 or heating in the presence of salt (F4 before extraction with ethanol 96%. The samples were used at 0.5% w/v as suspending agents in acetaminophen acetaminophen suspension to deliver 125 mg/5 mL acetaminophen. A binary mixture of F2 and F4 (1:1 was also used. Similar suspensions of acetaminophen containing either hydroxymethylpropylcellulose (HPMC or tragacanth gum (TRAGA were produced. Some physicochemical properties of the formulations were evaluated. The rheological properties of acetaminophen-containing treated okra gums (F2-F5 were generally similar. Changes in viscosity with storage were slower in the F2-F5 formulations as compared with F1. Particle size and particle size distribution were different for all formulations, and hysteresis was a function of time and the suspending agent used. The re-dispersion time of the formulations with treated okra gums was generally shorter than that observed with the untreated okra gum. The use of a binary mixture of F2 and F4 resulted in different physicochemical properties from those of either F2 or F4. The physicochemical properties of the formulations were comparable to those with HPMC and TRAGA. It can thus be concluded that treating okra gum with acid, base or salt impacted better physicochemical properties on an acetaminophen pediatric suspension when they were used as suspending agents.

  15. Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes.

    Science.gov (United States)

    Kon, Kazuyoshi; Kim, Jae-Sung; Uchiyama, Akira; Jaeschke, Hartmut; Lemasters, John J

    2010-09-01

    Acetaminophen induces the mitochondrial permeability transition (MPT) in hepatocytes. Reactive oxygen species (ROS) trigger the MPT and play an important role in AAP-induced hepatocellular injury. Because iron is a catalyst for ROS formation, our aim was to investigate the role of chelatable iron in MPT-dependent acetaminophen toxicity to mouse hepatocytes. Hepatocytes were isolated from fasted male C3Heb/FeJ mice. Necrotic cell killing was determined by propidium iodide fluorometry. Mitochondrial membrane potential was visualized by confocal microscopy of tetramethylrhodamine methylester. Chelatable ferrous ion was monitored by calcein quenching, and 70 kDa rhodamine-dextran was used to visualize lysosomes. Cell killing after acetaminophen (10mM) was delayed and decreased by more than half after 6 h by 1mM desferal or 1mM starch-desferal. In a cell-free system, ferrous but not ferric iron quenched calcein fluorescence, an effect reversed by dipyridyl, a membrane-permeable iron chelator. In hepatocytes loaded with calcein, intracellular calcein fluorescence decreased progressively beginning about 4 h after acetaminophen. Mitochondria then depolarized after about 6 h. Dipyridyl (20mM) dequenched calcein fluorescence. Desferal and starch-desferal conjugate prevented acetaminophen-induced calcein quenching and mitochondrial depolarization. As calcein fluorescence became quenched, lysosomes disappeared, consistent with release of iron from ruptured lysosomes. In conclusion, an increase of cytosolic chelatable ferrous iron occurs during acetaminophen hepatotoxicity, which triggers the MPT and cell killing. Disrupted lysosomes are the likely source of iron, and chelation of this iron decreases acetaminophen toxicity to hepatocytes.

  16. Electrochemical behavior and voltammetric determination of acetaminophen based on glassy carbon electrodes modified with poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite films

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Wencai [Key Laboratory for Colloid and Interface Chemistry of State Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China); School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250013 (China); Huang, Hui; Gao, Xiaochun [Key Laboratory for Colloid and Interface Chemistry of State Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China); Ma, Houyi, E-mail: hyma@sdu.edu.cn [Key Laboratory for Colloid and Interface Chemistry of State Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China)

    2014-12-01

    Poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite film modified glassy carbon electrodes (4-ABA/ERGO/GCEs) were fabricated by a two-step electrochemical method. The electrochemical behavior of acetaminophen at the modified electrode was investigated by means of cyclic voltammetry. The results indicated that 4-ABA/ERGO composite films possessed excellent electrocatalytic activity towards the oxidation of acetaminophen. The electrochemical reaction of acetaminophen at 4-ABA/ERGO/GCE is proved to be a surface-controlled process involving the same number of protons and electrons. The voltammetric determination of acetaminophen performed with the 4-ABA/ERGO modified electrode presents a good linearity in the range of 0.1–65 μM with a low detection limit of 0.01 μM (S/N = 3). In the case of using the 4-ABA/ERGO/GCE, acetaminophen and dopamine can be simultaneously determined without mutual interference. Furthermore, the 4-ABA/ERGO/GCE has good reproducibility and stability, and can be used to determine acetaminophen in tablets. - Highlights: • The 4-ABA/ERGO/GCE was fabricated by a two-step electrochemical method. • Electrochemical behavior of acetaminophen at the 4-ABA/ERGO/GCE was investigated. • The electrochemical sensor exhibited a low detection limit and good selectivity. • This sensor was applied to the detection of acetaminophen in commercial tablets.

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

    Science.gov (United States)

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

    2011-12-01

    The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus. PMID:21975853

  18. Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage

    Directory of Open Access Journals (Sweden)

    Sreenivasan Sasidharan

    2012-11-01

    Full Text Available The aim of the present study was to evaluate the hepatoprotective activity of lantadene A against acetaminophen-induced liver toxicity in mice was studied. Activity was measured by monitoring the levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP and bilirubin, along with histo-pathological analysis. Silymarin was used as positive control. A bimodal pattern of behavioural toxicity was exhibited by the lantadene A-treated group at the beginning of the treatment. However, treatment with lantadene A and silymarin resulted in an increase in the liver weight compared with the acetaminophen treated group. The results of the acetaminophen-induced liver toxicity experiments showed that mice treated with lantadene A (500 mg/kg showed a significant decrease in the activity of ALT, AST and ALP and the level of bilirubin, which were all elevated in the acetaminophen treated group (p < 0.05. Histological studies supported the biochemical findings and a maximum improvement in the histoarchitecture was seen. The lantadene A-treated group showed remarkable protective effects against histopathological alterations, with comparable results to the silymarin treated group. The current study confirmed the hepatoprotective effects of lantadene A against the model hepatotoxicant acetaminophen, which is likely related to its potent antioxidative activity.

  19. Removal of acetaminophen and naproxen by combined coagulation and adsorption using biochar: influence of combined sewer overflow components.

    Science.gov (United States)

    Jung, Chanil; Oh, Jeill; Yoon, Yeomin

    2015-07-01

    The combined coagulation and adsorption of targeted acetaminophen and naproxen using activated biochar and aluminum sulfate were studied under various synthetic "combined sewer overflow" (CSO) conditions. The biochar demonstrated better adsorption performance for both acetaminophen and naproxen (removal, 94.1 and 97.7%, respectively) than that of commercially available powdered activated carbon (removal, 81.6 and 94.1%, respectively) due to superior carbonaceous structure and surface properties examined by nuclear magnetic resonance analysis. The adsorption of naproxen was more favorable, occupying active adsorption sites on the adsorbents by naproxen due to its higher adsorption affinity compared to acetaminophen. Three classified CSO components (i.e., representing hydrophobic organics, hydrophilic organics, and inorganics) played different roles in the adsorption of both adsorbates, resulted in inhibition by humic acid complexation or metal ligands and negative electrostatic repulsion under adsorption and coagulation combined system. Adsorption alone with biochar was determined to be the most effective adsorptive condition for the removal of both acetaminophen and naproxen under various CSO conditions, while both coagulation alone and combined adsorption and coagulation failed to remove the acetaminophen and naproxen adequately due to an increase in ionic strength in the presence of spiked aluminum species derived from the coagulant. PMID:25680690

  20. Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli.

    Science.gov (United States)

    Durso, Geoffrey R O; Luttrell, Andrew; Way, Baldwin M

    2015-06-01

    Acetaminophen, an effective and popular over-the-counter pain reliever (e.g., the active ingredient in Tylenol), has recently been shown to blunt individuals' reactivity to a range of negative stimuli in addition to physical pain. Because accumulating research has shown that individuals' reactivity to both negative and positive stimuli can be influenced by a single factor (an idea known as differential susceptibility), we conducted two experiments testing whether acetaminophen blunted individuals' evaluations of and emotional reactions to both negative and positive images from the International Affective Picture System. Participants who took acetaminophen evaluated unpleasant stimuli less negatively and pleasant stimuli less positively, compared with participants who took a placebo. Participants in the acetaminophen condition also rated both negative and positive stimuli as less emotionally arousing than did participants in the placebo condition (Studies 1 and 2), whereas nonevaluative ratings (extent of color saturation in each image; Study 2) were not affected by drug condition. These findings suggest that acetaminophen has a general blunting effect on individuals' evaluative and emotional processing, irrespective of negative or positive valence. PMID:25862546

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

    Science.gov (United States)

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

    2016-06-01

    Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P<0.0001) and more surprisingly; (ii) the fact of having no children (parentality: OR=0.1; P=0.006). Responses corresponding to involuntary overdosage were mostly due to a too short interval between drug intakes (3hours). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet. Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity. Package leaflets have also to be more informative. PMID:27235652

  2. Ginkgolide A contributes to the potentiation of acetaminophen toxicity by Ginkgo biloba extract in primary cultures of rat hepatocytes

    International Nuclear Information System (INIS)

    The present cell culture study investigated the effect of Ginkgo biloba extract pretreatment on acetaminophen toxicity and assessed the role of ginkgolide A and cytochrome P450 3A (CYP3A) in hepatocytes isolated from adult male Long-Evans rats provided ad libitum with a standard diet. Acetaminophen (7.5-25 mM for 24 h) conferred hepatocyte toxicity, as determined by the lactate dehydrogenase (LDH) assay. G. biloba extract alone increased LDH leakage in hepatocytes at concentrations ≥ 75 μg/ml and ≥ 750 μg/ml after a 72 h and 24 h treatment period, respectively. G. biloba extract (25 or 50 μg/ml once every 24 h for 72 h) potentiated LDH leakage by acetaminophen (10 mM for 24 h; added at 48 h after initiation of extract pretreatment). The effect was confirmed by a decrease in [14C]-leucine incorporation. At the level present in a modulating concentration (50 μg/ml) of the extract, ginkgolide A (0.55 μg/ml), which increased CYP3A23 mRNA levels and CYP3A-mediated enzyme activity, accounted for part but not all of the potentiating effect of the extract on acetaminophen toxicity. This occurred as a result of CYP3A induction by ginkgolide A because triacetyloleandomycin (TAO), a specific inhibitor of CYP3A catalytic activity, completely blocked the effect of ginkgolide A. Ginkgolide B, ginkgolide C, ginkgolide J, quercetin, kaempferol, isorhamnetin, and isorhamnetin-3-O-rutinoside did not alter the extent of LDH leakage by acetaminophen. In summary, G. biloba pretreatment potentiated acetaminophen toxicity in cultured rat hepatocytes and ginkgolide A contributed to this novel effect of the extract by inducing CYP3A

  3. Effect of over-the-counter dosages of naproxen sodium and acetaminophen on plasma lithium concentrations in normal volunteers.

    Science.gov (United States)

    Levin, G M; Grum, C; Eisele, G

    1998-06-01

    Prescription doses of nonsteroidal antiinflammatory agents have been shown to decrease clearance and increase plasma concentrations of lithium. This study was designed to evaluate whether over-the-counter (OTC) doses of naproxen sodium or acetaminophen have the same potential to affect lithium concentration. This was a prospective, crossover, 3-phase study conducted at the Clinical Pharmacology Studies Unit of the Albany Medical Center Hospital during July and August of 1995. The 3-phase study comprised the following: phase 1, lithium carbonate (300 mg every 12 hours) alone for 7 days; phase 2, lithium and either naproxen sodium (220 mg every 8 hours) or acetaminophen (650 mg every 6 hours) for 5 days; and phase 3, a 2-day washout period followed by a crossover to lithium with the alternate drug (acetaminophen or naproxen sodium) for 5 days. Twelve healthy male volunteers were recruited, nine of whom completed the study and were included in the statistical analysis. Mean (+/-SD) plasma lithium concentrations for subjects in treatment group 1 (lithium in phase 1, lithium and naproxen sodium in phase 2, lithium and acetaminophen in phase 3) were 0.38 (+/-0.11), 0.40 (+/-0.07), and 0.36 (+/-0.11) mEq/L, respectively. Mean plasma lithium concentrations for subjects in treatment group 2 (lithium in phase 1, lithium and acetaminophen in phase 2, lithium and naproxen sodium in phase 3) were 0.43 (+/-0.05), 0.48 (+/-0.10), and 0.48 (+/-0.05) mEq/L, respectively. One-way repeated-measures analysis of variance and paired t-test showed no statistically significant differences (p>0.05) in plasma lithium concentrations during any phase of the study. The results of this study demonstrated that OTC doses of naproxen sodium and acetaminophen did not increase plasma lithium concentrations in these volunteers when taken for short periods of time. PMID:9617983

  4. Gastric emptying in rats following administration of a range of different fats measured as acetaminophen concentration in plasma

    DEFF Research Database (Denmark)

    Porsgaard, Trine; Straarup, Ellen Marie; Høy, Carl-Erik

    2003-01-01

    an indirect measure of gastric emptying. Emulsified fats with added acetaminophen were fed by gavage to rats, and the plasma concentration of acetaminophen was followed for 3 h by repeated blood sampling from the carotid artery. The fats administered included rapeseed, corn, and fish oils, lard, and cocoa...... in gastric emptying between the groups fed the different fats, except for the emptying of tridecanoin (tri-10:0) that was statistically significantly slower than that of randomized oil, cocoa butter, and rapeseed oil (p

  5. Comparison of the effects of preemptive acetaminophen, ibuprofen, and meloxicam on pain after separator placement: a randomized clinical trial

    OpenAIRE

    Zarif Najafi, Hooman; Oshagh, Morteza; Salehi, Parisa; Babanouri, Neda; Torkan, Sepideh

    2015-01-01

    Background This study aims to evaluate and compare the effect of pre-procedural administration of acetaminophen, ibuprofen, and meloxicam in reducing pain after separator placement. Methods Three hundred twenty-one patients who needed orthodontic treatment and aged above 15 were randomly assigned to one of the three study groups: group A: 650 mg acetaminophen, group B: 400 mg ibuprofen, and group C: 7.5 mg meloxicam. All subjects received a single dose of medication 1 h prior to separator pla...

  6. Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.

    Directory of Open Access Journals (Sweden)

    Miaozong Wu

    Full Text Available BACKGROUND: Aged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention. PRINCIPAL FINDINGS: Compared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308 was higher in soleus muscles of very aged rats (33-months. Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR phosphorylation, along with decreased levels of insulin receptor beta (IR-beta, phosphoinositide 3-kinase (PI3K, phosphatase and tensin homolog deleted on chromosome 10 (PTEN and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1 (Ser241. In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS. Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month animals with acetaminophen (30 mg/kg body weight/day for 6-months. CONCLUSIONS: These data demonstrate that Akt dysfunction and increased S-nitrosylation of Akt may contribute to age-associated disorders in skeletal muscle and that acetaminophen may be efficacious for the treatment of age-related muscle dysfunction.

  7. Transformation of acetaminophen during water chlorination treatment: kinetics and transformation products identification.

    Science.gov (United States)

    Cao, Fei; Zhang, Mengtao; Yuan, Shoujun; Feng, Jingwei; Wang, Qiquan; Wang, Wei; Hu, Zhenhu

    2016-06-01

    As a high-consumption drug in the world, acetaminophen (AAP) has been widely detected in natural waters and wastewaters. Its reactivity and the transformation products formed during chlorination may greatly threaten the safety of drinking water. The reaction kinetics of AAP during chlorination was investigated in this study. The results showed that the reaction kinetics could be well described with a kinetics model of -d[AAP]/dt = k app[AAP]t (0.63)[Cl2]t (1.37). The values of apparent rate constant (k app) were dependent on reaction temperature, ammonium, and pH. With the increase in reaction temperature from 5.0 ± 1.0 to 40.0 ± 1.0 °C, the removal efficiency of AAP increased from 60 to 100 %. When ammonium was present in the solution at 2.0 mg/L, the transformation of AAP was inhibited due to the rapid formation of chloramines. The maximum of k app was 0.58 × 10(2) M(-1) · min(-1) at pH 9.0, and the minimum was 0.27 M(-1) · min(-1) at pH 11.0. A low mineralization of AAP (about 7.2 %) with chlorination was observed through TOC analysis, implying the formation of plenty of transformation products during chlorination. The main transformation products, hydroquinone and two kinds of chlorinated compounds, monochlorinated acetaminophen and dichlorinated acetaminophen, were detected in gas chromatography-mass spectrometry analysis.

  8. Photodegradation of acetaminophen in TiO{sub 2} suspended solution

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Xu [School of Resources and Environmental Science, Hubei Key Laboratory of Biomass-Resources, Wuhan University, Wuhan 430079 (China); Wu Feng [School of Resources and Environmental Science, Hubei Key Laboratory of Biomass-Resources, Wuhan University, Wuhan 430079 (China)], E-mail: fengwu@whu.edu.cn; Wu Xuwei; Chen Pengyu; Deng Nansheng [School of Resources and Environmental Science, Hubei Key Laboratory of Biomass-Resources, Wuhan University, Wuhan 430079 (China)

    2008-09-15

    This study investigated the photocatalytic degradation of acetaminophen (APAP) in TiO{sub 2} suspended solution under a 250 W metal halide lamp. The influence of some parameters on the degradation of acetaminophen was studied and described in details, such as initial APAP concentration, initial pH value and TiO{sub 2} dosage. After 100 min irradiation, about 95% of APAP is decomposed in the 1.0 g L{sup -1} TiO{sub 2} aqueous solution with an initial concentration of 100 {mu}mol L{sup -1}. The effect of adsorption at three different pH values has also been analyzed and it has been conducted that pH 3.5, at which APAP was readily adsorbed also degraded at a faster rate. Reaction rate at pH 6.9 and pH 9.5 was 2.84 and 2.96 {mu}M min{sup -1}, respectively. Direct hole (h{sup +}) oxidation and ipso-substitution was found to be the main initial step for APAP degradation. Main reaction intermediates and products were identified by GC/MS analysis. The mechanism of acetaminophen photocatalytic degradation in TiO{sub 2} suspended solution was studied not only experimentally but also theoretically by calculating the frontier electron density of APAP. The results obtained indicated that TiO{sub 2} photocatalytic degradation is a highly effective way to remove APAP from wastewater and drinking water without any generation of more toxic products.

  9. Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity.

    Science.gov (United States)

    Kanji, Hussein D; Mithani, Shazma; Boucher, Paul; Dias, Valerian C; Yarema, Mark C

    2013-01-01

    We present a case of early coma, metabolic acidosis and methemoglobinemia after substantial acetaminophen toxicity in the absence of hepatic failure. A 77-year-old female presented to the emergency department with a decreased level of consciousness. She was found unresponsive by a family member in her bed, and was reported to be acting normally when she was last seen eight hours earlier. Laboratory results on arrival were: pH 7.19, sodium 139 mmol/L, chloride 106 mmol/L, potassium 3.3 mmol/L, CO2 8 mmol/L, and an anion gap of 25. Both venous lactate (10.2 mmol/L) and methemoglobin (9.4 %) were elevated. The patient's acetaminophen concentration was markedly elevated at 7138 µmol/L (1078 µg/ml). Hepatic enzymes and coagulation tests were normal [alanine transaminase (ALT) 8 U/L, international normalized ratio (INR) 1.0]. Intravenous N-acetylcysteine (NAC) was initiated at a dose of 150 mg/kg over 15 minutes, followed by 50 mg/kg over the next four hours, followed by 100 mg/kg over the next 16 hours. Twenty-four hours after admission, the anion gap metabolic acidosis had resolved, and the methemoglobin was 2.1%. Aminotransferases peaked at 44 U/L and INR peaked at 1.9. A urine 5-oxoproline assay performed five days after admission was negative, suggesting no evidence of a 5-oxoprolinase deficiency. We describe the pathophysiology and discuss the literature on acetaminophen-induced coma and metabolic acidosis in the absence of hepatic injury; and propose mechanisms for associated methemoglobinemia. 

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

    Science.gov (United States)

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

    2010-09-01

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

  11. Transformation of acetaminophen during water chlorination treatment: kinetics and transformation products identification.

    Science.gov (United States)

    Cao, Fei; Zhang, Mengtao; Yuan, Shoujun; Feng, Jingwei; Wang, Qiquan; Wang, Wei; Hu, Zhenhu

    2016-06-01

    As a high-consumption drug in the world, acetaminophen (AAP) has been widely detected in natural waters and wastewaters. Its reactivity and the transformation products formed during chlorination may greatly threaten the safety of drinking water. The reaction kinetics of AAP during chlorination was investigated in this study. The results showed that the reaction kinetics could be well described with a kinetics model of -d[AAP]/dt = k app[AAP]t (0.63)[Cl2]t (1.37). The values of apparent rate constant (k app) were dependent on reaction temperature, ammonium, and pH. With the increase in reaction temperature from 5.0 ± 1.0 to 40.0 ± 1.0 °C, the removal efficiency of AAP increased from 60 to 100 %. When ammonium was present in the solution at 2.0 mg/L, the transformation of AAP was inhibited due to the rapid formation of chloramines. The maximum of k app was 0.58 × 10(2) M(-1) · min(-1) at pH 9.0, and the minimum was 0.27 M(-1) · min(-1) at pH 11.0. A low mineralization of AAP (about 7.2 %) with chlorination was observed through TOC analysis, implying the formation of plenty of transformation products during chlorination. The main transformation products, hydroquinone and two kinds of chlorinated compounds, monochlorinated acetaminophen and dichlorinated acetaminophen, were detected in gas chromatography-mass spectrometry analysis. PMID:26983813

  12. Serum acetaminophen assay using activated charcoal adsorption and gas chromatography without derivatization.

    Science.gov (United States)

    Jeevanandam, M; Novic, B; Savich, R; Wagman, E

    1980-01-01

    A quantitative assay of acetaminophen in serum has been developed. The drug, together with an internal standard 2-acetamidophenol, is adsorbed on activated charcoal and then extracted into a mixture of ethyl acetate and isopropanol. This extract is then analyzed, without any derivatization, by gas chromatography. The isothermal analysis yielded a good, highly reproducible separation. The drug peak was symmetrical and without any tailing. The peak height response ratio was found to be linear with concentrations ranging from 25-500 ng/L. No interference was observed with the various drugs or metabolites which are commonly encountered in human serum. PMID:7421146

  13. High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

    OpenAIRE

    Yang Runkuan; Zhang Shutian; Cotoia Antonella; Oksala Niku; Zhu Shengtao; Tenhunen Jyrki

    2012-01-01

    Abstract Background Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whethe...

  14. Simultaneous Chronoamperometric Sensing of Ascorbic Acid and Acetaminophen at a Boron-Doped Diamond Electrode

    OpenAIRE

    Ciprian Radovan; Codruţa Cofan

    2008-01-01

    Cyclic voltammetry (CV) and chronoamperometry (CA) have been used to sense and determine simultaneously L-ascorbic acid (AA) and acetaminophen (AC) at a boron-doped diamond electrode (BDDE) in a Britton-Robinson buffer solution. The calibration plots of anodic current peak versus concentration obtained from CV and CA data for both investigated compounds in single and di-component solutions over the concentration range 0.01 mM – 0.1 mM proved to be linear, with very good correlation param...

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

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Ridge regression spectrophotometry (LHG) is used for the simultaneous determination of five components (acetaminophen, p-aminophenol, caffeine, chlorphenamine maleate and guaifenesin) in cough syrup. The computer program of LHG is based on VB language.The difficulties in overlapping of absorption spectrums of five compounds are overcome by this procedure. The experimental results show that the average recovery of each component is in the range from 97.9% to 103.3% and each component obtains satisfactory results without any pre-separation.

  16. Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle.

    Science.gov (United States)

    Emmett, Michael

    2014-01-01

    The acquired form of 5-oxoproline (pyroglutamic acid) metabolic acidosis was first described in 1989 and its relationship to chronic acetaminophen ingestion was proposed the next year. Since then, this cause of chronic anion gap metabolic acidosis has been increasingly recognized. Many cases go unrecognized because an assay for 5-oxoproline is not widely available. Most cases occur in malnourished, chronically ill women with a history of chronic acetaminophen ingestion. Acetaminophen levels are very rarely in the toxic range; rather, they are usually therapeutic or low. The disorder generally resolves with cessation of acetaminophen and administration of intravenous fluids. Methionine or N-acetyl cysteine may accelerate resolution and methionine is protective in a rodent model. The disorder has been attributed to glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle. However, the specific metabolic derangements that cause the 5-oxoproline accumulation remain unclear. An ATP-depleting futile 5-oxoproline cycle can explain the accumulation of 5-oxoproline after chronic acetaminophen ingestion. This cycle is activated by the depletion of both glutathione and cysteine. This explanation contributes to our understanding of acetaminophen-induced 5-oxoproline metabolic acidosis and the beneficial role of N-acetyl cysteine therapy. The ATP-depleting futile 5-oxoproline cycle may also play a role in the energy depletions that occur in other acetaminophen-related toxic syndromes.

  17. The analgesic efficacy of etoricoxib compared with oxycodone/acetaminophen in an acute postoperative pain model: a randomized, double-blind clinical trial.

    Science.gov (United States)

    Chang, David J; Desjardins, Paul J; King, Thomas R; Erb, Tara; Geba, Gregory P

    2004-09-01

    Our objective in this study was to compare the analgesic effects of etoricoxib and oxycodone/acetaminophen in a postoperative dental pain model. Patients experiencing moderate to severe pain after extraction of two or more third molars were randomized to single doses of etoricoxib 120 mg (n = 100), oxycodone/acetaminophen 10/650 mg (n = 100), or placebo (n = 25). The primary end-point was total pain relief over 6 h. Other end-points included patient global assessment of response to therapy; onset, peak, and duration of effect; and rescue opioid analgesic use. Active treatments were statistically significantly superior to placebo for all efficacy measures. Total pain relief over 6 h for etoricoxib was significantly more than for oxycodone/acetaminophen (P acetaminophen by 5 min. The peak effect was similar for both drugs. Compared with oxycodone/acetaminophen patients, etoricoxib patients experienced a longer analgesic duration, had a smaller percentage requiring rescue opioids during 6 and 24 h, and required less rescue analgesia during 6 and 24 h. Oxycodone/acetaminophen treatment resulted in more frequent adverse events (AEs), drug-related AEs, nausea, and vomiting compared with etoricoxib treatment. In conclusion, etoricoxib 120 mg provided superior overall efficacy compared with oxycodone/acetaminophen 10/650 mg and was associated with significantly fewer AEs. PMID:15333415

  18. The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

    International Nuclear Information System (INIS)

    Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug

  19. The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Blazquez, Alba G., E-mail: albamgb@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Briz, Oscar, E-mail: obriz@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Gonzalez-Sanchez, Ester, E-mail: u60343@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); Perez, Maria J., E-mail: mjperez@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); University Hospital of Salamanca, IECSCYL-IBSAL, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Ghanem, Carolina I., E-mail: cghanem@ffyb.uba.ar [Instituto de Investigaciones Farmacologicas, Facultad de Farmacia y Bioquimica, CONICET, Universidad de Buenos Aires, Buenos Aires (Argentina); Marin, Jose J.G., E-mail: jjgmarin@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain)

    2014-05-15

    Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug.

  20. The Effect of Polymer Content on the Non-Newtonian Behavior of Acetaminophen Suspension

    Directory of Open Access Journals (Sweden)

    Eskandar Moghimipour

    2013-01-01

    Full Text Available Acetaminophen is used as an analgesic and antipyretic agent. The aim of the study was evaluation of the effect of different polymers on rheological behavior of acetaminophen suspension. In order to achieve controlled flocculation, sodium chloride was added. Then structural vehicles such as carboxymethyl cellulose (CMC, polyvinyl pyrrolidone (PVP, tragacanth, and magnesium aluminum silicate (Veegum were evaluated individually and in combination. Physical stability parameters such as sedimentation volume (F, redispersibility (n, and growth of crystals of the suspensions were determined. Also, the rheological properties of formulations were studied. The results of this study showed that the combination of suspending agents had the most physical stability and pseudoplastic behavior with some degree of thixotropy. Viscosity of suspensions was increased by adding NaCl 0.02%. Presence of PVP is necessary for improving rheological behavior of suspensions by NaCl. This may be related to the cross-linking between the carbonyl group in the PVP segment and Na+ ions.

  1. Strong opioids for noncancer pain due to musculoskeletal diseases: Not more effective than acetaminophen or NSAIDs.

    Science.gov (United States)

    Berthelot, Jean-Marie; Darrieutort-Lafitte, Christelle; Le Goff, Benoit; Maugars, Yves

    2015-12-01

    The classification of morphine as a step III analgesic, based on pharmacological data, creates a strong bias toward a belief in the efficacy of this drug. However, double-blind emergency-room trials showed similar levels of pain relief with intravenous acetaminophen as with intravenous morphine in patients with renal colic, low back pain or acute limb pain. In patients with chronic noncancer low back pain, morphine and other strong opioids in dosages of up to 100mg/day were only slightly more effective than their placebos, no more effective than acetaminophen, and somewhat less effective than nonsteroidal anti-inflammatory drugs (NSAIDs). In patients with osteoarthritis, strong opioids were not more effective than NSAIDs and, in some studies, than placebos. The only randomized controlled trial in patients with sciatica found no difference with the placebo. Chronic use of strong opioids can induce hyperalgesia in some patients. Hyperpathia with increased sensitivity to cold leading the patient to request higher dosages should suggest opioid-induced hyperalgesia. Pain specialists in the US have issued a petition asking that strong opioids be used in dosages no higher than 100mg/day of morphine-equivalent, in an effort to decrease the high rate of mortality due to the misuse and abuse of strong opioids (10,000 deaths/year in the US). Healthcare providers often overestimate the efficacy of step III analgesics, despite pain score decreases of only 0.8 to 1.2 points. PMID:26453108

  2. Sub-acute toxicity studies of acetaminophen in Sprague Dawley rats.

    Science.gov (United States)

    Venkatesan, Pachaiyappan Sampath; Deecaraman, Munuswamy; Vijayalakshmi, Melanathuru; Sakthivelan, Sigamany Masilamani

    2014-01-01

    The aim of the present study was to evaluate the sub-acute oral toxicity of acetaminophen in Sprague Dawley (SD) rats at 250 to 1000 mg/kg body weight (b.wt.). The following observations were noticed during the study. No mortality in male and female rats, at and up to the dose of 1000 mg/kg b.wt. There were abnormal clinical signs observed on female animals at 1000 mg/kg b.wt. dose level. There were no difference in body weight gain and no effect on the daily feed consumption. No toxicologically significant effect on the haematological parameters but liver and kidney related biochemical parameter showed significant difference at 1000 mg/kg b.wt. in females. No toxicologically significant effect on the urinalysis parameters, absolute and relative organ weights and gross pathological alterations; whereas histopathological alterations were observed in female liver at dose level of 1000 mg/kg b.wt. were observed. Based on the findings of this study, the No Observed Adverse Effect Level (NOAEL) of acetaminophen in SD rats, following oral administration at the doses of 250, 500 and 1000 mg/kg on daily basis was found to be 500 mg/kg b.wt.

  3. Hepatoprotective effects of Iranian Hypericum scabrum essential oils against oxidative stress induced by acetaminophen in rats

    Directory of Open Access Journals (Sweden)

    Abolfazl Dadkhah

    2014-06-01

    Full Text Available This studied examined the protective role of Hypericum scabrum oils (100 and 200 mg/kg b.w, i.p on acetaminophen-induced liver damages in the rat. The hepatic oxidative/antioxidant parameters such as lipid peroxidation (LP, glutathione (GSH, superoxide dismutase (SOD, catalase (CAT and ferric reducing ability of plasma (FRAP were measured 2, 4, 8, 16 and 24h after the treatments confirmed by histopathological consideration. The results indicated that increased levels of hepatic LP and FRAP and SOD activity were reversed in the rats treated with oils. In addition, the depleted GSH were compensated with the oil treatments. The protective effect of the oils was further confirmed by the histophatological examination carried out on liver biopsies. The data pointed out that H. scabrum oil could modulate the hepatic toxicity induced by the APAP through adjusting the oxidative stress/antioxidant parameters and could be of potential candidate for the treatment of acetaminophen induced oxidative stress liver damages.

  4. Hyperlactatemia in patients with non-acetaminophen-related acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Pilar Taurá; Graciela Martinez-Palli; Julia Martinez-Ocon; Joan Beltran; Gerard Sanchez-Etayo; Jaume Balust; Teresa Anglada; Antoni Mas; Juan-Carlos Garcia-Valdecasas

    2006-01-01

    AIM: To characterize hyperlactatemia in patients with non-acetaminophen acute liver failure (ALF) in an attempt to clarify the mechanisms implicated and the role as a prognosis factor.METHODS: In the setting of liver transplantation, 63 consecutive patients with non-acetaminophen acute liver failure were studied in relation to tissue oxygenation,hemodynamic and metabolic parameters. Before and after transplantation, the number of infected patients and outcome were registered.RESULTS: Acute ALF showed higher levels of lactate than subacute ALF (5.4±1 mmol/L versus 2.2 ± 0.6 mmol/L, P=0.01). Oxygenation parameters were within the normal range. Lactate levels showed good correlation with respiratory quotient (r= 0.759, P< 0.005), mean glucose administration (r=0.664, P=0.01) and encephalopathy (r=0.698, P= 0.02), but not with splanchnic arteriovenous difference in PCO2, pH and the presence of infection (P=0.1). Portal vein lactate was higher (P< 0.05) than arterial and mixed venous lactate,suggesting its production of hyperlactatemia in the intestine and spleen. The presence of infection was an independent predictor of survival. CONCLUSION: Hyperlactatemia is not a prognosis factor due to byproduct of the overall acceleration in glycolysis.

  5. Acetaminophen and zinc phosphide for lethal management of invasive lizards Ctenosaura similis

    Institute of Scientific and Technical Information of China (English)

    Michael L. AVERY; John D. EISEMANN; Kandy L. KEACHER; Peter J. SAVARIE

    2011-01-01

    Reducing populations of invasive lizards through trapping and shooting is feasible in many cases but effective integrated management relies on a variety of tools,including toxicants.In Florida,using wild-caught non-native black spiny-tailed iguanas Ctenosaura similis,we screened acetaminophen and zinc phosphide to determine their suitability for effective population management of this prolific invasive species.Of the animals that received acetaminophen,none died except at the highest test dose,240 mg per lizard,which is not practical for field use.Zinc phosphide produced 100% mortality at dose levels as little as 25 mg per lizard,equivalent to about 0.5% in bait which is lower than currently used in commercial baits for eommensal rodent control.We conclude that zinc phosphide has potential as a useful tool for reducing populations of invasive lizards such as the black spiny-tailed iguana provided target-selective delivery methods are developed [Current Zoology 57 (5):625-629,2011].

  6. Evaluation of the antipyretic effect of ketorolac, acetaminophen, and placebo in endotoxin-induced fever.

    Science.gov (United States)

    Vargas, R; Maneatis, T; Bynum, L; Peterson, C; McMahon, F G

    1994-08-01

    The authors studied the antipyretic effect of three intramuscular doses of ketorolac (15, 30, and 60 mg), acetaminophen 650 mg PO, and placebo in healthy male volunteers using an endotoxin-induced fever model. In this double-blind, double-dummy, parallel study, subjects were assigned randomly with equal probability to one of the above treatment groups. Thirty minutes after study medication administration, a 20 unit per kilogram dose of reference standard endotoxin (RSE) was administered intravenously, and temperature was determined every 15 minutes for an 8-hour period. Compared with placebo, all active treatment groups demonstrated a statistically significant reduction in both adjusted area under the temperature-by-time curve (AAUC) and the maximum increase over baseline temperature (dTmax). Furthermore, the 30 mg intramuscular dose of ketorolac demonstrated approximately the same antipyretic activity as the 650 mg oral dose of acetaminophen, and there was a statistically significant dose response across the three ketorolac doses studied (P < .0001). The majority of side effects reported during this study were symptoms associated with fever, including chills, headache, myalgia, and dizziness, all of which are effects of RSE. The frequency of side effects tended to be less in the treatment groups with the greatest antipyretic activity. PMID:7962674

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

    Science.gov (United States)

    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

  8. Acetaminophen (Paracetamol) Use, Measles-Mumps-Rubella Vaccination, and Autistic Disorder: The Results of a Parent Survey

    Science.gov (United States)

    Schultz, Stephen T.; Klonoff-Cohen, Hillary S.; Wingard, Deborah L.; Akshoomoff, Natacha A.; Macera, Caroline A.; Ji, Ming

    2008-01-01

    The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80…

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

    Science.gov (United States)

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

    2008-08-15

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

  10. Controlled production of the elusive metastable form II of acetaminophen (paracetamol): a fully scalable templating approach in a cooling environment.

    Science.gov (United States)

    Agnew, Lauren R; Cruickshank, Dyanne L; McGlone, Thomas; Wilson, Chick C

    2016-05-31

    A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent "templating" approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples.

  11. Development of a rapid derivative spectrophotometric method for simultaneous determination of acetaminophen, diphenhydramine and pseudoephedrine in tablets.

    Science.gov (United States)

    Souri, Effat; Rahimi, Aghil; Shabani Ravari, Nazanin; Barazandeh Tehrani, Maliheh

    2015-01-01

    A mixture of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride is used for the symptomatic treatment of common cold. In this study, a derivative spectrophotometric method based on zero-crossing technique was proposed for simultaneous determination of acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride. Determination of these drugs was performed using the (1)D value of acetaminophen at 281.5 nm, (2)D value of diphenhydramine hydrochloride at 226.0 nm and (4)D value of pseudoephedrine hydrochloride at 218.0 nm. The analysis method was linear over the range of 5-50, 0.25-4, and 0.5-5 µg/mL for acetaminophen, diphenhydramine hydrochloride and pseudoephedrine hydrochloride, respectively. The within-day and between-day CV and error values for all three compounds were within an acceptable range (CV<2.2% and error<3%). The developed method was used for simultaneous determination of these drugs in pharmaceutical dosage forms and no interference from excipients was observed.

  12. Ultra Low-Dose Naloxone and Tramadol/Acetaminophen in Elderly Patients Undergoing Joint Replacement Surgery: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Ngozi N Imasogie

    2009-01-01

    Full Text Available OBJECTIVE: A pilot study was conducted to assess whether both the rationale and feasibility exist for future randomized clinical trials to evaluate the combined use of naloxone infusion and tramadol/acetaminophen as opioid-sparing drugs in elderly patients undergoing lower extremity joint replacement surgery.

  13. Controlled production of the elusive metastable form II of acetaminophen (paracetamol): a fully scalable templating approach in a cooling environment.

    Science.gov (United States)

    Agnew, Lauren R; Cruickshank, Dyanne L; McGlone, Thomas; Wilson, Chick C

    2016-05-31

    A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent "templating" approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples. PMID:26926388

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

    Directory of Open Access Journals (Sweden)

    Robim M. Rodrigues

    2016-06-01

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

  15. Protective Properties of Flavonoid Extract of Coagulated Tofu (Curdled Soy Milk Against Acetaminophen-Induced Liver Injury in Rats

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    Ndatsu Yakubu

    2016-01-01

    Full Text Available The total flavonoid contents of the various coagulated tofu and the hepatoprotective potential of all tofu flavonoid extracts were investigated. Tofu was prepared from locally sourced coagulants (steep water, alum, lemon, and lemon peel ash extract. Total flavonoid contents of all coagulated tofu were investigated as established in vitro flavonoid assay. The hepatoprotective activities of tofu flavonoid extracts against acetaminophen-induced hepatic cell toxicity in rats was also investigated in this study. The activity was analyzed by assessing the levels of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP and lactate dehydrogenase (LDH. The concentrations of the serum sugar, total protein, albumin, and cholesterol as well as prothrombin time (PT of experimental rats with histopathological analysis were also conducted. The range of the total flavonoid contents of tofu was 4.3-6.4 mg/g. Tofu flavonoid extracts significantly reduced the activities of serum AST, ALT, ALP, and LDH; total cholesterol, and sugar levels, but total protein and albumin concentrations increased compared to acetaminophen-intoxicated rats. Also, the prothrombin time prolongation of serum in acetaminophen intoxicated rats was reduced. Histology of the liver tissue demonstrated that tofu flavonoid extracts inhibited the acetaminophen-induced hepatic cell necrosis, decreased inflammatory cell infiltration and accelerated hepatocellular regeneration. Therefore, all tofus exhibited high total flavonoid contents, and the tofu supplement in human diets is highly recommended as it can be used as a functional food to prevent liver injuries.

  16. Modulation of alpha-interferon's antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteers.

    Science.gov (United States)

    Hendrix, C W; Petty, B G; Woods, A; Kuwahara, S K; Witter, F R; Soo, W; Griffin, D E; Lietman, P S

    1995-10-01

    The magnitude and duration of the antiviral and clinical effect of alpha-interferon was measured in healthy volunteers. A single 3 million unit intramuscular dose of interferon was given either alone (controls) or after 72 h of concomitant medications. These medications included either aspirin (650 mg every 4 h), acetaminophen (650 mg every 4 h), or prednisone (40 mg per day). Peripheral blood mononuclear cells were assayed for resistance to vesicular stomatitis virus infection and induction of 2'-5'-oligoadenylate synthetase activity as evidence of interferon's antiviral effect. Co-administration of acetaminophen increased both antiviral parameters by more than 70% (P acetaminophen, aspirin, and prednisone reduced the clinical symptoms by 47% compared to controls (P = 0.03) after interferon dosing, although individual drug comparisons failed to reach statistical significance. Independent of treatment group, the changes in antiviral markers after interferon dosing correlated closely with each other (r = 0.72, P 0.05). Acetaminophen enhances the antiviral effects of a single intramuscular dose of alpha-interferon, considering the parameters measured in these healthy volunteers. PMID:8585766

  17. Evaluation of hepatoprotective effect of methanolic extract of Clitoria ternatea (Linn.) flower against acetaminophen-induced liver damage

    Science.gov (United States)

    Nithianantham, Kuppan; Ping, Kwan Yuet; Latha, Lachimanan Yoga; Jothy, Subramanion L; Darah, Ibrahim; Chen, Yeng; Chew, Ai-Lan; Sasidharan, Sreenivasan

    2013-01-01

    Objective To evaluate the hepatoprotective and antioxidant activity of Clitoria ternatea (C. ternatea) flower extract against acetaminophen-induced liver toxicity. Methods The antioxidant property of C. ternatea flower extract was investigated by employing established in vitro antioxidant assay. The C. ternatea flower extract was studied in this work for its hepatoprotective effect against acetaminophen-induced liver toxicity in mice. Activity was measured by monitoring the levels of aspartate aminotransferase, alanine aminotransferase, billirubin and glutathione with histopathological analysis. Results The amount of total phenolics and flavonoids were estimated to be 105.40±2.47 mg/g gallic acid equivalent and 72.21±0.05 mg/g catechin equivalent respectively. The antioxidant activity of C. ternatea flower extract was 68.9% at a concentration of 1 mg/mL and was also concentration dependant, with an IC50 value of 327.00 µg/mL. The results of acetaminophen-induced liver toxicity experiment showed that mice treated with the extract (200 mg/kg) showed a significant decrease in alanine aminotransferase, aspartate aminotransferase, and bilirubin levels, which were all elevated in the paracetamol group (Pternatea flower against model hepatotoxicant acetaminophen.

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

    OpenAIRE

    Renata Grespan; Rafael Pazinatto Aguiar; Frederico Nunes Giubilei; Rafael Rocco Fuso; Marcio José Damião; Expedito Leite Silva; Jane Graton Mikcha; Luzmarina Hernandes; Ciomar Bersani Amado; Roberto Kenji Nakamura Cuman

    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), ...

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

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    Howie Forbes

    2010-03-01

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

  20. Prophylactic Use of Oral Acetaminophen or IV Dexamethasone and Combination of them on Prevention Emergence Agitation in Pediatric after Adenotonsillectomy

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    Parvin Sajedi

    2014-01-01

    Full Text Available Background: The present study was aimed to evaluate the efficacy of acetaminophen plus dexamethasone on post-operative emergence agitation in pediatric adenotonsillectomy. Methods: A total of 128 patients were randomized and assigned among four groups as: Intravenous (IV dexamethasone, oral acetaminophen, IV dexamethasone plus oral acetaminophen, placebo. Group 1 received 0.2 mg/kg dexamethasone plus 0.25 mg/kg strawberry syrup 2 h before surgery. Group 2 received 20 mg/kg oral acetaminophen (0.25 ml/kg with 0.05 ml/kg IV normal saline. Group 3 received 20 mg/kg acetaminophen and 0.2 mg/kg dexamethasone intravenously. Group 4 received 0.25 ml/kg strawberry syrup and 0.05 ml/kg normal saline. Agitation was measured according to Richmond agitation sedation score in the post anesthetic care unit (PACU after admission, 10, 20 and 30 min after extubation. Pain score was measured with FACE scale. Nurse satisfaction was measured with verbal analog scale. If agitation scale was 3 ≥ or pain scale was 4 ≥ meperidine was prescribed. If symptoms did not control wit in 15 min midazolam was prescribed. Patients were discharged from PACU according Modified Alderet Score. Data were analyzed with ANOVA, Chi-square, and Kruskal-Wallis among four groups. P < 0.05 was considered statistically significant. Results: A total of 140 patients were recruited in the study, which 12 of them were excluded. Thus, 128 patients were randomized and assigned among four groups. The four treatment groups were generally matched at baseline data. Median of pain score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001, 0.003 respectively. Also median of agitation score in 0, 10, 20 and 30 min after extubation were different between each study group with the control group (<0.001. Incidence of pain and incidence of agitation after extubation were not statistically identical among groups (P < 0.001 and P = 0

  1. Prenatal and Infant Exposure to Acetaminophen and Ibuprofen and the Risk for Wheeze and Asthma in Children

    Science.gov (United States)

    Sordillo, Joanne E.; Scirica, Christina V.; Rifas-Shiman, Sheryl L.; Gillman, Matthew W.; Bunyavanich, Supinda; Camargo, Carlos A.; Weiss, Scott T.; Gold, Diane R.; Litonjua, Augusto A.

    2014-01-01

    Background Several studies have reported an association between use of over-the-counter antipyretics during pregnancy or infancy and increased asthma risk. An important potential limitation of these observational studies is confounding by indication. Objectives We investigated the association of antipyretic intake, 1) during pregnancy and 2) during the first year of life (infancy), with asthma-related outcomes, before and after controlling for early life respiratory infections. Methods We included 1490 mother-child pairs in Project Viva, a longitudinal pre-birth cohort study. We categorized prenatal acetaminophen exposure as the maximum intake (never, 1–9 or ≥ 10 times) in early or mid-pregnancy, and ibuprofen intake as presence or absence in early pregnancy. We expressed intakes of antipyretics in infancy as never, 1–5, 6–10, or >10 times. We examined the associations of acetaminophen and ibuprofen (per unit increase in exposure category) during pregnancy and infancy with wheeze, asthma and allergen sensitization in early (3–5 y) (n= 1419) and mid-childhood (7–10 y) (n= 1220). Results Unadjusted models showed an elevated asthma risk in early childhood for higher infant acetaminophen (OR 1.21, 95% CI 1.04, 1.41) and ibuprofen (OR 1.35, 95% CI 1.19, 1.52) intake. Controlling for respiratory infections attenuated estimates for acetaminophen (OR 1.03, 95% CI 0.88, 1.22) and ibuprofen (OR 1.19, 95% CI 1.05, 1.36). Prenatal acetaminophen was associated with increased asthma (OR 1.26, 95% CI 1.02, 1.58) in early but not mid-childhood. Conclusions Adjustment for respiratory infections in early life substantially diminished associations between infant antipyretics and early childhood asthma. Respiratory infections should be accounted for in studies of antipyretics and asthma, to mitigate bias due to confounding by indication. PMID:25441647

  2. A comparative study on Benzydamine HCL 0.5% and Acetaminophen Codeine in pain reduction following periodontal surgery

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    Khoshkhoonejad AA.

    2004-07-01

    Full Text Available Statement of Problem: Systemic analgesics are frequently prescribed for pain reduction following periodontal surgery. This type of treatment, however, brings about some disadvantages due to its late effect and inherent side effects. Benzydamine hydrochloride mouth wash is a non steroidal anti-inflammatory drug with local anaesthetic properties. Side effects of benzydamine are minor such as tissue numbness, burning and stinging. It brings relief to pain and inflammation rapidly. Purpose: The goal of this study was to compare benzydamine HCL 0.15% and Acetaminophen codeine as analgesics following periodontal surgery. Materials and Methods: This clinical study was performed on 18 patients referred to periodontics Department, Faculty of Dentistry, Tehran University of Medical Sciences. All patients were affected with chronic mild or moderate periodontitis and required surgery at least at two oral sites with similar lesions. Each patient received benzdamine HCL after first surgery and Acetaminophen codein following second operation. Pain reduction was evaluated by Visual Analog Scale (VAS. Data were analyzed with Wilcoxon-Signed and Mann-Whitney non-parametric tests. Results: Analgesic effect of Acetaminophene codeine was significantly more than that of benzydamine HCL following Reriodontal surgery (P=0.008. No significant difference was found between analgesic effects of Acetaminophene codeine and benzydamine HCL in patients with chronic mild periodontitis (P=0.9, and in cases that osteoplasty (P=0-31 or no osseous surgery (P=0.18 were performed. Conclusion: In cases with mild post-operative pain following periodontal surgery, Benzydamine HCL and be prescribed as an analgesic. However, in other cases this mouth wash should be prescribed along with Acetaminophene codein to reduce systemic drugs consumption.

  3. 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

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    Franke RM

    2015-08-01

    Full Text Available Ryan M Franke, Terri Morton, Krishna Devarakonda Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA Abstract: 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. Keywords: acetaminophen, acute pain, biphasic, extended release, fixed

  4. Hepatoprotective and antioxidant effects of Azolla microphylla based gold nanoparticles against acetaminophen induced toxicity in a fresh water common carp fish (Cyprinus carpio L.

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    Selvaraj Kunjiappan

    2015-04-01

    Conclusion: Azolla microphylla phytochemically synthesized GNaP protects liver against oxidative damage and tissue damaging enzyme activities and could be used as an effective protector against acetaminophen-induced hepatic damage in fresh water common carp fish.

  5. Effectiveness of diclofenac versus acetaminophen in primary care patients with knee osteoarthritis: [NTR1485], DIPA-Trial: design of a randomized clinical trial

    OpenAIRE

    Bohnen Arthur M; Koes Bart W; Luijsterburg Pim AJ; Verkleij Saskia PJ; Bierma-Zeinstra Sita MA

    2010-01-01

    Abstract Background Osteoarthritis is the most frequent chronic joint disease which causes pain and disability of especially hip and knee. According to international guidelines and the Dutch general practitioners guidelines for non-traumatic knee symptoms, acetaminophen should be the pain medication of first choice for osteoarthritis. However, of all prescribed pain medication in general practice, 90% consists of non-steroidal anti-inflammatory drugs compared to 10% of acetaminophen. Because ...

  6. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

    Science.gov (United States)

    Nassar, Inthisham; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio

    2010-06-01

    Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

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

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    Roko Martinić

    2014-08-01

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

  8. Simultaneous Determination of Five Components Including Acetaminophen by Reversed-phase High Performance Liquid Chromatography

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li-qing; WU Xiao-hua; LU Ying; WANG Xia

    2004-01-01

    High performance liquid chromatography with a C18 reverse-phase column was used to separatethe five components in cough syrup, including acetaminophen, p-aminophenol, caffeine, chlorphenamine maleateand guaifenesin. The mobile phase consists of 15wi% acetonitrile, 0.004mol/L sodium heptyl sulfonate,0.03 mole/L potassium di- hydrogen phosphate and triethylamine ( volume ratio 13: 40: 44: 3), the pH of which isadjusted to 3.0 by phosphoric acid. The contents of the five components are analyzed on an ultraviolet spectropho-tometer at 254nm, with a flow rate of 0.4mL/min. The results show that the calibration curves are linear in acertain range. The average recovery of five components is between 96.31% and 102.3% .

  9. General approach for electrochemical detection of persistent pharmaceutical micropollutants: Application to acetaminophen.

    Science.gov (United States)

    Shi, S; Reisberg, S; Anquetin, G; Noël, V; Pham, M C; Piro, B

    2015-10-15

    We propose in this work a general and versatile methodology for electrochemical monitoring of persistent pharmaceutical micropollutants. The system presented is based on an electroactive and electropolymerized hapten (mimetic molecule of the pollutant to be detected) and a specific antibody that competitively binds either the hapten or the pollutant. The current delivered by the device depends on this competitive equilibrium and therefore on the pollutant's concentration. The determination of the pharmaceutical product operates within minutes, using square wave voltammetry without labeling or addition of a reactant in solution; the competitive hapten/antibody transduction produces a "signal-on" (a current increase). Applied to acetaminophen, this electrochemical immunosensor presents a very low detection limit of ca. 10 pM, (S/N=3) and a very high selectivity towards structural analogs (aspirin, BPA, and piperazine) even in a mixture. PMID:25982729

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    Sharma, Chandra Kant; Sharma, Vinay

    2012-01-01

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

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

    Science.gov (United States)

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

    2012-01-25

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

  13. Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Clinical Trial

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    Mehrdad Esmailian

    2015-07-01

    Full Text Available Introduction: Rib fracture is one of the common causes of trauma disabilities in many events and the outcome of these patients are very extensive from temporary pain management to long-term significant disability. Control and management of the pain in such patients is one of the most important challenges in emergency departments. Thus, the aim of the present study was assessing the efficacy of IV acetaminophen in pain control of patients with rib fracture. Methods: In this double-blind study, 54 patients over 18 years of age, referred to two educational hospitals with rib fracture, were entered. Patients were randomly categorized in two groups of morphine sulfate (0.1 milligram per kilogram of body weight and IV acetaminophen (1gram, as single-dose infused in 100 cc normal saline. The pain severity was measured by Numeric Rating Scale on arrival and 30 minutes after drug administration. At least three scores reduction was reported as therapeutic success. Results: The mean and standard deviation of patients’ age was 41.2 ± 14.1 years. There is no difference in gender (p=0.24 and age frequency (p=0.77 between groups. 30 minutes after drug administration the mean of pain severity were 5.5 ± 2.3 and 4.9 ± 1.7 in morphine and acetaminophen groups, respectively (p=0.23. Success rate in morphine and acetaminophen groups were 58.6% (95% Cl: 39.6-77.7 and 80% (95% Cl: 63.2-96.7, respectively, (p=0.09. Only 3 (5.6% patients had dizziness (p=0.44 and other effects were not seen in any of patients. Conclusion: The findings of the present study shows that intravenous acetaminophen and morphine have the same therapeutic value in relieving the pain of rib fracture. The success rate after 30 minutes drug administration were 80% and 58.6% in acetaminophen and morphine groups, respectively. Presentation of side effects was similar in both groups.

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

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    Yi Ding

    Full Text Available 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.

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

    International Nuclear Information System (INIS)

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

  16. Evaluation of Cellular Toxicity for Cisplatin, Arsenic And Acetaminophen in the Cancer and Normal Cell Line

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    S Saeedi Saravi

    2007-12-01

    Full Text Available Introduction: Cell culture is a process in which the cells ware isolated from original tissue, dispersed in liquid media and then placed in culture plate where the cells adhere together and propagate. Today, this method is used for assessment of cell toxicity, its mechanisms and effect of different compounds on intracellular components. Methods: Clonogenic assay was used for assessment of cell toxicity and amount of cell death after a specific time during which cells were exposed to different compounds. Thus, IC50 in caner cell lines (HePG2, SKOV3 and A549 and normal cell (LLCPK1, CHO and HGF1 was assessed after exposure to cisplatin, acetaminophen and arsenic. Results: Results showed that acetaminophen has maximum resistance and minimum sensitivity in CHO line with IC50=16.7±1.06 HePG2 with IC50=18.6±1.29. On the other hand, cisplatin showed minimum resistance and maximum sensitivity in HePG2 with IC50 = 0.87±0.07 and HGF1 with IC50 = 1.6±0.21 and lastly, arsenic showed minimum resistance and maximum sensitivity in A549 with IC50 = 4.59±0.29 and LLCPK1 with IC50= 1±0.37. Discussion: According to the evaluated IC50, there were differences between results of sensitivity of cell lines exposed to the three drugs (P<0.05. Entirely, resistance in cancer cell lines was lower than normal cells. The results showed the importance of cell defensive mechanisms encountering different substances like glutathione.

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

    Directory of Open Access Journals (Sweden)

    Francesco Di Pierro

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jean Matthieu Prot

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

  19. Pharmacokinetics of Acetaminophen in Hind Limbs Unloaded Mice: A Model System Simulating the Effects of Low Gravity on Astronauts in Space

    Science.gov (United States)

    Peterson, Amanda; Risin, Semyon A.; Ramesh, Govindarajan T.; Dasgupta, Amitava; Risin, Diana

    2008-01-01

    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in Space. Low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration in astronauts. Acquiring of such knowledge has inherent difficulties due to limited opportunities for experimenting in Space. One of the approaches is to use model systems that simulate some of the Space conditions on Earth. In this study we used hind limbs unloaded mice (HLU) to investigate the possible changes in PK of acetaminophen, a widely used analgesic with high probability of use by astronauts. The HLU is recognized as an appropriate model for simulating the effects of low gravity on hemodynamic parameters. Mice were tail suspended (n = 24) for 24-96 hours prior to introduction of acetaminophen (150 - 300 mg/kg). The drug (in aqueous solution containing 10% ethyl alcohol by volume) was given orally by a gavage procedure and after the administration of acetaminophen mice were additionally suspended for 30 min, 1 and 2 hours. Control mice (n = 24) received the same dose of acetaminophen and were kept freely all the time. Blood specimens were obtained either from retroorbital venous sinuses or from heart. Acetaminophen concentration was measured in plasma by the fluorescent polarization immunoassay and the AxSYM analyzer (Abbott Laboratories). In control mice peak acetaminophen concentration was achieved at 30 min. By 1 hour the concentration decreased to less than 50% of the peak level and at 2 hours the drug was almost undetectable in the serum. HLU for 24 hours significantly altered the acetaminophen pharmacokinetic: at 30 min the acetaminophen concentrations were significantly (both statistically and medically significant) lower than in control mice. The concentrations also reduced less

  20. Acetaminophen and diphenhydramine as premedication for platelet transfusions: a prospective randomized double-blind placebo-controlled trial.

    Science.gov (United States)

    Wang, Stephen E; Lara, Primo N; Lee-Ow, Angie; Reed, Jeanne; Wang, Lori R; Palmer, Patti; Tuscano, Joseph M; Richman, Carol M; Beckett, Laurel; Wun, Ted

    2002-07-01

    Non-hemolytic transfusion reactions (NHTR) occur in up to 30% of patients receiving platelet transfusions. Premedication with acetaminophen and diphenhydramine is a common strategy to prevent NHTR, but its efficacy has not been studied. In this prospective trial, transfusions in patients receiving pre-storage leukocyte-reduced single-donor apheresis platelets (SDP) were randomized to premedication with either acetaminophen 650 mg PO and diphenhydramine 25 mg IV, or placebo. Fifty-one patients received 98 transfusions. Thirteen patients had 15 NHTR: 15.4% (8/52) in the treatment arm and 15.2% (7/46) in the placebo arm. Premedication prior to transfusion of pre-storage leukocyte reduced SDP does not significantly lower the incidence of NHTR as compared to placebo. PMID:12111764

  1. Pathogenic Role of NKT and NK Cells in Acetaminophen-Induced Liver Injury is Dependent on the Presence of DMSO

    OpenAIRE

    Masson, Mary Jane; Carpenter, Leah D.; Graf, Mary L.; Pohl, Lance R.

    2008-01-01

    Dimethyl sulfoxide (DMSO) is commonly used in biological studies to dissolve drugs and enzyme inhibitors with low solubility. While DMSO is generally thought of as being relatively inert, it can induce biological effects that are often overlooked. An example highlighting this potential problem is found in the recent report demonstrating a pathogenic role for NKT and NK cells in acetaminophen-induced liver injury (AILI) in C57Bl/6 mice in which DMSO was used to facilitate APAP dissolution. We ...

  2. Protective Properties of Flavonoid Extract of Coagulated Tofu (Curdled Soy Milk) Against Acetaminophen-Induced Liver Injury in Rats

    OpenAIRE

    Ndatsu Yakubu; Umaru Alhassan Mohammed

    2016-01-01

    The total flavonoid contents of the various coagulated tofu and the hepatoprotective potential of all tofu flavonoid extracts were investigated. Tofu was prepared from locally sourced coagulants (steep water, alum, lemon, and lemon peel ash extract). Total flavonoid contents of all coagulated tofu were investigated as established in vitro flavonoid assay. The hepatoprotective activities of tofu flavonoid extracts against acetaminophen-induced hepatic cell toxicity in rats was also investigate...

  3. Secretory phospholipase A2-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2

    International Nuclear Information System (INIS)

    We have previously reported that among the other death proteins, hepatic secretory phospholipase A2 (sPLA2) is a leading mediator of progression of liver injury initiated by CCl4 in rats. The aim of our present study was to test the hypothesis that increased hepatic sPLA2 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 sPLA2-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 14C-APAP in the livers of KO mice. Hepatic sPLA2 activity and plasma TNF-α were significantly higher after APAP administration in the KO mice. This was accompanied by a corresponding fall in hepatic PGE2 and lower compensatory liver regeneration and repair (3H-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 sPLA2-mediated progression of liver injury. These findings are consistent with the destructive role of sPLA2 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.

  4. Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Clinical Trial

    OpenAIRE

    Mehrdad Esmailian; Roshanak Moshiri; Majid Zamani

    2015-01-01

    Introduction: Rib fracture is one of the common causes of trauma disabilities in many events and the outcome of these patients are very extensive from temporary pain management to long-term significant disability. Control and management of the pain in such patients is one of the most important challenges in emergency departments. Thus, the aim of the present study was assessing the efficacy of IV acetaminophen in pain control of patients with rib fracture. Methods: In this double-blind study,...

  5. Effect of Oral Administration of Acetaminophen and Topical Application of EMLA on Pain during Transrectal Ultrasound-Guided Prostate Biopsy

    OpenAIRE

    Kim, Seol; Yoon, Byung Il; Kim, Su Jin; Cho, Hyuk Jin; Kim, Hyo Sin; Hong, Sung Hoo; Lee, Ji Youl; Hwang, Tae-Kon; Kim, Sae Woong

    2011-01-01

    Purpose Transrectal ultrasound-guided prostate biopsy is the procedure of choice for diagnosing prostate cancer. We compared with pain-relieving effect of acetaminophen, a known drug for enhancing the pain-relieving effect of tramadol, and eutectic mixture of local anesthetics (EMLA), a local anesthetic agent, with that of the conventional periprostatic nerve block method. Materials and Methods This was a prospective, randomized, single-blinded study. A total of 430 patients were randomly ass...

  6. Comparison of Preoperative Administration of Rectal Diclofenac and Acetaminophen for Reducing Post Operative Pain in Septorhinoplastic Surgeries

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    E Allahyry

    2006-04-01

    Full Text Available ABSTRACT: Introduction & Objective: Post operative pain is usually treated by opioids, which is expensive and may induce various side effects. Non steroidal anti-inflammatory drugs have been considered recently for controlling pain due to their cheapness, fewer side effects and availability. This study compares the analgesic efficacy of preoperative administration of single dose of rectally diclofenac and acetaminophen for post operative analgesia in septorhinoplasty, one of the most common head and neck surgeries. Materials & Methods: Sixty adult patients with ASA =1 underwent septorhinoplasty were randomly divided into two equal groups. Thirty minutes before induction of anesthesia, 100 mg diclofenac suppository and 325 mg of rectal acetaminophen were given to group I and group II respectively. Induction and maintenance of anesthesia were similar in all patients. Then the severity of pain was graded 1, 2 and 4 hours after operation according to Visual Analogue Scale. Also the first time of analgesic request and total administered dose of analgesics were assessed by another person in all patients. Results: Results revealed that severity of pain in diclofenac group in all three defined times was significantly less than that in the other group (p<0.05. Also the average of first time analgesic request in group 1 and 2 was 205 and 97 minutes respectively and the average dose of administered pehtidine was 12.25 mg in diclofenac and 37.15 mg in acetaminophen group. Conclusion: The pre-operative administration of rectal diclofenac was more effective for post septorhioplasty analgesia than the rectal acetaminophen and thus it could be used and recommended as a safe, compensive and effective method for post operative pain relief in this common surgery.

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

    Science.gov (United States)

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

    2015-10-22

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

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

    OpenAIRE

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

    2009-01-01

    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 o...

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

    Science.gov (United States)

    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

  10. 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.

    Science.gov (United States)

    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

  11. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey.

    Science.gov (United States)

    Schultz, Stephen T; Klonoff-Cohen, Hillary S; Wingard, Deborah L; Akshoomoff, Natacha A; Macera, Caroline A; Ji, Ming

    2008-05-01

    The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80 control children. Acetaminophen use after measles-mumps-rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less (OR 6.11, 95% CI 1.42-26.3), after limiting cases to children with regression in development (OR 3.97, 95% CI 1.11-14.3), and when considering only children who had post-vaccination sequelae (OR 8.23, 95% CI 1.56-43.3), adjusting for age, gender, mother's ethnicity, and the presence of illness concurrent with measles-mumps-rubella vaccination. Ibuprofen use after measles-mumps-rubella vaccination was not associated with autistic disorder. This preliminary study found that acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder.

  12. Toxicity monitoring with primary cultured hepatocytes underestimates the acetaminophen-induced inflammatory responses of the mouse liver.

    Science.gov (United States)

    Tachibana, Shinjiro; Shimomura, Akiko; Inadera, Hidekuni

    2011-01-01

    In vitro gene expression profiling with isolated hepatocytes has been used to assess the hepatotoxicity of certain chemicals because of animal welfare issues. However, whether an in vitro system can completely replace the in vivo system has yet to be elucidated in detail. Using a focused microarray established in our laboratory, we examined gene expression profiles in the mouse liver and primary cultured hepatocytes after treatment with different doses of acetaminophen, a widely used analgesic that frequently causes liver injury. The acute hepatotoxicity of acetaminophen was confirmed by showing the induction of an oxidative stress marker, heme oxygenase-1, elevated levels of serum transaminase, and histopathological findings. In vivo microarray and network analysis showed that acetaminophen treatment provoked alterations in relation to the inflammatory response, and that tumor necrosis factor-α plays a central role in related pathway alterations. By contrast, pathway analyses in in vitro isolated hepatocytes did not find such prominent changes in the inflammation-related networks compared with the in vivo situation. Thus, although in vitro gene expression profiles are useful for evaluating the direct toxicity of chemicals, indirect toxicities including inflammatory responses mediated by cell-cell interactions or secondary toxicity due to pathophysiological changes in the whole body may be overlooked. Our results indicate that the in vitro hepatotoxicity prediction system using isolated hepatocytes does not fully reflect the in vivo cellular response. An in vitro system may be appropriate, therefore, for high throughput screening to detect the direct hepatotoxicity of a test compound.

  13. Acetaminophen Versus Liquefied Ibuprofen for Control of Pain During Separation in Orthodontic Patients: A Randomized Triple Blinded Clinical Trial.

    Science.gov (United States)

    Hosseinzadeh Nik, Tahereh; Shahsavari, Negin; Ghadirian, Hannaneh; Ostad, Seyed Nasser

    2016-07-01

    The aim of this randomized clinical study was to investigate the effectiveness of acetaminophen 650 mg or liquefied ibuprofen 400 mg in pain control of orthodontic patients during separation with an elastic separator. A total of 101 patients with specific inclusion criteria were divided randomly into three groups (acetaminophen, liquefied ibuprofen, and placebo). They were instructed to take their drugs one hour before separator placement and every six hours afterward (five doses in total). They recorded their discomfort on visual analog scales immediately after separator placement, 2 hours later, 6 hours later, at bedtime, and 24 hours after separator placement. Repeated measure analysis of variance (ANOVA) was used to compare the mean pain scores between the three groups. Data were collected from 89 patients. The pain increased with time in all groups. Pain scores were statistically lower in the analgesic groups compared with the placebo group (P.valueacetaminophen and liquefied ibuprofen) (P.value=1). Acetaminophen and liquefied ibuprofen have similar potential in pain reduction during separation. PMID:27424011

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Renata Grespan

    2014-01-01

    Full Text Available 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.

  16. Naproxen 500 mg bid versus acetaminophen 1000 mg qid: effect on swelling and other acute postoperative events after bilateral third molar surgery.

    Science.gov (United States)

    Bjørnsson, G A; Haanaes, H R; Skoglund, L A

    2003-08-01

    A controlled, randomized, double-blind crossover study, in which the patients acted as their own controls, was carried out to test the efficacy of naproxen 500 mg x 2 versus acetaminophen 1000 mg x 4 for 3 days on the postoperative course following third molar surgery. Acetaminophen reduced the mean swelling on the 3rd postoperative day by 22.4% (p = 0.023) compared to that after naproxen. On the 6th postoperative day, there was 20.9% less mean swelling with naproxen (p = 0.44), although the total swelling measurements were much less than those measured on the 3rd postoperative day. Summed pain intensity (SUMPI3.5-11) on the day of surgery revealed no statistically significant difference between the acetaminophen or naproxen regimen with the exception of 0.5 hours (p = 0.002) and 1 hour (p = 0.009) after first medication when acetaminophen gave less pain than naproxen. Since the drug regimens were different, summed PI for the first acetaminophen dose interval (SUMPI3.5-6) and the first naproxen dose interval (SUMPI3.5-9) was calculated. There was a tendency toward a statistically significant difference in favor of acetaminophen for SUMPI3.5-6 (p = 0.055) but no statistically significant difference (p = 0.41) between the treatments with respect to SUMPI3.5-9. Naproxen was statistically superior (p surgery. A 3-day acetaminophen regimen reduces acute postoperative swelling better than naproxen on the 3rd postoperative day after third molar surgery but not on the 6th postoperative day when the total swelling is less. PMID:12953342

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

    Directory of Open Access Journals (Sweden)

    Hyunseong Kim

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

  18. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure.

    Science.gov (United States)

    Kortsalioudaki, Christine; Taylor, Rachel M; Cheeseman, Paul; Bansal, Sanjay; Mieli-Vergani, Giorgina; Dhawan, Anil

    2008-01-01

    Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminophen-induced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) > 2 and abnormal liver function or INR >1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989-1994), standard care (n = 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995-2004), standard care and NAC administration (n = 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P = not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P = ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P = 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P = 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P = 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P = ns; and LT was performed in 32 (54%) vs. 42 (38%), P = ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8

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

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    Xie, Yuchao; Ramachandran, Anup [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Breckenridge, David G.; Liles, John T. [Department of Biology, Gilead Sciences, Inc., Foster City, CA (United States); Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    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

  20. In vitro antioxidant and hepatoprotective potential of Azolla microphylla phytochemically synthesized gold nanoparticles on acetaminophen - induced hepatocyte damage in Cyprinus carpio L.

    Science.gov (United States)

    Kunjiappan, Selvaraj; Bhattacharjee, Chiranjib; Chowdhury, Ranjana

    2015-06-01

    The present study aims to evaluate the hepatoprotective and antioxidant effects of gold nanoparticles (GNaP) biosynthesized through the mediation of Azolla microphylla and A. microphylla extract on acetaminophen-induced hepatocyte damage in common carp fish (Cyprinus carpio L.). The gold nanoparticles (100, 150, 200 μg/ml) and A. microphylla extract powder (100, 200, 400 μg/ml) were added to the primary hepatocytes in different conditions: treatment I (before 12 mM acetaminophen), treatment II (after 12 mM acetaminophen), and treatment III (both before and after 12 mM acetaminophen), and incubated. Among these, control group treated with 12 mM acetaminophen produced significantly elevated levels (50-80%) of lactate dehydrogenase (LDH), catalase (CAT), glutamate oxalate transaminase (GOT), glutamate pyruvate transaminase (GPT), and malondialdehyde (MDA), and significantly decreased the levels (60-75%) of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Treatment with methanol extract of A. microphylla phytochemically biosynthesized gold nanoparticles (100, 150, 200 μg/ml) and A. microphylla methanol extract powder (100, 200, 400 μg/ml) significantly improved the viability of cells in a culture medium. It also significantly reduced the levels of LDH, CAT, GOT, GPT, and MDA, and significantly increased the levels of SOD and GSH-Px. In conclusion, gold nanoparticles biosynthesized through A. microphylla demonstrated effective hepatoprotective and antioxidant effects than methanol extract of A. microphylla. PMID:25862331

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

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    Shim Eugene

    2011-10-01

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

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    González-Ponce, Herson Antonio; Martínez-Saldaña, María Consolación; Rincón-Sánchez, Ana Rosa; Sumaya-Martínez, María Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juárez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-l-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800 mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20 mmol/L APAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF. PMID:27782042

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

    Science.gov (United States)

    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 (pneon shrimp.

  5. Acetaminophen/paracetamol: A history of errors, failures and false decisions.

    Science.gov (United States)

    Brune, K; Renner, B; Tiegs, G

    2015-08-01

    Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side-effect 'epidemy' (phenacetin nephropathy, drug-induced interstitial nephritis) and ends with the discovery of second-generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound. PMID:25429980

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

    Directory of Open Access Journals (Sweden)

    Jun Ho Shin

    2013-03-01

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

  7. Assessing the treatment of acetaminophen-contaminated brewery wastewater by an anaerobic packed-bed reactor.

    Science.gov (United States)

    Abdullah, Norhayati; Fulazzaky, Mohamad Ali; Yong, Ee Ling; Yuzir, Ali; Sallis, Paul

    2016-03-01

    The treatment of high-strength organic brewery wastewater with added acetaminophen (AAP) by an anaerobic digester was investigated. An anaerobic packed-bed reactor (APBR) was operated as a continuous process with an organic loading rate of 1.5-g COD per litre per day and a hydraulic retention time of three days. The results of steady-state analysis showed that the greatest APBR performances for removing COD and TOC were as high as 98 and 93%, respectively, even though the anaerobic digestibility after adding the different AAP concentrations of 5, 10 and 15 mg L(-1) into brewery wastewater can affect the efficiency of organic matter removal. The average CH4 production decreased from 81 to 72% is counterbalanced by the increased CO2 production from 11 to 20% before and after the injection of AAP, respectively. The empirical kinetic models for substrate utilisation and CH4 production were used to predict that, under unfavourable conditions, the performance of the APBR treatment process is able to remove COD with an efficiency of only 6.8%. PMID:26760229

  8. Electrochemical detection of acetaminophen on the functionalized MWCNTs modified electrode using layer-by-layer technique

    Energy Technology Data Exchange (ETDEWEB)

    Manjunatha, Revanasiddappa [Chemistry Research Centre, S.S.M.R.V. Degree College, IV ' T' Block, Jayanagar, Bangalore 560041 (India); Nagaraju, Dodahalli Hanumantharayudu [Mechanical Engineering Department, National University of Singapore, 119615 (Singapore); Suresh, Gurukar Shivappa, E-mail: sureshssmrv@yahoo.co.in [Chemistry Research Centre, S.S.M.R.V. Degree College, IV ' T' Block, Jayanagar, Bangalore 560041 (India); Melo, Jose Savio; D' Souza, Stanislaus F. [Nuclear Agriculture and Biotechnology Division, Bhabha Atomic Research Centre, Mumbai 400085 (India); Venkatesha, Thimmappa Venkatarangaiah [Department of Chemistry, Kuvempu University, Jnanasahyadri, Shimoga 577451 (India)

    2011-07-30

    A selective electrochemical method is fabricated via layer-by-layer (LBL) method using both positively and negatively charged multi walled carbon nanotubes (MWCNTs) on poly (diallyldimetheylammonium chloride) (PDDA)/poly styrene sulfonate (PSS) modified graphite electrode, for the determination of acetaminophen (ACT) in the presence of dopamine (DA) and high concentration of ascorbic acid (AA). The modified electrode was characterized by cyclic voltammetry (CV) electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM) and scanning electron microscopy (SEM). Experimental conditions such as pH, accumulation potential and time, effect of potential sweep rates and interferents were studied. In CV well defined peaks for AA, ACT and DA are obtained at 24, 186 and 374 mV, respectively. The separations of peaks were 210, 188 and 398 mV between AA and DA, DA and ACT and AA and ACT, respectively. The diffusion coefficient was calculated by chronocoulometric. Chronoamperometric studies showed the linear relationship between oxidation peak current and concentration of ACT in the range 25-400 {mu}M (R = 0.9991). The detection limit was 5 x 10{sup -7} mol/L. The proposed method gave satisfactory results in the determination of ACT in pharmaceutical and human serum samples.

  9. Combined Effect of Ethanol and Acetaminophen on the Central Nervous System of Daphnia magna

    Directory of Open Access Journals (Sweden)

    Brigid Bleaken

    2010-01-01

    Full Text Available The combined consumption of acetaminophen (APAP and ethanol (EtOH has been an issue with clinical implications. Previous findings regarding the simultaneous consumption of APAP and EtOH have reported harmful effects on the liver and stomach; however, little is known about the effects on the central nervous system (CNS. We hypothesized that EtOH and APAP will have a synergistic effect on the CNS of Daphnia magna (D. magna, causing a pronounced decrease in heart rate at a toxic dose of EtOH. To better understand the effects of the combined consumption of EtOH and APAP on the CNS, the heart rates of D. magna were measured under a dissection microscope after exposure to EtOH, APAP, or a combined EtOH-APAP solution. Interestingly, the average heart rates of D. magna exposed to the EtOH-APAP solution and D. magna exposed only to APAP were approximately the same. Although our results did not support our original hypothesis, the data demonstrated that APAP exerted a dominant effect over EtOH. APAP and EtOH are known to have inhibitory effects on the CNS. Therefore, these findings suggest that APAP and EtOH may compete against each other on similar pathways to be the substance that exerts an inhibitory effect in the CNS.

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

    Science.gov (United States)

    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.

  11. Toxicity Thresholds for Diclofenac, Acetaminophen and Ibuprofen in the Water Flea Daphnia magna.

    Science.gov (United States)

    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

  12. Au nanoparticles/poly(caffeic acid) composite modified glassy carbon electrode for voltammetric determination of acetaminophen.

    Science.gov (United States)

    Li, Tianbao; Xu, Juan; Zhao, Lei; Shen, Shaofei; Yuan, Maosen; Liu, Wenming; Tu, Qin; Yu, Ruijin; Wang, Jinyi

    2016-10-01

    An Au nanoparticles/poly(caffeic acid) (AuNPs/PCA) composite modified glassy carbon (GC) electrode was prepared by successively potentiostatic technique in pH 7.4 phosphate buffer solution containing 0.02mM caffeic acid and 1.0mM HAuCl4. Electrochemical characterization of the AuNPs/PCA-GC electrode was investigated by electrochemical impedance spectroscopy and cyclic voltammetry. The electrochemical behavior of acetaminophen (AP) at the AuNPs/PCA-GC electrode was also studied by cyclic voltammetry. Compared with bare GC and poly(caffeic acid) modified GC electrode, the AuNPs/PCA-GC electrode was exhibited excellent electrocatalytic activity toward the oxidation of AP. The plot of catalytic current versus AP concentration showed two linear segments in the concentration ranges 0.2-20µM and 50-1000µM. The detection limit of 14 nM was obtained by using the first range of the calibration plot. The AuNPs/PCA-GC electrode has been successfully applied and validated by analyzing AP in blood, urine and pharmaceutical samples. PMID:27474318

  13. Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen Exposure

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    Jingjing Liu

    2012-11-01

    Full Text Available Autism is a condition characterized by impaired cognitive and social skills, associated with compromised immune function. The incidence is alarmingly on the rise, and environmental factors are increasingly suspected to play a role. This paper investigates word frequency patterns in the U.S. CDC Vaccine Adverse Events Reporting System (VAERS database. Our results provide strong evidence supporting a link between autism and the aluminum in vaccines. A literature review showing toxicity of aluminum in human physiology offers further support. Mentions of autism in VAERS increased steadily at the end of the last century, during a period when mercury was being phased out, while aluminum adjuvant burden was being increased. Using standard log-likelihood ratio techniques, we identify several signs and symptoms that are significantly more prevalent in vaccine reports after 2000, including cellulitis, seizure, depression, fatigue, pain and death, which are also significantly associated with aluminum-containing vaccines. We propose that children with the autism diagnosis are especially vulnerable to toxic metals such as aluminum and mercury due to insufficient serum sulfate and glutathione. A strong correlation between autism and the MMR (Measles, Mumps, Rubella vaccine is also observed, which may be partially explained via an increased sensitivity to acetaminophen administered to control fever.

  14. Adsorption behaviors of acetaminophen onto sediment in the Weihe River, Shaanxi, China

    Institute of Scientific and Technical Information of China (English)

    Yue Zhao; Shengke Yang; Huihui Li; Di Wang

    2015-01-01

    abstract Adsorption behaviors of acetaminophen onto sediment in the Weihe River were described. The impact factors in the processes of adsorption, such as contact time, solution pH, temperature, and ionic strength, were determined by experiments. The experimental results were analyzed by kinetic and isotherm models. The adsorption kinetics was found to follow a pseudo-first-order model. The equilibrium adsorption data fitted well with the Langmuir and Freundlich isotherm models. However, the Langmuir isotherm was more suitable to describe the adsorption. Thermodynamics parameters such as Gibbs-free energy change (ΔG0), enthalpy change (ΔH0) and entropy change (ΔS0) were calculated. Results showed that the adsorption was feasible, spontaneous, entropy increasing, and endothermic in nature, which reached equilibrium in about 24 hours. The adsorption capacity did not cause obvious change at solution pH 3.0–9.0, and decreased in solution pH 9.0–11.0. The presence of electrolytes such as NaCl in aqueous solution had a significant negative effect on the adsorption. The mechanisms controlling the adsorption were supposed to be chemisorption.

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

    Science.gov (United States)

    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

  16. Ascorbic acid prevents acetaminophen-induced hepatotoxicity in mice by ameliorating glutathione recovery and autophagy.

    Science.gov (United States)

    Kurahashi, Toshihiro; Lee, Jaeyong; Nabeshima, Atsunori; Homma, Takujiro; Kang, Eun Sil; Saito, Yuka; Yamada, Sohsuke; Nakayama, Toshiyuki; Yamada, Ken-Ichi; Miyata, Satoshi; Fujii, Junichi

    2016-08-15

    Aldehyde reductase (AKR1A) plays a role in the biosynthesis of ascorbic acid (AsA), and AKR1A-deficient mice produce about 10-15% of the AsA that is produced by wild-type mice. We found that acetaminophen (AAP) hepatotoxicity was aggravated in AKR1A-deficient mice. The pre-administration of AsA in the drinking water markedly ameliorated the AAP hepatotoxicity in the AKR1A-deficient mice. Treatment of the mice with AAP decreased both glutathione and AsA levels in the liver in the early phase after AAP administration, and an AsA deficiency delayed the recovery of the glutathione content in the healing phase. While in cysteine supply systems; a neutral amino acid transporter ASCT1, a cystine transporter xCT, enzymes for the transsulfuration pathway, and autophagy markers, were all elevated in the liver as the result of the AAP treatment, the AsA deficiency suppressed their induction. Thus, AsA appeared to exert a protective effect against AAP hepatotoxicity by ameliorating the supply of cysteine that is available for glutathione synthesis as a whole. Because some drugs produce reactive oxygen species, resulting in the consumption of glutathione during the metabolic process, the intake of sufficient amounts of AsA would be beneficial for protecting against the hepatic damage caused by such drugs. PMID:27288086

  17. Pain relief after arthroscopy: naproxen sodium compared to propoxyphene napsylate with acetaminophen.

    Science.gov (United States)

    Drez, D; Ritter, M; Rosenberg, T D

    1987-04-01

    We compared naproxen sodium (550 mg) and propoxyphene napsylate with acetaminophen (PN/A, 100 mg with 650 mg) for pain relief after arthroscopy or arthroscopic meniscectomy. Fifty-two patients entered this multicenter, double-blind, randomized, parallel trial. In each drug group, pain intensity values dropped consistently throughout this six-hour study from mean baseline levels of approximately 55 on a scale of 0 to 100. Pain intensity values were lower at each hour in the naproxen sodium than in the PN/A group and significantly lower at hour 1 (P = .008). Pain intensity differences (PID, reflecting change from baseline) mirrored this trend: greater mean PIDs were seen in the naproxen sodium group at each hour, and this difference between drug groups was statistically significant at hour 1 (P = .017). One patient in the naproxen sodium group and seven patients using PN/A took a second dose within the six hours. Patients in each drug group reported five complaints. PMID:2882607

  18. Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis

    Directory of Open Access Journals (Sweden)

    Donald Albert

    2013-05-01

    Full Text Available Introduction: There are few reports summarizing the effectiveness of oral and intravenous (IV acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L when treated with oral and IV acetylcysteine.Methods: Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment.Results: We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity.Conclusion: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration. [West J Emerg Med. 2013;14(3:218–226.

  19. Plantago major treatment enhanced innate antioxidant activity in experimental acetaminophen toxicity

    Institute of Scientific and Technical Information of China (English)

    Farida Hussan; Rina Haryani Osman Basah; Mohd Rafizul Mohd Yusof; Nur Aqilah Kamaruddin; Faizah Othman

    2015-01-01

    To determine the effect of Plantago major (P. major) extract on the liver injury following acetaminophen (APAP) toxicity. Methods: The male Sprague Dawley rats (n = 38) were randomly divided into normal control (n= 6) and experiment (n = 32) groups. The latter was subdivided into four groups and induced with APAP (1000 mg/kg) per oral, followed by P. major extract and N-acetylcysteine orally to the respective groups for six days. Results: On the seventh day, the serum bilirubin, liver enzymes and tissue malondialdehyde were increased in APAP groups whereas the total protein in serum, tissue superoxide dismutase and glutathione levels were reduced. The plant extract treatment reduced the histological deteriorations such as aggregation of hepatocellular cords, formation of binucleated cells and vacuolisation of the cells with scanty cytoplasm. It also revealed significant reduction of malondialdehyde and increased level of superoxide dismutase and glutathione. The findings in the extract treated groups were comparable to the group treated with N-acetylcysteine. Conclusions: In conclusion, P. major can enhance innate antioxidant activity and ameliorate the APAP-induced liver injury.

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

    Science.gov (United States)

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

    2012-04-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Jeanine Ward; Shashi Bala; Jan Petrasek; Gyongyi Szabo

    2012-01-01

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

  2. Plantago major treatment enhanced innate antioxidant activity in experimental acetaminophen toxicity

    Institute of Scientific and Technical Information of China (English)

    Farida; Hussan; Rina; Haryani; Osman; Basah; Mohd; Rai; zul; Mohd; Yusof; Nur; Aqilah; Kamaruddin; Faizah; Othman

    2015-01-01

    Objective: To determine the ef ect of Plantago major(P. major) extract on the liver injury following acetaminophen(APAP) toxicity. Methods: The male Sprague Dawley rats(n = 38) were randomly divided into normal control(n = 6) and experiment(n = 32) groups. The latter was subdivided into four groups and induced with APAP(1 000 mg/kg) per oral, followed by P. major extract and N-acetylcysteine orally to the respective groups for six days. Results: On the seventh day, the serum bilirubin, liver enzymes and tissue malondialdehyde were increased in APAP groups whereas the total protein in serum, tissue superoxide dismutase and glutathione levels were reduced. The plant extract treatment reduced the histological deteriorations such as aggregation of hepatocellular cords, formation of binucleated cells and vacuolisation of the cells with scanty cytoplasm. It also revealed signii cant reduction of malondialdehyde and increased level of superoxide dismutase and glutathione. The i ndings in the extract treated groups were comparable to the group treated with N-acetylcysteine. Conclusions: In conclusion, P. major can enhance innate antioxidant activity and ameliorate the APAP-induced liver injury.

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

    Science.gov (United States)

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

    2012-02-01

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

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

    Science.gov (United States)

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

    2009-10-01

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

  5. Comparison of the effect of vanadium and deferoxamine on acetaminophen toxicity in rats

    Directory of Open Access Journals (Sweden)

    H Najafzadeh

    2011-01-01

    Full Text Available Aim: Acetaminophen (APAP can change to toxic metabolites at high dose; if these metabolites are in high amounts, the body will be unable to neutralize them, and several tissues including liver will be damaged. In the present study, the effect of vanadium was compared with deferoxamine on hepatotoxicity and also kidney function during APAP administration in rats. Material and Methods: The study was done in 5 groups (5 rats in each group: group I to V, respectively, received normal saline, APAP, APAP + deferoxamine, APAP + vanadium, and vanadium. At the end of the study, blood was collected and serum was separated for laboratory tests. The serum levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST, blood urea nitrogen (BUN, creatinine, sodium, and potassium were determined. The liver of the rats were separated for tissue processing and light microscopic examination. Results: APAP significantly increased; ALT level and deferoxamine and vanadium prevented its elevation. Also, deferoxamine and vanadium prevented increase of AST by APAP. The change of factors, which are related to the kidney function, i.e., BUN, creatinine, sodium, and potassium were not considerable. Conclusion: Thus, it was observed that vanadium had better effect than deferoxamine in the prevention of hepatotoxicity induced by APAP.

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

    Science.gov (United States)

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

    2014-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Yang Runkuan

    2011-11-01

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

  8. Bioactivation and toxicity of acetaminophen in a rat hepatocyte micropatterned coculture system.

    Science.gov (United States)

    Ukairo, Okechukwu; McVay, Michael; Krzyzewski, Stacy; Aoyama, Simon; Rose, Kelly; Andersen, Melvin E; Khetani, Salman R; Lecluyse, Edward L

    2013-10-01

    We have recently shown that primary rat hepatocytes organized in micropatterned cocultures with murine embryonic fibroblasts (HepatoPac™) maintain high levels of liver functions for at least 4 weeks. In this study, rat HepatoPac was assessed for its utility to study chemical bioactivation and associated hepatocellular toxicity. Treatment of HepatoPac cultures with acetaminophen (APAP) over a range of concentrations (0-15 mM) was initiated at 1, 2, 3, or 4 weeks followed by the assessment of morphological and functional endpoints. Consistent and reproducible concentration-dependent effects on hepatocyte structure, viability, and basic functions were observed over the 4-week period, and were exacerbated by depleting glutathione using buthionine sulfoximine or inducing CYP3A using dexamethasone, presumably due to increased reactive metabolite-induced stress and adduct formation. In conclusion, the results from this study demonstrate that rat HepatoPac represents a structurally and functionally stable hepatic model system to assess the long-term effects of bioactivated compounds.

  9. Simultaneous Chronoamperometric Sensing of Ascorbic Acid and Acetaminophen at a Boron-Doped Diamond Electrode

    Directory of Open Access Journals (Sweden)

    Ciprian Radovan

    2008-06-01

    Full Text Available Cyclic voltammetry (CV and chronoamperometry (CA have been used to sense and determine simultaneously L-ascorbic acid (AA and acetaminophen (AC at a boron-doped diamond electrode (BDDE in a Britton-Robinson buffer solution. The calibration plots of anodic current peak versus concentration obtained from CV and CA data for both investigated compounds in single and di-component solutions over the concentration range 0.01 mM – 0.1 mM proved to be linear, with very good correlation parameters. Sensitivity values and RSD of 2-3% were obtained for various situations, involving both individual and simultaneous presence of AA and AC. The chronoamperometric technique associated with standard addition in sequential one step and/or two successive and continuous chronoamperograms at two characteristic potential levels represented a feasible option for the simultaneous determination of AA and AC in real sample systems such as pharmaceutical formulations. The average values indicated by the supplier were confirmed to a very close approximation from chronoamperomgrams by using several additions with the application of suitable current correction factors.

  10. Acetaminophen Changes Intestinal Epithelial Cell Membrane Properties, Subsequently Affecting Absorption Processes

    Directory of Open Access Journals (Sweden)

    Christine Schäfer

    2013-08-01

    Full Text Available Background/Aims: Acetaminophen (APAP effects on intestinal barrier properties are less investigated. APAP may lead to a changed bioavailability of a subsequently administered drug or diet in the body. We investigated the influence of APAP on enterocytic cell membrane properties that are able to modify the net intestinal absorption of administered substances across the Caco-2 barrier model. Methods: The effect of APAP on cytotoxicity was measured by LDH assay, TER value and cell capacitance label-free using impedance monitoring, membrane permeability by FITC-dextrans, and efflux transporter MDR1 activity by Rh123. APAP levels were determined by HPLC analysis. Cell membrane topography and microvilli were investigated using SEM and intestinal alkaline phosphatase (Alpi and tight junction protein 1 (TJP1 expression by western blot analysis. Results: APAP changed the apical cell surface, reduced the number of microvilli and protein expression of Alpi as a brush border marker and TJP1, increased the membrane integrity and concurrently decreased cell capacitance over time. In addition, APAP decreased the permeability to small molecules and increased the efflux transporter activity, MDR1. Conclusion: APAP alters the Caco-2 cell membrane properties by different mechanisms and reduces the permeability to administered substances. These findings may help to optimize therapeutic implications.

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

    Institute of Scientific and Technical Information of China (English)

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

    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.

  12. Kinetics of acetaminophen degradation by Fenton oxidation in a fluidized-bed reactor.

    Science.gov (United States)

    de Luna, Mark Daniel G; Briones, Rowena M; Su, Chia-Chi; Lu, Ming-Chun

    2013-01-01

    Acetaminophen (ACT), an analgesic and antipyretic substance, is one of the most commonly detected pharmaceutical compound in surface waters and wastewaters. In this study, fluidized-bed Fenton (FB-Fenton) was used to decompose ACT into its final degradation products. The 1.45-L cylindrical glass reactor had inlet, outlet and recirculating sections. SiO(2) carrier particles were supported by glass beads with 2-4 mm in diameter. ACT concentration was determined by high performance liquid chromatography (HPLC). During the first 40 min of reaction, a fast initial ACT removal was observed and the "two-stage" ACT degradation conformed to a pseudo reaction kinetics. The effects of ferrous ion dosage and [Fe(2+)]/[H(2)O(2)] (FH ratio) were integrated into the derived pseudo second-order kinetic model. A reaction pathway was proposed based on the intermediates detected through SPME/GC-MS. The aromatic intermediates identified were hydroquinone, benzaldehydes and benzoic acids while the non-aromatic substances include alcohols, ketones, aldehydes and carboxylic acids. Rapid initial ACT degradation rate can be accomplished by high initial ferrous ion concentration and/or low FH ratio.

  13. Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen syrup in children with pyrexia associated with infectious diseases and treated with antibiotics.

    Science.gov (United States)

    Autret, E; Breart, G; Jonville, A P; Courcier, S; Lassale, C; Goehrs, J M

    1994-01-01

    A double-blind, randomised, parallel group study has been done comparing the efficacy and tolerability of 7.5 mg/kg ibuprofen syrup (n = 77) and 10 mg.kg-1 acetaminophen syrup (n = 77) in 154 children (6 months to 5 years) with fever (> or = 38 degrees C) associated with infectious diseases and treated with antibiotic therapy. The area under the percentage reduction in temperature curve captured the net effect of each drug and provided the best estimate for comparison of efficacy during a defined period. Temperature evolution over time was not significantly different between the two groups. Nevertheless, the temperature reduction over the first 4 h of treatment (H0-H4) was significantly higher after ibuprofen (60%) than acetaminophen (45%). Both ibuprofen and acetaminophen were well tolerated. In conclusion, significant antipyretic activity, good tolerability and its availability as a syrup make ibuprofen an effective means of fever control in children. PMID:8070499

  14. [Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency].

    Science.gov (United States)

    Voloshchuk, O N; Kopylchuk, G P

    2016-01-01

    Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD(+)/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deprivation. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD(+)/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein caused a more pronounced decrease in the activity of NAD(+)-dependent dehydrogenases studied and a 2.2-fold increase of the mitochondrial NAD(+)/NADН ratio. This suggests that alimentary protein deprivation potentiated drug-induced liver damage.

  15. The Effects of Diclofenac Suppository and Intravenous Acetaminophen and their Combination on the Severity of Postoperative Pain in Patients Undergoing Spinal Anaesthesia During Cesarean Section

    Science.gov (United States)

    Niaki, Alireza Seyedi; Jafari, Seyed Yaghoub; Yousefi, Zahra; Aryaie, Mohammad

    2016-01-01

    Introduction The main tasks of postoperative care are postoperative pain and complications control which play an important role in accelerating the recovery of patient’s general condition. Aim This study was performed in order to compare the effects of diclofenac suppository, intravenous acetaminophen and their combination on the severity of postoperative pain in patients undergoing spinal anaesthesia for cesarean section in Sayyad Shirazi teaching Hospital, Gorgon, Iran. Materials and Methods This was a double-blind clinical trial on 90 patients undergoing cesarean section. The patients were randomly divided into three groups, group A: 100 mg diclofenac suppository, group B: 1000 mg intravenous acetaminophen, group C: 100 mg diclofenac suppository and 500 mg intravenous acetaminophen. The same spinal anaesthesia circumstances were applied for all the participants. At the end of surgery, pain severity was assessed according to VAS scale at different times. Data were then analysed by SPSS 18 statistical software. Results The mean age of participants was (28.27±6.07). There was significant difference between the mean pain scores of the three groups before the intervention (p=0.018), which was considered as co-variate. This difference was more notable between the combination of acetaminophen – diclofenac group and diclofenac alone. After the intervention, significant difference was observed in mean pain severity between acetaminophen group and the combination group and also between diclofenac and the combination group. During the study, the least mean pain severity was found in the combination group and the highest was observed in the diclofenac group. Conclusion Results of this study indicates a significant effect of concomitant use of intravenous acetaminophen and diclofenac suppository on pain severity reduction and reducing the need for repeated doses of narcotics and prolonging the postoperative analgesia. PMID:27630929

  16. The role of the glutathione S-transferase genes GSTT1, GSTM1, and GSTP1 in acetaminophen-poisoned patients

    DEFF Research Database (Denmark)

    Buchard, Anders; Eefsen, Martin; Semb, Synne;

    2012-01-01

    The aim of this study was to assess if genetic variants in the glutathione-S-transferase genes GST-T1, M1, and P1 reflect risk factors in acetaminophen (APAP)-poisoned patients assessed by investigation of the relation to prothrombin time (PT), which is a sensitive marker of survival in these pat......The aim of this study was to assess if genetic variants in the glutathione-S-transferase genes GST-T1, M1, and P1 reflect risk factors in acetaminophen (APAP)-poisoned patients assessed by investigation of the relation to prothrombin time (PT), which is a sensitive marker of survival...

  17. Comparison of Clinical Efficacy of Intravenous Acetaminophen with Intravenous Morphine in Acute Renal Colic: A Randomized, Double-Blind, Controlled Trial

    OpenAIRE

    Kambiz Masoumi; Arash Forouzan; Ali Asgari Darian; Maryam Feli; Hassan Barzegari; Ali Khavanin

    2014-01-01

    The aim of this study was to compare the clinical efficacy of intravenous acetaminophen with intravenous morphine in acute renal colic pain management. In this double-blind controlled trial, patients aged 18–55 years, diagnosed with acute renal colic, who met the inclusion and exclusion criteria, were randomized into two groups. First, using the visual analogue scale (VAS), intensity of pain was assessed in both groups. Then, one gram of intravenous acetaminophen or 0.1 mg/kg morphine was inf...

  18. Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450-independent mitochondrial toxicity of acetaminophen and amiodarone.

    Science.gov (United States)

    Prill, Sebastian; Bavli, Danny; Levy, Gahl; Ezra, Elishai; Schmälzlin, Elmar; Jaeger, Magnus S; Schwarz, Michael; Duschl, Claus; Cohen, Merav; Nahmias, Yaakov

    2016-05-01

    Prediction of drug-induced toxicity is complicated by the failure of animal models to extrapolate human response, especially during assessment of repeated dose toxicity for cosmetic or chronic drug treatments. In this work, we present a 3D microreactor capable of maintaining metabolically active HepG2/C3A spheroids for over 28 days in vitro under stable oxygen gradients mimicking the in vivo microenvironment. Mitochondrial respiration was monitored using two-frequency phase modulation of phosphorescent microprobes embedded in the tissue. Phase modulation is focus independent and unaffected by cell death or migration. This sensitive measurement of oxygen dynamics revealed important information on the drug mechanism of action and transient subthreshold effects. Specifically, exposure to antiarrhythmic agent, amiodarone, showed that both respiration and the time to onset of mitochondrial damage were dose dependent showing a TC50 of 425 μm. Analysis showed significant induction of both phospholipidosis and microvesicular steatosis during long-term exposure. Importantly, exposure to widely used analgesic, acetaminophen, caused an immediate, reversible, dose-dependent loss of oxygen uptake followed by a slow, irreversible, dose-independent death, with a TC50 of 12.3 mM. Transient loss of mitochondrial respiration was also detected below the threshold of acetaminophen toxicity. The phenomenon was repeated in HeLa cells that lack CYP2E1 and 3A4, and was blocked by preincubation with ascorbate and TMPD. These results mark the importance of tracing toxicity effects over time, suggesting a NAPQI-independent targeting of mitochondrial complex III might be responsible for acetaminophen toxicity in extrahepatic tissues. PMID:26041127

  19. Electrocatalytical oxidation and sensitive determination of acetaminophen on glassy carbon electrode modified with graphene–chitosan composite

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Meixia; Gao, Feng [Department of Chemistry and Environmental Science, Zhangzhou Normal University, Zhangzhou 363000 (China); Wang, Qingxiang, E-mail: axiang236@126.com [Department of Chemistry and Environmental Science, Zhangzhou Normal University, Zhangzhou 363000 (China); Cai, Xili [Department of Chemistry and Environmental Science, Zhangzhou Normal University, Zhangzhou 363000 (China); Jiang, Shulian; Huang, Lizhang [Zhangzhou Product Quality Supervision and Inspection Institute, Zhangzhou 363000 (China); Gao, Fei [Department of Chemistry and Environmental Science, Zhangzhou Normal University, Zhangzhou 363000 (China)

    2013-04-01

    The electrochemical behaviors of acetaminophen (ACOP) on a graphene–chitosan (GR–CS) nanocomposite modified glassy carbon electrode (GCE) were investigated by cyclic voltammetry (CV), chronocoulometry (CC) and differential pulse voltammetry (DPV). Electrochemical characterization showed that the GR–CS nanocomposite had excellent electrocatalytic activity and surface area effect. As compared with bare GCE, the redox signal of ACOP on GR–CS/GCE was greatly enhanced. The values of electron transfer rate constant (k{sub s}), diffusion coefficient (D) and the surface adsorption amount (Γ{sup ⁎}) of ACOP on GR–CS/GCE were determined to be 0.25 s{sup −1}, 3.61 × 10{sup −5} cm{sup 2} s{sup −1} and 1.09 × 10{sup −9} mol cm{sup −2}, respectively. Additionally, a 2e{sup −}/2H{sup +} electrochemical reaction mechanism of ACOP was deduced based on the acidity experiment. Under the optimized conditions, the ACOP could be quantified in the range from 1.0 × 10{sup −6} to 1.0 × 10{sup −4} M with a low detection limit of 3.0 × 10{sup −7} M based on 3S/N. The interference and recovery experiments further showed that the proposed method is acceptable for the determination of ACOP in real pharmaceutical preparations. Highlights: ► A chitosan–graphene nanocomposite modified glassy carbon electrode was prepared. ► The modified electrode was electrochemically characterized by CV and EIS. ► Electro-oxidation of acetaminophen was examined on the modified electrode. ► Sensing analysis of the modified electrode toward acetaminophen was studied.

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

    Energy Technology Data Exchange (ETDEWEB)

    Chaudhuri, Shubhra, E-mail: SCHAUDHURI@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); McCullough, Sandra S., E-mail: mcculloughsandras@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Hennings, Leah, E-mail: lhennings@uams.edu [Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Brown, Aliza T., E-mail: brownalizat@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Li, Shun-Hwa [Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI (United States); Simpson, Pippa M., E-mail: psimpson@mcw.edu [Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI (United States); Hinson, Jack A., E-mail: hinsonjacka@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); James, Laura P., E-mail: jameslaurap@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States)

    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.

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

    Science.gov (United States)

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

    2015-12-01

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

  2. Some physicochemical properties of acetaminophen pediatric suspensions formulated with okra gums obtained from different extraction processes as suspending agent

    OpenAIRE

    Ikoni Ogaji

    2011-01-01

    The purpose of this work was to evaluate the effect of the extraction process and the potential of okra gum as a suspending agent in pharmaceutical oral formulations containing acetaminophen as a model drug. Clarified mucilage of dried okra was either extracted directly with ethanol 96% (F1) or was first treated with base (F2), acid (F3) or heating in the presence of salt (F4) before extraction with ethanol 96%. The samples were used at 0.5% w/v as suspending agents in ac...

  3. Gentiana manshurica Kitagawa prevents acetaminophen-induced acute hepatic injury in mice via inhibiting JNK/ERK MAPK pathway

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To investigate the in vivo hepatoprotective effects and mechanisms of Gentiana manshurica Kitagawa (GM) in acetaminophen (APAP)-induced liver injury in mice.METHODS: GM (200, 150 or 50 mg/kg body weight) or N-acetyl-L-cysteine (NAC; 300 mg/kg body weight) was administrated orally with a single dose 2 h prior to APAP (300 mg/kg body weight) injection in mice.RESULTS: APAP treatment significantly depleted hepatic glutathione (GSH), increased serum aspartate aminot ransferase (AST), alanine aminotransferas...

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

    Directory of Open Access Journals (Sweden)

    Nélson R Carvalho

    Full Text Available 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 [(PhSe2], 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 (PhSe2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe2 to the N-acetylcysteine (NAC during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg, (PhSe2 (15.6 mg/kg, NAC (1200 mg/kg, APAP+(PhSe2 or APAP+NAC, where the (PhSe2 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 (PhSe2. The effectiveness of (PhSe2 was similar at a lower dose than NAC. In summary, (PhSe2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.

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

    Science.gov (United States)

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

    2012-01-01

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

  6. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

    Directory of Open Access Journals (Sweden)

    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

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

    Science.gov (United States)

    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

  8. High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

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    Yang Runkuan

    2012-05-01

    Full Text Available Abstract Background Acetaminophen (APAP overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1, and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose. Methods Male C57BL/6 mice were treated with a single dose of APAP (350 mg/kg. 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose or non-immune (sham IgG every 24 hours for a total of 2 doses. Results 24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST, markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration. Conclusion HMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.

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

    Science.gov (United States)

    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

  10. Simultaneous voltammetric determination of tramadol and acetaminophen using carbon nanoparticles modified glassy carbon electrode

    Energy Technology Data Exchange (ETDEWEB)

    Ghorbani-Bidkorbeh, Fatemeh [Department of Chemistry, Sharif University of Technology, Tehran 11155-9516 (Iran, Islamic Republic of); Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Shahrokhian, Saeed, E-mail: shahrokhian@sharif.ed [Department of Chemistry, Sharif University of Technology, Tehran 11155-9516 (Iran, Islamic Republic of); Institute for Nanoscience and Technology, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Mohammadi, Ali [Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Dinarvand, Rassoul [Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of)

    2010-03-01

    A sensitive and selective electrochemical sensor was fabricated via the drop-casting of carbon nanoparticles (CNPs) suspension onto a glassy carbon electrode (GCE). The application of this sensor was investigated in simultaneous determination of acetaminophen (ACE) and tramadol (TRA) drugs in pharmaceutical dosage form and ACE determination in human plasma. In order to study the electrochemical behaviors of the drugs, cyclic and differential pulse voltammetric studies of ACE and TRA were carried out at the surfaces of the modified GCE (MGCE) and the bare GCE. The dependence of peak currents and potentials on pH, concentration and the potential scan rate were investigated for these compounds at the surface of MGCE. Atomic force microscopy (AFM) was used for the characterization of the film modifier and its morphology on the surface of GCE. The results of the electrochemical investigations showed that CNPs, via a thin layer model based on the diffusion within a porous layer, enhanced the electroactive surface area and caused a remarkable increase in the peak currents. The thin layer of the modifier showed a catalytic effect and accelerated the rate of the electron transfer process. Application of the MGCE resulted in a sensitivity enhancement and a considerable decrease in the anodic overpotential, leading to negative shifts in peak potentials. An optimum electrochemical response was obtained for the sensor in the buffered solution of pH 7.0 and using 2 muL CNPs suspension cast on the surface of GCE. Using differential pulse voltammetry, the prepared sensor showed good sensitivity and selectivity for the determination of ACE and TRA in wide linear ranges of 0.1-100 and 10-1000 muM, respectively. The resulted detection limits for ACE and TRA was 0.05 and 1 muM, respectively. The CNPs modified GCE was successfully applied for ACE and TRA determinations in pharmaceutical dosage forms and also for the determination of ACE in human plasma.

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Jack Hinson

    2013-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Liwen eZhang

    2012-09-01

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

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

    Science.gov (United States)

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

    2010-07-19

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

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

    Directory of Open Access Journals (Sweden)

    Arash Omidi

    2014-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Antonio Saad

    Full Text Available 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.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.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.This study refutes that hypothesis that prenatal exposure to APAP causes hyperkinetic dysfunction in mouse offspring. Due to lack

  18. Crystallization of bifonazole and acetaminophen within the matrix of semicrystalline, PEO-PPO-PEO triblock copolymers.

    Science.gov (United States)

    Chen, Zhen; Liu, Zhengsheng; Qian, Feng

    2015-02-01

    The morphology and microstructure of crystalline drug/polymer solid dispersions could influence their physical stability and dissolution performance. In this study, the drug crystallization mechanism within PEG, PPG, and poloxamer matrix was investigated, and the resultant microstructure of various solid dispersions of acetaminophen (ACM) and bifonazole (BFZ) in the aforementioned polymers was characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and wide/small-angle X-ray diffraction (WAXD/SAXS). With a stronger molecular interaction with the PEG segments, ACM decreased the crystallization onset temperature and crystallinity of PEG and poloxamers much more than BFZ. The stronger molecular interaction and better miscibility between ACM and PEG also induced a more defective lamellar structure in the ACM solid dispersions compared with that in the BFZ systems, as revealed by DSC and SAXS investigation. Observed under polarized optical microscopy, PEG, PPG, and poloxamer could all significantly improve the crystallization rate of ACM and BFZ, because of the largely reduced Tg of the solid dispersions by these low Tg polymers. Moreover, when the drug loading was below 60%, crystallization of BFZ in PEG or poloxamer occurred preferably along the radial direction of PEG spherulite, rather than the perpendicular direction, which was attributed to the geometric restriction of well-ordered polymer lamellar structure in the BFZ solid dispersions. Similar phenomena were not observed in the ACM solid dispersions regardless of the drug loading, presumably because ACM could diffuse freely across the perpendicular direction of the PEG spherulite, through the well-connected interlamellar or interfibrillar spaces produced by the defective PEG lamellar structure. The different drug-polymer interaction also caused a difference in the microstructure of polymer crystal, as well as a difference in drug distribution within the polymer matrix, which

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2012-09-01

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

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

    Science.gov (United States)

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

    2013-09-01

    Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required. PMID:23927622

  2. Health literacy as controversy: an online community's discussion of the U.S. Food and Drug Administration acetaminophen recommendations.

    Science.gov (United States)

    Mackert, Michael; Love, Brad; Donovan-Kicken, Erin; Uhle, Katharine A

    2011-12-01

    Adults in the United States increasingly use the Internet for health information, and online discussions can provide insights into public perceptions of health issues. The purpose of this project was to investigate public perceptions of issues related to health literacy, within the context of a conversation about recommendations to the U.S. Food and Drug Administration, driven by concerns about acetaminophen-related liver injuries due in part to health literacy issues. The discussion took place July 2-8, 2009, on a technology/science blog and included 625 comments. Participants debated the risks and benefits of acetaminophen, and most believed responsibility for taking medication safely falls on consumers. Some were implicitly aware of issues related to health literacy and its relationship to patient outcomes; most felt improved education is all that is needed, whereas others acknowledged that health information is confusing--particularly for the elderly and sick. Recommendations for future research into public perceptions of health literacy are discussed. PMID:21788648

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

    Energy Technology Data Exchange (ETDEWEB)

    Prot, Jean-Matthieu [CNRS UMR 6600, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, BP20529, F-60205 (France); Bunescu, Andrei; Elena-Herrmann, Bénédicte [Université de Lyon, Centre de RMN à Très Hauts Champs, CNRS/ENS Lyon/UCB Lyon 1, 5 rue de la Doua, F-69100 Villeurbanne (France); Aninat, Caroline [Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes (France); Université de Rennes 1, F-35043 Rennes (France); Snouber, Leila Choucha [CNRS UMR 6600, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, BP20529, F-60205 (France); Griscom, Laurent; Razan, Florence [CNRS-UMR 8029, SATIE, Ecole Normale Supérieure de Cachan-Bretagne, Campus de Ker Lann, Bruz (France); Bois, Frederic Y. [Institut National de l' Environnement Industriel et des Risques (INERIS), Unité Modèles pour l' Ecotoxicologie et la Toxicologie, Parc ALATA, BP2, F-60550 Verneuil en Halatte (France); Legallais, Cécile [CNRS UMR 6600, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, BP20529, F-60205 (France); 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. Voltammetric determination of norepinephrine in the presence of acetaminophen using a novel ionic liquid/multiwall carbon nanotubes paste electrode

    International Nuclear Information System (INIS)

    A novel multiwall carbon nanotubes (MWCNTs) modified carbon ionic liquid electrode (CILE) was fabricated and used to investigate the electrochemical behavior of norepinephrine (NP). MWCNTs/CILE was prepared by mixing hydrophilic ionic liquid, 1-methyl-3-butylimidazolium bromide (MBIDZBr), with graphite powder, MWCNTs, and liquid paraffin. The fabricated MWCNTs/CILE showed great electrocatalytic ability to the oxidation of NE. The electron transfer coefficient, diffusion coefficient, and charge transfer resistant (Rct) of NE at the modified electrode were calculated. Differential pulse voltammetry of NE at the modified electrode exhibited two linear dynamic ranges with slopes of 0.0841 and 0.0231 μA/μM in the concentration ranges of 0.3 to 30.0 μM and 30.0 to 450.0 μM, respectively. The detection limit (3σ) of 0.09 μM NP was achieved. This modified electrode exhibited a good ability for well separated oxidation peaks of NE and acetaminophen (AC) in a buffer solution, pH 7.0. The proposed sensor was successfully applied for the determination of NE in human urine, pharmaceutical, and serum samples. Highlights: ► Electrochemical behavior of norepinephrine study using carbon ionic liquid electrode ► This sensor resolved the overlap response of norepinephrine and acetaminophen. ► This sensor is also used for the determination of above compounds in real samples.

  5. First Use of a New Device for Administration of Buspirone and Acetaminophen to Suppress Shivering During Therapeutic Hypothermia.

    Science.gov (United States)

    Honasoge, Akilesh; Parker, Braden; Wesselhoff, Kelly; Lyons, Neal; Kulstad, Erik

    2016-03-01

    Therapeutic hypothermia or targeted temperature management has been used after cardiac arrest to improve neurological outcomes and mortality. However, a side effect of temperature modulation is a centrally mediated shivering response. The Columbia Anti-Shivering Protocol sets up a systematic method of intravenous (IV) and oral medication escalation to suppress this response and preserve the benefits of this therapy. We present the case of a 59-year-old male who began shivering after therapeutic hypothermia for cardiac arrest, leading to a persistent rise in core temperature despite adequate sedation. He was also found to have gastric contents similar to coffee grounds through nasogastric tube suction. The shivering was effectively suppressed and the rising core temperature plateaued using rectal acetaminophen and buspirone administered by means of a novel device, the Macy Catheter. Also, when used in conjunction with other protocol-driven medications, the patient was able to achieve a core temperature of 33°C. The Macy Catheter appears to be a useful approach to rectally administer buspirone and acetaminophen, using an easy-to-place, nonsterile atraumatic device that requires no radiographic confirmation of placement. PMID:26807775

  6. Effect of chronic exposure to acetaminophen and lincomycin on Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa, and potential mechanisms of endocrine disruption.

    Science.gov (United States)

    Kim, PanGyi; Park, Yena; Ji, Kyunghee; Seo, Jihyun; Lee, Sangwoo; Choi, Kyunghee; Kho, Younglim; Park, Jeongim; Choi, Kyungho

    2012-09-01

    Chronic toxicity of acetaminophen and lincomycin were evaluated using freshwater organisms including two crustaceans (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). H295R, a human adrenal cell was also used to understand the effects on steroidogenesis. In 21 d D. magna exposure, survival NOEC was found at 5.72 mg L(-1) and no reproduction related effects were noted at this level of exposure to acetaminophen, while 21 d survival or growth effects were not observed even at the highest exposure levels (153 mg L(-1)) for lincomycin. In the chronic fish toxicity test, significant reduction in juvenile survival was observed at 30 d post-hatch (dph) at 95 mg L(-1) of acetaminophen, and 0.42 mg L(-1) of lincomycin. After the exposure to both pharmaceuticals, vitellogenin levels tended to increase in male fish at 90 dph. In the eggs which were prenatally exposed to 9.5 mg L(-1) of acetaminophen, reduced hatchability was observed. The results of H295R cell assay showed that both pharmaceuticals could alter steroidogenic pathway and increase estrogenicity. Endocrine disruption potentials and their ecological implication may deserve further studies. Our observations suggest however that ecological risks of both pharmaceuticals are negligible at the concentrations currently found in the environment. PMID:22560975

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

    Science.gov (United States)

    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...

  8. N-acetyl-meta-aminophenol, the alleged nontoxic isomer of acetaminophen, is toxic in both rat and human precision-cut liver slices

    NARCIS (Netherlands)

    Hadi, Mackenzie; Herpers, Bram; Dragovic, Sanja; van Swelm, Rachel P. L.; Russel, Frans G. M.; Commandeur, Jan N. M.; van de Water, Bob; Groothuis, Genoveva

    2012-01-01

    N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic regioisomer of the well-known hepatotoxicant acetaminophen (APAP). However, so far AMAP has only been shown to be non-toxic in mice and hamsters. To investigate whether AMAP could also be used as non-toxic analog of APAP in stud

  9. Effectiveness of diclofenac versus acetaminophen in primary care patients with knee osteoarthritis: [NTR1485], DIPA-Trial: Design of a randomized clinical trial

    NARCIS (Netherlands)

    S.P.J. Verkleij (Saskia ); P.A.J. Luijsterburg (Pim); B.W. Koes (Bart); A.M. Bohnen (Arthur); S.M. Bierma-Zeinstra (Sita)

    2010-01-01

    textabstractBackground. Osteoarthritis is the most frequent chronic joint disease which causes pain and disability of especially hip and knee. According to international guidelines and the Dutch general practitioners guidelines for non-traumatic knee symptoms, acetaminophen should be the pain medica

  10. Pharmacokinetic Herb-Drug Interaction between Essential Oil of Aniseed (Pimpinella anisum L., Apiaceae) and Acetaminophen and Caffeine: A Potential Risk for Clinical Practice.

    Science.gov (United States)

    Samojlik, Isidora; Petković, Stojan; Stilinović, Nebojša; Vukmirović, Saša; Mijatović, Vesna; Božin, Biljana

    2016-02-01

    Aniseed (Pimpinella anisum L., Apiaceae) and its essential oil (EO) have been widely used. Because there are some data about the impact of aniseed EO on drug effects, this survey aimed to assess the potential of pharmacokinetic herb-drug interaction between aniseed EO and acetaminophen and caffeine in mice. The chemical analysis (gas chromatography-mass spectrometry) of aniseed EO has confirmed trans-anethole (87.96%) as the main component. The pharmacokinetic studies of intraperitoneally (i.p.) and orally applied acetaminophen (200 mg/kg) and caffeine (20 mg/kg) were performed in mice after 5 days of oral treatment with human equivalent dose of aniseed EO (0.3 mg/kg/day). The analysis of pharmacokinetic data showed that in the group treated by aniseed EO, the significant decrease in the peak plasma concentration of acetaminophen after oral application (p = 0.024) was revealed when compared with control group and the reduction of systemic exposure to the drug after oral application (74 ± 32% vs. 85 ± 35% in the control) was noted. The bioavailability of orally applied caffeine was also significantly decreased (p = 0.022) after the EO treatment in comparison with the control (57 ± 24% vs. 101 ± 29%). Therefore, the compromised therapeutic efficacy of acetaminophen and caffeine during the usage of aniseed EO preparations should be considered.

  11. Evaluating in vitro and in vivo the interference of ascorbate and acetaminophen on glucose detection by a needle-type glucose sensor.

    Science.gov (United States)

    Moatti-Sirat, D; Velho, G; Reach, G

    1992-01-01

    The aim of this work was to assess, in vitro and in vivo, the interference of ascorbate and acetaminophen on glucose measurements by a needle-type glucose sensor detecting hydrogen peroxide generated during the enzymatic oxidation of glucose, and to ascertain whether the protection against interference by the membranes used in the construction of the electrode is feasible. The oxidation of ascorbate and acetaminophen on a platinum electrode set at a 650 mV potential yielded a current representing 75 +/- 5% and 25 +/- 6% of that generated by the oxidation of an equimolar concentration of hydrogen peroxide, respectively. The bias introduced by the presence of 100 mumol l-1 ascorbate on the reading of 5 mmol l-1 glucose by the complete sensor (electrode + membranes) would be minimal (approximately 0.4 mmol l-1). By contrast, the bias introduced by 200 mumol l-1 of acetaminophen (a plasma concentration easily reached in clinical practice) was about 7 mmol l-1. The sensor was implanted subcutaneously in anaesthetized rats (n = 3). Using the current generated in the presence of a plasma acetaminophen concentration of about 200 mumol l-1 for glucose monitoring would lead to a major underestimation (approx. 6 mmol l-1) of subcutaneous glucose concentrations. PMID:1632948

  12. The development of spectrophotometric and electroanalytical methods for ascorbic acid and acetaminophen and their applications in the analysis of effervescent dosage forms.

    Science.gov (United States)

    Săndulescu, R; Mirel, S; Oprean, R

    2000-08-01

    The electroanalytical study of ascorbic acid, acetaminophen and of several mixtures of these compounds in different ratios has been made by using a carbon paste electrode (CPE-graphite:solid paraffin 2:1) as working electrode and an Ag/AgCl reference electrode. The potential curves were recorded using different concentrations of ascorbic acid and acetaminophen by measuring samples between 10 and 50 microl. The oxidation reactions were studied in a potential range from -0.1 to +1.3 V with different sweep rates, at different current sensitivities, in stationary working conditions and stirring before each replicate. The oxidation of ascorbic acid occurs at +0.31 +/- 0.02 V and the oxidation of acetaminophen at +0.60 +/- 0.05 V; meanwhile, the current has a linear variation for the following concentration ranges: 10(-3)-10(-2) M for the ascorbic acid and 3 x 10(-6)-7.5 x 10(-3) M for acetaminophen (r2 = 0.999 for both ascorbic acid and acetaminophen). The mixtures of ascorbic acid and acetaminophen were made as follows: 1:1, 1:2, 1:3, 2:1, and 3:1. The studies revealed the alteration of the voltammograms processed according to the validation methodology. The best potential variation range for different current sensitivities, the influence of the sweep rate, of the solvent volume and of the pH were studied. The mutual interferences of the compounds in the mixtures and the electroactive compounds in the pharmaceutical dosage forms, especially effervescent ones, also made the object of the research. The same mixtures were studied using the direct spectrophotometric method that revealed a lot of spectral interferences. In order to solve this problem, an appropriate separation or an indirect spectrophotometric method (the apparent content curves method) were used. The spectrophotometric and voltammetric methods developed were used to determine ascorbic acid and acetaminophen in different dosage forms (vials, tablets, suppositories and effervescent dosage forms). The results

  13. Effectiveness of diclofenac versus acetaminophen in primary care patients with knee osteoarthritis: [NTR1485], DIPA-Trial: design of a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Bohnen Arthur M

    2010-01-01

    Full Text Available Abstract Background Osteoarthritis is the most frequent chronic joint disease which causes pain and disability of especially hip and knee. According to international guidelines and the Dutch general practitioners guidelines for non-traumatic knee symptoms, acetaminophen should be the pain medication of first choice for osteoarthritis. However, of all prescribed pain medication in general practice, 90% consists of non-steroidal anti-inflammatory drugs compared to 10% of acetaminophen. Because general practitioners may lack evidence showing a similar efficacy of acetaminophen and non-steroidal anti-inflammatory drugs, we present the design of a randomized open-label trial to investigate the efficacy of a non-steroidal anti-inflammatory drug (diclofenac compared with acetaminophen in new consulters with knee osteoarthritis in general practice. Methods/Design Patients aged 45 years or older consulting their general practitioner with non-traumatic knee pain, meeting the clinical American College of Rheumatology criteria, and with a pain severity score of 2 or higher (on a 0-10 scale, will be randomly allocated to either diclofenac (maximum daily dose of 150 mg or acetaminophen (maximum daily dose of 3000 mg for 2 weeks and, if required, an additional 1-2 weeks, with a total follow-up period of 12 weeks. The primary outcomes are knee pain measured with a daily diary, and pain and function measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS at baseline, and at 3, 6, 9, and 12-weeks follow-up. Secondary outcomes are patients' perceived recovery, quality of life, medical, patient, and productivity costs, compliance to therapy, co-interventions, and adverse reactions. Discussion The successful completion of this trial would lead to a better understanding of which medication should be used in the treatment of primary care patients with mild knee osteoarthritis. Trial registration Dutch trial registry NTR1485.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-15

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

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

    Directory of Open Access Journals (Sweden)

    Pickering G

    2014-09-01

    Full Text Available Gisèle Pickering,1–3 Nicolas Macian,1 Frédéric Libert,2,4 J Michel Cardot,1 Séverine Coissard,1 Philippe Perovitch,5 Marc Maury,5 Claude Dubray1–3 1CHU Clermont-Ferrand, Centre de Pharmacologie Clinique, Clermont-Ferrand, France; 2Inserm, Clermont-Ferrand, France; 3Clermont Université, Laboratoire de Pharmacologie, Faculté de Médecine, Clermont-Ferrand, France; 4Laboratoire de Pharmacologie, CHU Clermont-Ferrand, France; 5Unither Pharamceuticals, Paris, France 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

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

    International Nuclear Information System (INIS)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xi, E-mail: Xi.Yang@fda.hhs.gov [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); Salminen, William F., E-mail: Willie.Salminen@parexel.com [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); Shi, Qiang, E-mail: Qiang.Shi@fda.hhs.gov [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); Greenhaw, James, E-mail: James.Greenhaw@fda.hhs.gov [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); Gill, Pritmohinder S., E-mail: PSGill@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR (United States); Clinical Pharmacology and Toxicology Section, Arkansas Children' s Hospital, Little Rock, AR (United States); Bhattacharyya, Sudeepa, E-mail: SBhattacharyya2@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR (United States); Clinical Pharmacology and Toxicology Section, Arkansas Children' s Hospital, Little Rock, AR (United States); Beger, Richard D., E-mail: Richard.Beger@fda.hhs.gov [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); Mendrick, Donna L., E-mail: Donna.Mendrick@fda.hhs.gov [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); Mattes, William B., E-mail: William.Mattes@fda.hhs.gov [Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR (United States); 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-09-15

    Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5 mM, 10 mM or 20 mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24 h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3 h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12 h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3 h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24 h and 48 h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6 h after APAP and a partial protection when given at 15 h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic. - Highlights: • APAP reproducibly causes cell death in freshly isolated primary human hepatocytes. • APAP induces adduct formation, JNK activation and mitochondrial dysfunction in PHH. • Mitochondrial adducts and JNK translocation are delayed in PHH compared to

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

    Science.gov (United States)

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

    2016-04-01

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

  20. Synthesis of the water-compatible p-acetaminophen resin and its adsorption performances for vanillin in aqueous solution

    Institute of Scientific and Technical Information of China (English)

    Gu Qing Xiao; Li Ping Long; Jiao Liang Wang

    2012-01-01

    A novel p-acetaminophen resin (named as GQ- 1) was synthesized with chloromethylated polystyrene andp-acetaminophan.It can be used without any wetting process.The objective of this work was to study the adsorption performances for vanillin onto GQ-1 with two kinds of the hydrogen bond site of acetamino group and hydroxyl group.The results showed that the adsorption property of vanillin onto GQ-1 was superior to XAD-4,H103,NDA150,and NDA88.The adsorption capacity of vanillin onto GQ-1 is not greatly discrepant until the solution pH is higher than 5.31.The saturated adsorption quantity of vanillin was up to 141.32 mg/mL (wet resin)according to the dynamic adsorption and desorption experiments at 293 K.The resin could be regenerated by 7 BV ethanol.

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

    Science.gov (United States)

    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 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

  2. Effect of 70-nm silica particles on the toxicity of acetaminophen, tetracycline, trazodone, and 5-aminosalicylic acid in mice.

    Science.gov (United States)

    Li, X; Kondoh, M; Watari, A; Hasezaki, T; Isoda, K; Tsutsumi, Y; Yagi, K

    2011-04-01

    Exposure to nano-sized particles is increasing because they are used in a wide variety of industrial products, cosmetics, and pharmaceuticals. Some animal studies indicate that such nanomaterials may have some toxicity, but their synergistic actions on the adverse effects of drugs are not well understood. In this study, we investigated whether 70-nm silica particles (nSP70), which are widely used in cosmetics and drug delivery, affect the toxicity of a drug for inflammatory bowel disease (5-aminosalicylic acid), an antibiotic drug (tetracycline), an antidepressant drug (trazodone), and an antipyretic drug (acetaminophen) in mice. Co-administration of nSP70 with trazodone did not increase a biochemical marker of liver injury. In contrast, co-administration increased the hepatotoxicity of the other drugs. Co-administration of nSP70 and tetracycline was lethal. These findings indicate that evaluation of synergistic adverse effects is important for the application of nano-sized materials.

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

    Science.gov (United States)

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

    2010-07-01

    We reported previously that vascular endothelial growth factor (VEGF) was increased in acetaminophen (APAP) toxicity in mice and treatment with a VEGF receptor inhibitor reduced hepatocyte regeneration. The effect of human recombinant VEGF (hrVEGF) on APAP toxicity in the mouse was examined. In early toxicity studies, B6C3F1 mice received hrVEGF (50 microg s.c.) or vehicle 30 min before receiving APAP (200 mg/kg i.p.) and were sacrificed at 2, 4, and 8 h. Toxicity was comparable at 2 and 4 h, but reduced in the APAP/hrVEGF mice at 8 h (p toxicity and increased hepatocyte regeneration in APAP toxicity in the mouse. Attenuation of sinusoidal cell endothelial dysfunction and changes in neutrophil dynamics may be operant mechanisms in the hepatoprotection mediated by hrVEGF in APAP toxicity.

  4. Tramadol/acetaminophen combination as add-on therapy in the treatment of patients with ankylosing spondylitis.

    Science.gov (United States)

    Chang, Jhi-Kai; Yu, Chen-Tung; Lee, Ming-Yung; Yeo, Kj; Chang, I-Chang; Tsou, Hsi-Kai; Wei, James Cheng-Chung

    2013-03-01

    This study aimed to determine the safety and efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (Ultracet®) in patients with ankylosing spondylitis (AS). This was a 12-week, randomized, double-blind, placebo-controlled study. Sixty patients with active AS according to the Modified New York Criteria were enrolled. Active disease was defined by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for more than 3 at randomization. Subjects were randomized equally into two groups: the treatment group received aceclofenac plus Ultracet® one tablet twice a day, and the control group received aceclofenac plus placebo for 12 weeks. The primary endpoint was a difference of Assessment in Ankylosing Spondylitis (ASAS20) response criteria between two groups at week 12. At week 12, ASAS20 was achieved by 53.3 % of the aceclofenac plus Ultracet group and 31 % of the aceclofenac alone group (p = 0.047). For the pain visual analogue scale at week 12, there was a reduction of 45.6 % in aceclofenac plus Ultracet group and 25.7 % in the aceclofenac alone group (p = 0.087). There was no statistically significant difference between two groups in BASDAI, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Global Index, Physician Global Assessment, spinal mobility, ESR, hs-CRP, and Ankylosing Spondylitis Quality of Life Questionnaire. A slight increase in total adverse events was noted with dizziness (7.5 vs 1.5 %), vertigo (4.5 vs 1.5 %), and nausea/vomiting (6 vs 0 %) in the Ultracet arm compared to placebo. The tramadol 37.5 mg/acetaminophen 325 mg combination tablet (Ultracet®) might has additional effect to nonsteroidal anti-inflammatory drugs in the treatment of patients with ankylosing spondylitis. It showed marginal benefit in pain and disease activity. However, a slight increase in minor adverse events was noted.

  5. Tramadol/acetaminophen combination as add-on therapy in the treatment of patients with ankylosing spondylitis.

    Science.gov (United States)

    Chang, Jhi-Kai; Yu, Chen-Tung; Lee, Ming-Yung; Yeo, Kj; Chang, I-Chang; Tsou, Hsi-Kai; Wei, James Cheng-Chung

    2013-03-01

    This study aimed to determine the safety and efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (Ultracet®) in patients with ankylosing spondylitis (AS). This was a 12-week, randomized, double-blind, placebo-controlled study. Sixty patients with active AS according to the Modified New York Criteria were enrolled. Active disease was defined by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for more than 3 at randomization. Subjects were randomized equally into two groups: the treatment group received aceclofenac plus Ultracet® one tablet twice a day, and the control group received aceclofenac plus placebo for 12 weeks. The primary endpoint was a difference of Assessment in Ankylosing Spondylitis (ASAS20) response criteria between two groups at week 12. At week 12, ASAS20 was achieved by 53.3 % of the aceclofenac plus Ultracet group and 31 % of the aceclofenac alone group (p = 0.047). For the pain visual analogue scale at week 12, there was a reduction of 45.6 % in aceclofenac plus Ultracet group and 25.7 % in the aceclofenac alone group (p = 0.087). There was no statistically significant difference between two groups in BASDAI, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Global Index, Physician Global Assessment, spinal mobility, ESR, hs-CRP, and Ankylosing Spondylitis Quality of Life Questionnaire. A slight increase in total adverse events was noted with dizziness (7.5 vs 1.5 %), vertigo (4.5 vs 1.5 %), and nausea/vomiting (6 vs 0 %) in the Ultracet arm compared to placebo. The tramadol 37.5 mg/acetaminophen 325 mg combination tablet (Ultracet®) might has additional effect to nonsteroidal anti-inflammatory drugs in the treatment of patients with ankylosing spondylitis. It showed marginal benefit in pain and disease activity. However, a slight increase in minor adverse events was noted. PMID:23192419

  6. Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

    Directory of Open Access Journals (Sweden)

    Isaac Mohar

    2014-01-01

    Full Text Available The mechanism by which acetaminophen (APAP causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD compared to male C57BL/6 mice in order to identify the cause(s of sensitivity. Furthermore, we use mice that are either heterozygous (HZ or null (KO for glutamate cysteine ligase modifier subunit (Gclm, in order to titrate the toxicity relative to wild-type (WT mice. Gclm is important for efficient de novo synthesis of glutathione (GSH. APAP (300 mg/kg, ip or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.

  7. Studies on the compressibility of wax matrix granules of acetaminophen and their admixtures with various tableting bases.

    Science.gov (United States)

    Uhumwangho, M U; Okor, R S

    2006-04-01

    Matrix granules of acetaminophen have been formed by a melt granulation process whereby the acetaminophen powder was triturated with the melted wax--goat wax, glyceryl monostearate or carnuba wax. The compressibility of the matrix granules and their admixture, with diluent granules (lactose, alpha-cellulose or microcrystalline cellulose) was investigated. The granules were compressed to tablets at a constant load (30 arbitrary units on the load scale) of a manesty single punch machine. Resulting tablets were evaluated for tensile strength (T) and disintegration times (DT). Granule flow was determined by measuring their angle of repose when allowed to fall freely on a level surface. Matrix granules prepared by melt granulation with goat wax or glyceryl monostearate were too sticky and therefore did not flow at all. They were also poorly compressible (T values = 0.20MN/m2). Inclusion of the diluent remarkably improved granule flow property and compressibility. The T values of the tablets (measure of compressibility) increased from about 0.24 to 0.65 MN/m2 during increase in diluent (lactose) content from 20 to 80 %w/w. Microcrystalline cellulose and alpha-cellulose were more effective than lactose in promoting compressibility of the granules. By contrast the matrix granules formed with carnuba wax were free flowing (angle of repose, 18.60). Addition of the diluent further improved flowability slightly. The matrix granules (without a diluent) were readily compressible (T value, 1.79MN/m2). Addition of the diluent (80%w/w) reduced T values (MN/m2) slightly to 1.32 (lactose), 1.48 (alpha-cellulose) and 1.74 (microcrystalline cellulose). Tablets of the matrix granules only, disintegrated rapidly within 3 minutes. DT was further reduced to wax proved most promising in the melt granulation of the test drug for sustained release applications.

  8. Au-Pd/reduced graphene oxide composite as a new sensing layer for electrochemical determination of ascorbic acid, acetaminophen and tyrosine.

    Science.gov (United States)

    Tadayon, Fariba; Vahed, Saba; Bagheri, Hasan

    2016-11-01

    An Au-Pd/reduced graphene oxide composite was employed as a novel electrode material for the sensitive and simultaneous determination of ascorbic acid, acetaminophen and tyrosine. The electrochemical response characteristics of the modified electrode toward the analytes were investigated by differential pulse voltammetry and cyclic voltammetry. The responses of the electrochemical sensor for the target analytes were found to be improved significantly in comparison with those obtained using a conventional carbon paste electrode (CPE) and reduced graphene oxide/CPE. The experimental conditions for simultaneous determination of these species have been established. Ternary mixtures of analytes can be determined in the ranges of 0.03-9.50μM. Under optimal conditions, the limits of detection were 15.7, 7.6 and 11.1nM for ascorbic acid, acetaminophen, and tyrosine, respectively. The method was applied successfully to determine the analytes in urine, serum and pharmaceutical samples simultaneously. PMID:27524083

  9. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery.

    Science.gov (United States)

    Moller, Philip Lange; Juhl, Gitte Irene; Payen-Champenois, Catherine; Skoglund, Lasse Ansgar

    2005-07-01

    We compared an acetaminophen (paracetamol) 1 g (n = 51) formulation for infusion with propacetamol 2 g (n = 51) and placebo (n = 50) in a randomized, controlled, double-blind, parallel group trial in patients with moderate-to-severe pain after third molar surgery. Treatment efficacy was assessed in house for 6 h after starting the 15-min infusion. Significant effects versus placebo (P propacetamol at 6 h). No significant differences were noted between active groups except at 1 h. Six-hour weighted sums of primary assessments showed significantly better efficacy than placebo (P propacetamol (49%). In conclusion, acetaminophen 1 g and propacetamol 2 g were superior to placebo regarding analgesic efficacy, with a more frequent incidence of local pain at the infusion site for propacetamol. PMID:15976212

  10. Synthesis of singly /sup 2/H-, /sup 3/H-, and /sup 14/C- and doubly labeled acetaminophen, phenacetin, and p-acetanisidine

    Energy Technology Data Exchange (ETDEWEB)

    Chan, K.K. (University of Southern California, Los Angeles (USA)); Pang, K.S. (Houston Univ., TX (USA))

    1982-03-01

    Several efficient procedures for the synthesis of deuterium, tritium, and /sup 14/C-labeled acetaminophen, phenacetin, and p-acetanisidine are described. p-Aminophenol was acylated by the appropriate acetic anhydride under mild conditions yielding labeled acetaminophen. With O-alkylation using NaCH/sub 2/SOCH/sub 3/ and appropriate labeled and unlabeled alkyl halides, labeled phenacetin and p-acetanisidine were also obtained. Phenacetin labeled both with /sup 14/C on the acyl group and deuterium on the ethoxy group was synthesized in high yield by acylation of p-phenetidine-d/sub 5/. The last compound was obtained by acid hydrolysis of phenacetin-d/sub 5/ synthesized previously.

  11. Electrogenerated chemiluminescence quenching of Ru(bpy)32+ (bpy=2,2′-bipyridine) in the presence of acetaminophen, salicylic acid and their metabolites

    International Nuclear Information System (INIS)

    Quenching of Ru(bpy) 32+ (bpy=2,2′-bipyridine) coreactant electrogenerated chemiluminescence (ECL) has been observed in the presence of acetaminophen, salicylic acid and related complexes. However, no quenching is observed with the acetylsalicylic acid. In most instances, quenching is observed with 100-fold excess of quencher (compared to ECL luminophore) with complete quenching observed between 10,000 and 100,000 fold excess. Fluorescence and UV–vis experiments coupled with bulk electrolysis support the formation of benzoquinone products upon electrochemical oxidation. The mechanism of quenching may involve the interaction of the electrochemically generated benzoquinone species with (i) the ⁎Ru(bpy)32+ excited state or (ii) highly energetic coreactant radicals. - Highlights: ▶ Efficient quenching of the electrogenerated chemiluminescence is observed. ▶ Acetaminophen, salicylic acid and related compounds can be detected. ▶ The mechanism of quenching involves benzoquinones formed upon electrolysis.

  12. Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury

    OpenAIRE

    Patrick Scheiermann; Malte Bachmann; Lorena Härdle; Thomas Pleli; Albrecht Piiper; Bernhard Zwissler; Josef Pfeilschifter; Heiko Mühl

    2015-01-01

    Overdosing of the analgesic acetaminophen (APAP, paracetamol) is a major cause of acute liver injury. Whereas toxicity is initiated by hepatocyte necrosis, course of disease is regulated by mechanisms of innate immunity having the potential to serve in complex manner pathogenic or pro-regenerative functions. Interleukin (IL)-36γ has been identified as novel IL-1-like cytokine produced by and targeting epithelial (-like) tissues. Herein, we investigated IL-36γ in acute liver disease focusing o...

  13. Comparing the analgesic effect of intravenous acetaminophen and morphine on patients with renal colic pain referring to the emergency department: A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Reza Azizkhani

    2013-01-01

    Full Text Available Background: Kidney stone is normally treated by opioids with a variety of side-effects including hypotension, respiratory depression and apnea, nausea and vomiting. Regarding less complications of intravenous acetaminophen, we aimed to compare it with intravenous morphine in management of renal colic pain. Materials and Methods: A randomized controlled clinical trial was applied with a convenience sampling method, as 124 patients suffering from renal colic pain were randomly assigned into two groups of 62 patients. Pain was assessed using visual analog scale ruler. Results were analyzed by SPSS.18 using the descriptive statistic, Chi-square, ANOVA, independent t-test and logistic regression. Results: According to the findings, 84 subjects (67.7% were male. The mean age of participants were 39.06 (11.58. The mean of pain scores were not significantly different between two groups before administration of drugs (P = 0.415, while the more pain relief was achieved in morphine group after the intervention. Sex and age as influencing factors did not develop a significant difference in both groups. About the adverse effects, morphine had more complications and both groups showed a significant difference in occurrence of dizziness (P = 0.000 and hypotension (P = 0.014. Conclusion: Comparing intravenous morphine and acetaminophen in renal colic pain reviled that morphine can develop greater pain relief, but more complications such as dizziness and hypotension. Acetaminophen can be also be effective in renal colic pain, so it is concluded that acetaminophen can be administered as a less harmful drug for patients with renal colic pain.

  14. Comparing the analgesic effect of intravenous acetaminophen and morphine on patients with renal colic pain referring to the emergency department: A randomized controlled trial

    OpenAIRE

    Reza Azizkhani; Seyed Mehdi Pourafzali; Elahe Baloochestani; Babak Masoumi

    2013-01-01

    Background: Kidney stone is normally treated by opioids with a variety of side-effects including hypotension, respiratory depression and apnea, nausea and vomiting. Regarding less complications of intravenous acetaminophen, we aimed to compare it with intravenous morphine in management of renal colic pain. Materials and Methods: A randomized controlled clinical trial was applied with a convenience sampling method, as 124 patients suffering from renal colic pain were randomly assigned into two...

  15. Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Double-Blind Clinical Trial

    OpenAIRE

    Esmailian, Mehrdad; Moshiri, Roshanak; Zamani, Majid

    2015-01-01

    Introduction: Rib fracture is one of the common causes of trauma disabilities in many events and the outcome of these patients are very extensive from temporary pain management to long-term significant disability. Control and management of the pain in such patients is one of the most important challenges in emergency departments. Thus, the aim of the present study was assessing the efficacy of IV acetaminophen in pain control of patients with rib fracture. Methods: In this double-blind clinic...

  16. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.

    Science.gov (United States)

    Edwards, Jayne E; McQuay, Henry J; Moore, R Andrew

    2002-02-01

    The primary aims of this study were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen in acute postoperative pain and to use meta-analysis to demonstrate the efficacy of the combination drug compared with its components. Individual patient data from seven randomized, double blind, placebo controlled trials of tramadol plus acetaminophen were supplied for analysis by the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA. All trials used identical methods and assessed single-dose oral tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) in adult patients with moderate or severe postoperative pain. Summed pain intensity and pain relief data over six and eight hours and global evaluations of treatment effect after eight hours were extracted. Number-needed-to-treat (NNT) for one patient to obtain at least 50% pain relief was calculated. NNTs derived from pain relief data were compared with those derived from pain intensity data and global evaluations. Information on adverse effects was collected. Combination analgesics (tramadol plus acetaminophen) had significantly lower (better) NNTs than the components alone, and comparable efficacy to ibuprofen 400 mg. This could be shown for dental but not postsurgical pain, because more patients were available for the former. Adverse effects were similar for the combination drugs and the opioid component alone. Common adverse effects were dizziness, drowsiness, nausea, vomiting, and headache. In sum, this meta-analysis demonstrated analgesic superiority of the combination drug over its components, without additional toxicity. PMID:11844632

  17. Effect of Momordica charantia (bitter melon) on serum glucose level and various protein parameters in acetaminophen intoxicated rabbits

    OpenAIRE

    Kanwal Zahra; Muhammad Imran Sohail; Muhammad Anwar Malik

    2012-01-01

    Aim: Liver function tests, including total plasma proteins, albumin, bilirubin and glucose were analyzed to find out the hepatocurative and hepatoprotective effects of Momordica charantia. Method: The study was divided into two categories. In first category, the livers of rabbits were intoxicated with acetaminophen, and then Momordica fruit extract was given to observe its hepatocurative effects. Results: The results indicated significant changes in concentrations of the parameters in...

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

    Science.gov (United States)

    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

  19. Membrane Stabilization and Detoxification of Acetaminophen-Mediated Oxidative Onslaughts in the Kidneys of Wistar Rats by Standardized Fraction of Zea mays L. (Poaceae, Stigma maydis

    Directory of Open Access Journals (Sweden)

    S. Sabiu

    2016-01-01

    Full Text Available This study evaluated membrane stabilization and detoxification potential of ethyl acetate fraction of Zea mays L., Stigma maydis in acetaminophen-induced oxidative onslaughts in the kidneys of Wistar rats. Nephrotoxic rats were orally pre- and posttreated with the fraction and vitamin C for 14 days. Kidney function, antioxidative and histological analyses were thereafter evaluated. The acetaminophen-mediated significant elevations in the serum concentrations of creatinine, urea, uric acid, sodium, potassium, and tissue levels of oxidized glutathione, protein-oxidized products, lipid peroxidized products, and fragmented DNA were dose-dependently assuaged in the fraction-treated animals. The fraction also markedly improved creatinine clearance rate, glutathione, and calcium concentrations as well as activities of superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase in the nephrotoxic rats. These improvements may be attributed to the antioxidative and membrane stabilization activities of the fraction. The observed effects compared favorably with that of vitamin C and are informative of the fraction’s ability to prevent progression of renal pathological conditions and preserve kidney functions as evidently supported by the histological analysis. Although the effects were prominently exhibited in the fraction-pretreated groups, the overall data from the present findings suggest that the fraction could prevent or extenuate acetaminophen-mediated oxidative renal damage via fortification of antioxidant defense mechanisms.

  20. Membrane Stabilization and Detoxification of Acetaminophen-Mediated Oxidative Onslaughts in the Kidneys of Wistar Rats by Standardized Fraction of Zea mays L. (Poaceae), Stigma maydis.

    Science.gov (United States)

    Sabiu, S; O'Neill, F H; Ashafa, A O T

    2016-01-01

    This study evaluated membrane stabilization and detoxification potential of ethyl acetate fraction of Zea mays L., Stigma maydis in acetaminophen-induced oxidative onslaughts in the kidneys of Wistar rats. Nephrotoxic rats were orally pre- and posttreated with the fraction and vitamin C for 14 days. Kidney function, antioxidative and histological analyses were thereafter evaluated. The acetaminophen-mediated significant elevations in the serum concentrations of creatinine, urea, uric acid, sodium, potassium, and tissue levels of oxidized glutathione, protein-oxidized products, lipid peroxidized products, and fragmented DNA were dose-dependently assuaged in the fraction-treated animals. The fraction also markedly improved creatinine clearance rate, glutathione, and calcium concentrations as well as activities of superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase in the nephrotoxic rats. These improvements may be attributed to the antioxidative and membrane stabilization activities of the fraction. The observed effects compared favorably with that of vitamin C and are informative of the fraction's ability to prevent progression of renal pathological conditions and preserve kidney functions as evidently supported by the histological analysis. Although the effects were prominently exhibited in the fraction-pretreated groups, the overall data from the present findings suggest that the fraction could prevent or extenuate acetaminophen-mediated oxidative renal damage via fortification of antioxidant defense mechanisms. PMID:27579048

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

    Institute of Scientific and Technical Information of China (English)

    H Balaji raghavendran; A Sathivel; T Devaki

    2006-01-01

    AIM: To assess the defensive nature of Sargassum polycystum (S. Polycystum) (Brown alga) against acetaminophen (AAP)-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor (TNF-α)and fine structural features of the liver during toxic hepatitis in rats.METHODS: Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group Ⅰ consisted of normal control rats fed with standard diet.Group Ⅱ rats were administered with acetaminophen (800 mg/kg body weight, intraperitoneally). Group Ⅲ rats were pre-treated with S. Polycystum extract alone.Group Ⅳ rats were orally pre-treated with S. Polycystum extract (200 mg/kg body weight for 21 d) prior to acetaminophen induction (800 mg/kg body weight,intraperitoneally). Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and b5.Serum TNF-α was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy.RESULTS: Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and b5 when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-α when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably prevented in the rats pretreated with S. Polycystum. The rats pretreated with S. Polycystum showed considerable inhibition in the elevation of TNF-α compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats,whereas the rats treated with S. Polycystum showed considerable protection against acetaminophen-induced alterations in

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

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-01-01

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

  4. Interaction between traditional Chinese medicine and western medicine in rats——In-Chen-How and acetaminophen%中西药相互作用研究:茵陈蒿与对乙酰氨基酚

    Institute of Scientific and Technical Information of China (English)

    陈丽芳; 刘文德; 林双金; 梁永昌; 王慧瑜

    2007-01-01

    The purpose of this study is to evaluate the interaction effects of In-Chen-How (Artemisia capillaries Thunb.) on the pharmacokinetics of acetaminophen and on liver microsomal cytochrome P450 enzyme activity in rats. The rats were divided into control group (n=8) without In-Chen-How and the pretreated group (n=8) administered with In-Chen-How (approximately 1.0 mL·kg-1, according to weight) for 5 consecutive days. Rats in the control group received water simultaneously. Each rat was then given acetaminophen. The pharmacokinetic parameters of acetaminophen of the two groups were significantly different. In the In-Chen-How pretreated group, the maximum concentration of acetaminophen and the area under the plasma concentration-time curve were reduced about 58.4%, 56.7% and 55.4%. To further explain the results, liver microsomal suspensions were obtained from rats that were randomly divided into control and In-Chen-How pretreated group. The levels of CYP1A2 and CYP2E1 in hepatic microsomal protein from pretreated group were increased as compared to that from the control group. It indicated that In-Chen-How can stimulate the activity of CYP isozymes. The changes in the pharmacokinetics of acetaminophen resulting from the administration of In-Chen-How are related to an increase in metabolic activity of CYP1A2 and CYP2E1.

  5. Preparation of NiFe₂O₄/graphene nanocomposite and its application as a modifier for the fabrication of an electrochemical sensor for the simultaneous determination of tramadol and acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Afkhami, Abbas, E-mail: afkhami@basu.ac.ir [Faculty of Chemistry, Bu-Ali Sina University, Hamedan (Iran, Islamic Republic of); Khoshsafar, Hosein [Faculty of Chemistry, Bu-Ali Sina University, Hamedan (Iran, Islamic Republic of); Bagheri, Hasan [Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran (Iran, Islamic Republic of); Madrakian, Tayyebeh [Faculty of Chemistry, Bu-Ali Sina University, Hamedan (Iran, Islamic Republic of)

    2014-06-01

    Highlights: • A new modified electrochemical sensor was constructed and used. • NiFe₂O₄/graphene was used as the modifier. • The sensor was used for the determination of tramadol and acetaminophen in real samples. • Modification improved the sensitivity and detection limit of the method. • The oxidation of tramadol and acetaminophen at the surface of the electrode was studied. Abstract: An effective electrochemical sensor for the rapid and simultaneous determination of tramadol and acetaminophen based on carbon paste electrode (CPE) modified with NiFe₂O₄/graphene nanoparticles was developed. The structures of the synthesized NiFe₂O₄/graphene nanocomposite and the electrode composition were confirmed by X-ray diffraction (XRD) spectrometry, Fourier transform infrared (FT-IR) spectrometry and scanning electron microscopy (SEM). The peak currents of square wave voltammetry of tramadol and acetaminophen increased linearly with their concentration in the range of 0.01–9 μmol L⁻¹. The detection limit for their determination was found to be 0.0036 and 0.0030 μmol L⁻¹, respectively. The results show that the combination of graphene and NiFe₂O₄ nanoparticles causes a dramatic enhancement in the sensitivity of the sensor. The fabricated sensor exhibited high sensitivity and good stability, and would be valuable for the clinical assay of tramadol and acetaminophen.

  6. A new electrochemical sensor for the simultaneous determination of acetaminophen and codeine based on porous silicon/palladium nanostructure.

    Science.gov (United States)

    Ensafi, Ali A; Ahmadi, Najmeh; Rezaei, Behzad; Abarghoui, Mehdi Mokhtari

    2015-03-01

    A porous silicon/palladium nanostructure was prepared and used as a new electrode material for the simultaneous determination of acetaminophen (ACT) and codeine (COD). Palladium nanoparticles were assembled on porous silicon (PSi) microparticles by a simple redox reaction between the Pd precursor and PSi in an aqueous solution of hydrofluoric acid. This novel nanostructure was characterized by different spectroscopic and electrochemical techniques including scanning electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy, fourier transform infrared spectroscopy and cyclic voltammetry. The high electrochemical activity, fast electron transfer rate, high surface area and good antifouling properties of this nanostructure enhanced the oxidation peak currents and reduced the peak potentials of ACT and COD at the surface of the proposed sensor. Simultaneous determination of ACT and COD was explored using differential pulse voltammetry. A linear range of 1.0-700.0 µmol L(-1) was achieved for ACT and COD with detection limits of 0.4 and 0.3 µmol L(-1), respectively. Finally, the proposed method was used for the determination of ACT and COD in blood serum, urine and pharmaceutical compounds.

  7. Simultaneous determination of acetaminophen, guaifenesin, pseudoephedrine, pholcodine, and paraben preservatives in cough mixture by high-performance liquid chromatography.

    Science.gov (United States)

    Carnevale, L

    1983-02-01

    The separation and simultaneous determination, by high-performance liquid chromatography, of acetaminophen (I), guaifenesin (II), pseudoephedrine hydrochloride (III), and pholcodine (IV), together with a series of parabens (methyl to butyl, V-VIII) in a cough mixture, has been demonstrated using a chemically bonded octadecylsilane stationary phase with a mobile phase of methanol-water-acetic acid (45:55:2) containing the ion-pairing agent octanesulfonic acid. Retention volumes for the active ingredients were 3.8 ml, 5.4 ml, 9.4 ml, and 15.6 ml for compounds I-IV, respectively. Corrected retention volumes for the parabens [5.4 ml for methyl (V), 9.6 ml for ethyl (VI), 18.5 ml for propyl (VII), and 37.9 ml for butyl (VIII)] showed an exponential relationship with chain length of the esterifying alcohols. Excipients did not interfere with the estimation of any of the compounds, hence pretreatment of the sample was unnecessary. Average recoveries of the active ingredients and of the parabens from laboratory prepared samples were essentially 100% of theoretical with standard deviations of 1.7, 0.3, 1.5, 0.3, 0.3, 3.3, 0.7, and 2.7% for I-VIII, respectively.

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

    Science.gov (United States)

    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 major extracts attenuate the inflammatory reaction following APAP-induced liver injury. PMID:26300946

  9. A new electrochemical sensor for the simultaneous determination of acetaminophen and codeine based on porous silicon/palladium nanostructure.

    Science.gov (United States)

    Ensafi, Ali A; Ahmadi, Najmeh; Rezaei, Behzad; Abarghoui, Mehdi Mokhtari

    2015-03-01

    A porous silicon/palladium nanostructure was prepared and used as a new electrode material for the simultaneous determination of acetaminophen (ACT) and codeine (COD). Palladium nanoparticles were assembled on porous silicon (PSi) microparticles by a simple redox reaction between the Pd precursor and PSi in an aqueous solution of hydrofluoric acid. This novel nanostructure was characterized by different spectroscopic and electrochemical techniques including scanning electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy, fourier transform infrared spectroscopy and cyclic voltammetry. The high electrochemical activity, fast electron transfer rate, high surface area and good antifouling properties of this nanostructure enhanced the oxidation peak currents and reduced the peak potentials of ACT and COD at the surface of the proposed sensor. Simultaneous determination of ACT and COD was explored using differential pulse voltammetry. A linear range of 1.0-700.0 µmol L(-1) was achieved for ACT and COD with detection limits of 0.4 and 0.3 µmol L(-1), respectively. Finally, the proposed method was used for the determination of ACT and COD in blood serum, urine and pharmaceutical compounds. PMID:25618731

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

    Directory of Open Access Journals (Sweden)

    Bruno da Cruz Pádua

    2014-01-01

    Full Text Available 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.

  11. Explaining electrostatic charging and flow of surface-modified acetaminophen powders as a function of relative humidity through surface energetics.

    Science.gov (United States)

    Jallo, Laila J; Dave, Rajesh N

    2015-07-01

    Powder flow involves particle-particle and particle-vessel contacts and separation resulting in electrostatic charging. This important phenomenon was studied for uncoated and dry-coated micronized acetaminophen (MAPAP) as a function of relative humidity. The main hypothesis is that by modifying powder surface energy via dry coating of MAPAP performed using magnetically assisted impaction coating, its charging tendency, flow can be controlled. The examination of the relationship between electrostatic charging, powder flow, and the surface energies of the powders revealed that an improvement in flow because of dry coating corresponded to a decrease in the charging of the particles. A general trend of reduction in both electrostatic charging and dispersive surface energy with dry coating and relative humidity were also observed, except that a divergent behavior was observed at higher relative humidities (≥55% RH). The uncoated powder was found to have strong electron acceptor characteristic as compared with the dry coated. The adhesion energy between the particles and the tubes used for the electrostatic charging qualitatively predicted the decreasing trend in electrostatic charging from plastic tubes to stainless steel. In summary, the surface energies of the powders and the vessel could explain the electrostatic charging behavior and charge reduction because of dry coating. PMID:25974039

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

    Directory of Open Access Journals (Sweden)

    Farida Hussan

    2015-01-01

    Full Text Available 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.

  13. CHANGES IN LEVELS OF ANTIOXIDANT MINERALS AND VITAMINS IN WISTAR MALE RATS EXPOSED TO METHIONINE CONTAINING ACETAMINOPHEN FORMULATION

    Directory of Open Access Journals (Sweden)

    Adeniyi Francis A. A.

    2011-05-01

    Full Text Available This study was carried out to determine the effect of toxic and subtoxic doses of acetaminophen on antioxidant vitamins and minerals in male Wistar rats. Five groups served as the test groups and received different doses of the acetaminophenmethionine formulation in ratio 9:1. The sixth group served as the control and received only the vehicle: physiologic saline. At the end of 24 hours of exposure, blood was obtained from each rat through retro-orbital bleeding, the levels of antioxidant vitamins and minerals were determined using high-performance liquid chromatography and atomic absorption spectrophotometric technique. Results showed that at 100 mg/kg BW level of exposure, niacin, vitamin A, vitamin E, zinc, copper, manganese, selenium were significantly increased (p0.05 compared with controls. At both 350 and 1000 mgkg BW levels of exposure, all these antioxidant indices were significantly decreased (p0.05 at 350 mgkg BW (body weight level of exposure compared with the control group. The animals in 3000 mgkg BW and 5000 mgkg groups suffered 40% and 100% mortality respectively by the end of the 24th hour. This study therefore showed that acetaminophenmethionine formulation in the ratio of 9:1 may cause alteration of vital elements and biomolecules not only at toxic levels but also at tolerable level of 100 mgkg BW.

  14. Simultaneous determination of acetaminophen, guaifenesin, pseudoephedrine, pholcodine, and paraben preservatives in cough mixture by high-performance liquid chromatography.

    Science.gov (United States)

    Carnevale, L

    1983-02-01

    The separation and simultaneous determination, by high-performance liquid chromatography, of acetaminophen (I), guaifenesin (II), pseudoephedrine hydrochloride (III), and pholcodine (IV), together with a series of parabens (methyl to butyl, V-VIII) in a cough mixture, has been demonstrated using a chemically bonded octadecylsilane stationary phase with a mobile phase of methanol-water-acetic acid (45:55:2) containing the ion-pairing agent octanesulfonic acid. Retention volumes for the active ingredients were 3.8 ml, 5.4 ml, 9.4 ml, and 15.6 ml for compounds I-IV, respectively. Corrected retention volumes for the parabens [5.4 ml for methyl (V), 9.6 ml for ethyl (VI), 18.5 ml for propyl (VII), and 37.9 ml for butyl (VIII)] showed an exponential relationship with chain length of the esterifying alcohols. Excipients did not interfere with the estimation of any of the compounds, hence pretreatment of the sample was unnecessary. Average recoveries of the active ingredients and of the parabens from laboratory prepared samples were essentially 100% of theoretical with standard deviations of 1.7, 0.3, 1.5, 0.3, 0.3, 3.3, 0.7, and 2.7% for I-VIII, respectively. PMID:6834261

  15. Application of CdS quantum dots modified carbon paste electrode for monitoring the process of acetaminophen preparation.

    Science.gov (United States)

    Pasandideh-Nadamani, M; Omrani, A; Sadeghi-Maleki, M R; Samadi-Maybodi, A

    2016-06-01

    In this research article, a novel, selective, and sensitive modified carbon paste electrode (CPE) using CdS quantum dots (QDs) is presented. The highly stable CdS QDs were successfully synthesized in an in situ process using Na2S2O3 as a precursor and thioglycolic acid as a catalyst and capping agent. The synthesis of CdS QDs was studied using X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. The synthesized CdS QDs were used for preparation of a modified carbon paste electrode (CdS/CPE). The electrochemical behavior of the electrode toward p-aminophenol (PAP) and acetaminophen (Ac) was studied, and the results demonstrated that the CdS/CPE exhibited good electrocatalytic performance toward PAP and Ac oxidation. The oxidation peak potential of each analyte in the mixture was well separated. As a result, a selective and reliable method was developed for the determination of PAP and Ac simultaneously without any chemical separations. Application of the fabricated electrode for monitoring the process of Ac preparation from PAP was investigated. The obtained results show that CdS/CPE has satisfactory analytical performance; it could be a kind of attractive and promising nanomaterial-based sensor for process monitoring via the electrochemical approach. PMID:26945834

  16. Toxicity of 50-nm polystyrene particles co-administered to mice with acetaminophen, 5-aminosalicylic acid or tetracycline.

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    L.A. Denzoin Vulcano

    2013-06-01

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

  18. Evaluation of protective effect of hydroalcoholic extract of saffron petals in prevention of acetaminophen-induced renal damages in rats

    Directory of Open Access Journals (Sweden)

    Arash Omidi

    2015-03-01

    Full Text Available In recent years more attention has been given to herbal drugs in the treatment and prevention of drug toxicity because of the harmful effects of chemical drugs. In this study, directed for this purpose, research was conducted on the protective effect of hydro-ethanolic extract of saffron petals (SPE against acetaminophen (APAP induced acute nephrotoxicity. Twenty-four male Wistar rats were distributed into four groups of six each. Group I, as a control group, received normal saline (0.09% orally (PO. Group II, as an intoxicated group was treated with APAP, PO (600 mg/kg. In the groups III and IV, SPE in a dose of 10 and 20 mg/kg along with APAP (600 mg/kg was administered, respectively. At the end of the trial (8th day, blood was taken from the heart of rats for assessment of biochemical parameters and the right kidney was placed in 10% buffered formalin for histopathological evaluations. In the APAP treatment group, higher serum creatinine and uric acid were observed. SPE in a dose of 20 mg/kg significantly reduced serum creatinine and uric acid. In pathologic evaluation, a dose of 20 mg/kg of SPE prevented the kidney injuries induced by APAP. Tissues changes were in accordance with biochemical findings. It is likely that the SPE contributed to the prevention of acute nephrotoxicity induced by APAP.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Huichang Bi

    2013-01-01

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

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

    Science.gov (United States)

    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

  2. Age-related pharmacokinetic changes of acetaminophen, antipyrine, diazepam, diphenhydramine, and ofloxacin in male cynomolgus monkeys and beagle dogs.

    Science.gov (United States)

    Koyanagi, Takashi; Yamaura, Yoshiyuki; Yano, Koji; Kim, Soonih; Yamazaki, Hiroshi

    2014-10-01

    1. The pharmacokinetics of acetaminophen (marker of gastric emptying), antipyrine (marker of hepatic metabolic activity and total body water), diazepam (lipophilic and highly distributed), diphenhydramine (hepatic blood flow-limited and alpha-1 acid glycoprotein bound) and ofloxacin (renally eliminated) were evaluated in cynomolgus monkeys (3-18 years old) and beagle dogs (2-11 years old) as models in elderly persons. 2. Gastric pH fluctuated with aging in monkeys and dogs. The concentration of alpha-1 acid glycoprotein appeared to be increased by aging. There were no age-related differences in the absorption rates of the drugs under the conditions used in the study. Total body fat increased and water decreased in monkeys, but these parameters did not change in dogs. 3. Hepatic blood flow decreased in both species, but a significant decrease of hepatic clearance was only seen in monkeys. Renal clearance decreased significantly with age in monkeys and showed a tendency to decrease in dogs. 4. Age-related alterations of physiological parameters in monkeys are in agreement with clinical observations in humans, except for the lack of a change in the plasma albumin concentration. Therefore, this study suggests that monkey might be a suitable animal model for prediction of age-related changes in pharmacokinetics in humans. PMID:24650193

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

    Science.gov (United States)

    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

  4. Oxidative removal of acetaminophen using zero valent aluminum-acid system:Efficacy, influencing factors, and reaction mechanism

    Institute of Scientific and Technical Information of China (English)

    Honghua Zhang; Beipei Cao; Wanpeng Liu; Kunde Lin; Jun Feng

    2012-01-01

    Commercial available zero valent aluminum under air-equilibrated acidic conditions (ZVA1/H+/air system) demonstrated an excellent capacity to remove aqueous organic compounds.Acetaminophen (ACTM),the active ingredient of the over-the-counter drug Tylenol(R),is widely present in the aquatic environment and therefore the treatment of ACTM-contaminated water calls for further research.Herein we investigated the oxidative removal of ACTM by ZVAl/H+/air system and the reaction mechanism.In acidic solutions (pH < 3.5),ZVAl displayed an excellent capacity to remove ACTM.More than 99% of ACTM was eliminated within 16 hr in pH 1.5 reaction solutions initially containing 2.0 g/L aluminum and 2.0 mg/L ACTM at 25 ± 1℃.Higher temperature and lower pH facilitated ACTM removal.The addition of different iron species Fe0,Fe2+ and Fe3+ into ZVAl/H+/air system dramatically accelerated the reaction likely due to the enhancing transformation of H2O2 to HO·via Fenton's reaction.Furthermore,the primary intermediate h.ydroquinone and the anions formate,acetate and nitrate,were identified and a possible reaction scheme was proposed.This work suggested that ZVA1/H+/air system may be potentially employed to treat ACTM-contaminated water.

  5. Electrochemical preparation of nickel and copper oxides-decorated graphene composite for simultaneous determination of dopamine, acetaminophen and tryptophan.

    Science.gov (United States)

    Liu, Bingdi; Ouyang, Xiaoqian; Ding, Yaping; Luo, Liqing; Xu, Duo; Ning, Yanqun

    2016-01-01

    In the present work, transition metal oxides decorated graphene (GR) have been fabricated for simultaneous determination of dopamine (DA), acetaminophen (AC) and tryptophan (Trp) using square wave voltammetry. Electro-deposition is a facile preparation strategy for the synthesis of nickel oxide (NiO) and copper oxide (CuO) nanoparticles. GR can be modified by using citric acid to produce more functional groups, which is conducive to the deposition of dispersed metal particles. The morphologies and interface properties of the obtained NiO-CuO/GR nanocomposite were examined by scanning electron microscopy, energy dispersive X-ray spectroscopy and Raman spectroscopy. Moreover, the electrochemical performances of the composite film were investigated by cyclic voltammetry and electrochemical impedance spectroscopy. The modified electrode exhibited that the linear response ranges for detecting DA, AC and Trp were 0.5-20 μM, 4-400 μM and 0.3-40 μM, respectively, and the detection limits were 0.17 μM, 1.33 μM and 0.1 μM (S/N=3). Under optimal conditions, the sensor displayed high sensitivity, excellent stability and satisfactory results in real samples analysis.

  6. Ultra-sensitive film sensor based on Al2O3-Au nanoparticles supported on PDDA-functionalized graphene for the determination of acetaminophen.

    Science.gov (United States)

    Li, Jianbo; Sun, Weiyan; Wang, Xiaojiao; Duan, Huimin; Wang, Yanhui; Sun, Yuanling; Ding, Chaofan; Luo, Chuannan

    2016-08-01

    An electrochemical sensor of acetaminophen based on poly(diallyldimethylammonium chloride) (PDDA)-functionalized reduced graphene-loaded Al2O3-Au nanoparticles coated onto glassy carbon electrode (Al2O3-Au/PDDA/reduced graphene oxide (rGO)/glass carbon electrode (GCE)) were prepared by layer self-assembly technique. The as-prepared electrode-modified materials were characterized by scanning electron microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy. The electrocatalytic performances of Al2O3-Au/PDDA/rGO-modified glassy carbon electrode toward the acetaminophen were investigated by cyclic voltammetry and differential pulse voltammetry. The modified electrodes of graphene oxide (GO)/GCE, PDDA/rGO/GCE, and Al2O3-Au/PDDA/rGO/GCE were constructed for comparison and learning the catalytic mechanism. The research showed Al2O3-Au/PDDA/rGO/GCE having good electrochemical performance, attributing to the synergetic effect that comes from the special nanocomposite structure and physicochemical properties of Al2O3-Au nanoparticles and graphene. A low detection limit of 6 nM (S/N = 3) and a wide linear detection range from 0.02 to 200 μM (R (2) = 0.9970) was obtained. The preparation of sensor was successfully applied for the detection of acetaminophen in commercial pharmaceutical pills. Graphical abstract Schematic diagram of synthesis of Al2O3-Au/PDDA/rGO/GCE. PMID:27255103

  7. 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

    Directory of Open Access Journals (Sweden)

    Devarakonda K

    2015-09-01

    Full Text Available Krishna Devarakonda,1 Kenneth Kostenbader,2 Michael J Giuliani,3 Jim L Young41Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, 2Mallinckrodt Pharmaceuticals, 3Research and Development, Mallinckrodt Pharmaceuticals, 4Department of Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USAObjective: 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

  8. Effect of galactosamine-induced hepatic UDP-glucuronic acid depletion on acetaminophen elimination in rats. Dispositional differences between hepatically and extrahepatically formed glucuronides of acetaminophen and other chemicals.

    Science.gov (United States)

    Gregus, Z; Madhu, C; Goon, D; Klaassen, C D

    1988-01-01

    Galactosamine (GAL) markedly depletes hepatic UDP-glucuronic acid (UDP-GA) whereas extrahepatic UDP-GA is minimally affected. This suggests that GAL predominantly inhibits hepatic glucuronidation. Therefore, the effect of GAL-induced hepatic UDP-GA depletion was examined in bile duct-cannulated rats to determine the role of hepatic glucuronidation in the disposition of acetaminophen (AA). GAL markedly altered the fate of AA-glucuronide but had little or no effect upon other AA metabolites. GAL decreased the biliary excretion of AA-glucuronide up to 92%, whereas reductions in blood levels and urinary excretion of AA-glucuronide did not exceed 50%. This suggests that AA-glucuronide excreted in bile is predominantly of hepatic origin whereas AA-glucuronide found in blood and urine is derived from both hepatic and extrahepatic tissues. Data in the present and previous studies [Gregus, Watkins, Thompson, Klaassen: J. Pharmacol. Exp. Ther. 225, 256, (1983)] indicate that GAL greatly reduced the biliary excretion of AA- and valproic acid-glucuronide whereas the biliary excretion of the glucuronides of phenolphthalein, iopanoic acid, bilirubin, and diethylstilbestrol was only partially decreased. This difference appears to be largely due to differential contributions by the liver and extrahepatic tissues in the glucuronidation of various compounds as well as the availability of glucuronides formed in extrahepatic tissues for biliary excretion. Specifically, the extrahepatically formed glucuronide conjugates of AA and valproic acid are not readily available for biliary excretion whereas the glucuronides of the other compounds are readily excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    Directory of Open Access Journals (Sweden)

    Xiaoyan Lu

    Full Text Available 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.

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

    Science.gov (United States)

    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. Particle design using a 4-fluid-nozzle spray-drying technique for sustained release of acetaminophen.

    Science.gov (United States)

    Chen, Richer; Okamoto, Hirokazu; Danjo, Kazumi

    2006-07-01

    We prepared matrix particles of acetaminophen (Act) with chitosan (Cht) as a carrier using a newly developed 4-fluid-nozzle spray dryer. Cht dissolves in acid solutions and forms a gel, but it does not dissolve in alkaline solutions. Therefore, we tested the preparation of controlled release matrix particles using the characteristics of this carrier. Act and Cht mixtures in prescribed ratios were dissolved in an acid solution. We evaluated the matrix particles by preparing a solid dispersion using a 4-fluid-nozzle spray dryer. Observation of the particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray drying process had atomized to several microns, and that they had become spherical. We investigated the physicochemical properties of the matrix particles by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analyses with a view to clarifying the effects of crystallinity on the dissolution rate. The powder X-ray diffraction peaks and the heat of the Act fusion in the spray-dried samples decreased with the increase of the carrier content, indicating that the drug was amorphous. These results indicate that the system formed a solid dispersion. Furthermore, we investigated the interaction between the drug and carrier using FT-IR analysis. The FT-IR spectroscopy for the Act solid dispersions suggested that the Act carboxyl group and the Cht amino group formed a hydrogen bond. In addition, the measurement results of the 13C CP/MAS solid-state NMR, indicated that a hydrogen bond had been formed between the Act carbonyl group and the Cht amino group. In the Act-Cht system, the 4-fluid-nozzle spray-dried preparation with a mixing ratio of 1 : 5 obtained a sustained release preparation in all pH test solutions. PMID:16819209

  12. A composite material based on nanoparticles of yttrium (III) oxide for the selective and sensitive electrochemical determination of acetaminophen.

    Science.gov (United States)

    Baytak, Aysegul Kutluay; Teker, Tugce; Duzmen, Sehriban; Aslanoglu, Mehmet

    2016-09-01

    An electrochemical sensor was prepared by modifying a glassy carbon electrode (GCE) with a composite of yttrium (III) oxide nanoparticles (Y2O3NPs) and carbon nanotubes (CNTs) for the determination of acetaminophen (ACT). Compared with a bare GCE and CNTs/GCE, the Y2O3NPs/CNTs/GCE exhibited a well-defined redox couple for ACT and highly enhanced the current response. The separations in the anodic and cathodic peak potentials (ΔEp) for ACT were 552mV, 24mV and 10mV at ba4re GCE, CNTs/GCE and Y2O3NPs/CNTs/GCE, respectively. The observation of only 10mV of ΔEp for ACT at Y2O3NPs/CNTs/GCE was a clear indication of a great acceleration of the electrode process compared to bare GCE and GCE modified with CNTs. Also, l-ascorbic acid (l-AA) and l-tyrosine (l-TRY) did not interfere with the selective determination of ACT. Square wave voltammetry (SWV) was performed for the quantification of ACT. A linear plot was obtained for current responses versus the concentrations of ACT over the range from 1.0×10(-10) to 1.8×10(-8)M with a detection limit of 3.0×10(-11)M (based on 3Sb/m). The proposed composite material provided high electrocatalytic activity, improved voltammetric behavior, good selectivity and good reproducibility. The accurate quantification of ACT makes the proposed electrode of great interest for the public health.

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

    Science.gov (United States)

    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

  14. Radical induced degradation of acetaminophen with Fe3O4 magnetic nanoparticles as heterogeneous activator of peroxymonosulfate

    International Nuclear Information System (INIS)

    Graphical abstract: - Highlights: • The APAP degradation exhibited a pseudo-first-order kinetics pattern well. • The Fe3O4 was stable without significant leaching of iron to water during reaction. • XPS and EPR results show that Fe2+-Fe3+ cycle was answerable for radical generation. • The removal of APAP is a result of oxidation due to both OH• and SO4−• . - Abstract: Magnetic nano-scaled particles Fe3O4 were studied for the activation of peroxymonosulfate (PMS) to generate active radicals for degradation of acetaminophen (APAP) in water. The Fe3O4 MNPs were found to effectively catalyze PMS for removal of APAP, and the reactions well followed a pseudo-first-order kinetics pattern (R2 > 0.95). Within 120 min, approximately 75% of 10 ppm APAP was accomplished by 0.2 mM PMS in the presence of 0.8 g/L Fe3O4 MNPs with little Fe3+ leaching (<4 μg/L). Higher Fe3O4 MNP dose, lower initial APAP concentration, neutral pH, and higher reaction temperature favored the APAP degradation. The production of sulfate radicals and hydroxyl radicals was validated through two ways: (1) indirectly from the scavenging tests with scavenging agents, tert-butyl alcohol (TBA) and ethanol (EtOH); (2) directly from the electron paramagnetic resonance (ESR) tests with 0.1 M 5,5-dimethyl-1-pyrrolidine N-oxide (DMPO). Plausible mechanisms on the radical generation from Fe3O4 MNP activation of PMS are proposed based on the results of radical identification tests and XPS analysis. It appeared that Fe2+-Fe3+ on the catalyst surface was responsible for the radical generation. The results demonstrated that Fe3O4 MNPs activated PMS is a promising technology for water pollution caused by contaminants such as pharmaceuticals

  15. A new electrochemical sensor containing a film of chitosan-supported ruthenium: detection and quantification of sildenafil citrate and acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Delolo, Fabio Godoy; Rodrigues, Claudia; Silva, Monize Martins da; Batista, Alzir Azevedo, E-mail: fabiodelolo@hotmail.com, E-mail: daab@power.ufscar.br [Universidade Federal de Sao Carlos (UFSCar), SP (Brazil). Departamento de Quimica. Lab. de Estrutura e Reatividade de Compostos Inorganicos; Dinelli, Luis Rogerio [Universidade Federal de Uberlandia (UFU), Ituiutaba, MG (Brazil). Faculdade de Ciencias Integradas do Pontal; Delling, Felix Nicolai; Zukerman-Schpector, Julio, E-mail: fabiodelolo@hotmail.com, E-mail: daab@power.ufscar.br [Universidade Federal de Sao Carlos (UFSCar), SP (Brazil). Departamento de Quimica. Lab. de Cristalografia Estereodinamica e Modelagem Molecular

    2014-03-15

    This work presents the construction of a novel electrochemical sensor for detection of organic analytes, using a glassy carbon electrode (GCE) modified with a chitosan-supported ruthenium film. The ruthenium-chitosan film was obtained starting from the mer-[RuCl{sub 3}(dppb)(H{sub 2}O)] complex as a [1,4-bis(diphenylphosphine)butane] (dppb) precursor, and chitosan (QT). The structure of the chitosan-supported ruthenium film on the surface of the glassy carbon electrode was characterized by UV-Vis spectroscopy, electron paramagnetic resonance (EPR), scanning electron microscopy (SEM), atomic force microscopy (AFM), powder X-ray diffraction (XRD) and atomic absorption spectroscopy (AAS) techniques. The glassy carbon electrode was modified with a film formed from the evaporation of 5 μL of a solution composed of 5 mg chitosan-supported ruthenium (RuQT) in 10 mL of 0.1 mol L{sup -1} acetic acid. The modified electrode was tested as a sensor for sildenafil citrate (Viagra® 50 mg) and acetaminophen (Tylenol®) detection. The technique utilized for these analyses was differential pulse voltammetry (DPV) in 0.1 mol L{sup -1} H{sub 2}SO{sub 4} (pH 1.0) and 0.1 mol L{sup -1} CH{sub 3}COOK (pH 6.5) as supporting electrolyte. All analyses were carried out during a month using the same electrode. The electrode was washed only with water in between the analyses, keeping it in the refrigerator when it was not in use. This electrode was stable during the period utilized showing no degradation and presenting a linear response over the evaluated concentration interval (1.25 × 10{sup -5} to 4.99 × 10{sup -4} mol L{sup -1}). (author)

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

    Science.gov (United States)

    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

  17. A composite material based on nanoparticles of yttrium (III) oxide for the selective and sensitive electrochemical determination of acetaminophen.

    Science.gov (United States)

    Baytak, Aysegul Kutluay; Teker, Tugce; Duzmen, Sehriban; Aslanoglu, Mehmet

    2016-09-01

    An electrochemical sensor was prepared by modifying a glassy carbon electrode (GCE) with a composite of yttrium (III) oxide nanoparticles (Y2O3NPs) and carbon nanotubes (CNTs) for the determination of acetaminophen (ACT). Compared with a bare GCE and CNTs/GCE, the Y2O3NPs/CNTs/GCE exhibited a well-defined redox couple for ACT and highly enhanced the current response. The separations in the anodic and cathodic peak potentials (ΔEp) for ACT were 552mV, 24mV and 10mV at ba4re GCE, CNTs/GCE and Y2O3NPs/CNTs/GCE, respectively. The observation of only 10mV of ΔEp for ACT at Y2O3NPs/CNTs/GCE was a clear indication of a great acceleration of the electrode process compared to bare GCE and GCE modified with CNTs. Also, l-ascorbic acid (l-AA) and l-tyrosine (l-TRY) did not interfere with the selective determination of ACT. Square wave voltammetry (SWV) was performed for the quantification of ACT. A linear plot was obtained for current responses versus the concentrations of ACT over the range from 1.0×10(-10) to 1.8×10(-8)M with a detection limit of 3.0×10(-11)M (based on 3Sb/m). The proposed composite material provided high electrocatalytic activity, improved voltammetric behavior, good selectivity and good reproducibility. The accurate quantification of ACT makes the proposed electrode of great interest for the public health. PMID:27207064

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

    Science.gov (United States)

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

    2011-02-01

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

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

    Science.gov (United States)

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

    2012-10-15

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

  20. The Effect of Rebadioside A on Attenuation of Oxidative Stress in Kidney of Mice under Acetaminophen Toxicity

    Directory of Open Access Journals (Sweden)

    Seyed Ali Hashemi

    2014-11-01

    Full Text Available Background: Acetaminophen (APAP overdose causes renal and hepatic injury. It is also believed that oxidative stress has a pivotal role in APAP-induced renal injury. Therefore, protective effects of different antioxidants have been examined in APAP-induced renal and hepatic toxicity models. Stevia rebadiana is a plant with a high degree of natural antioxidant activity in its leaf extract. The aim of this study was to investigate the possible protective effects of rebadioside A; one of the main components of stevia extract, on APAP-induced oxidative stress in kidney of mice. Methods: Oxidative stress was induced in kidney of BALB/c mice by the intraperitoneal (i.p. administration of a single dose of 300 mg/kg APAP. Some of these mice also received rebadioside A (700 mg/kg (i.p. 30 minutes after APAP injection. Two and six hours after APAP injection, all mice were sacrificed and malondialdehyde (MDA, glutathione (GSH, free APAP, and glutathione conjugated of APAP (APAP-GSH were determined in the kidney tissue. Results: GSH depletion and MDA levels significantly (P<0.05 increased in mice treated with either APAP or APAP plus Rebadioside A, respectively in 2 and 6 hours intervals after APAP administration. Significantly (P<0.05 higher levels of free APAP and APAP-GSH levels detected in kidney of mice administrated with APAP plus rebadioside A compared to APAP treated ones. Conclusion: Rebadioside A may be a potential compound in alleviation of APAP-induced oxidative stress in kidney of mice after APAP overdoses.

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

    Science.gov (United States)

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

    2009-08-01

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

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

    Science.gov (United States)

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

    2012-07-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Nilesh Kumar Jain; Abhay K Singhai

    2011-01-01

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

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

    Science.gov (United States)

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

    2014-02-01

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

  5. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers

    Science.gov (United States)

    Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

    2013-01-01

    Aims Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. Methods A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Results Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively). Conclusion The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. PMID:22725836

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

    Directory of Open Access Journals (Sweden)

    Kenji Takemoto

    2014-01-01

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

  7. DEVELOPMENT AND VALIDATION OF HP LC METHOD FOR THE SIMULTANEOUS QUANTIFICATION OF ACETAMINOPHEN AND TRAMADOL IN COMBINED PHARMACEUTICAL DOSAGE FO RMS WITH UV DETECTION

    Directory of Open Access Journals (Sweden)

    Devalaraju Ravisankar

    2015-05-01

    Full Text Available A new high performance liquid chromatography (HPLC with ultraviolet detection method is developed for the simultaneous quant ification of acetaminophen and trama dol in bulk and in its combined pharmaceutical dosage form. The chromatographic separa tion was performed on Waters symmetry C8 column (250 mm × 4.6 mm I.D., 5 μm particle size using isocra tic elution. The optimized mobile phase consists of phosphate buffer (pH 6.8 and methanol (80:20, v/v. Th e eluted analytes are monitored at 215 nm wavelength using a UV detector. The developed method separates acetam inophen and tramadol within a run time of 6 min. The developed method was validated as per International C onference of Harmonization guidelines with respect to linearity, sensitivity (limit of detection and limit of quan tification, selectivity, accuracy, precision and robustness. The developed and validated method was successfully app lied to the determination of acetaminophen and tramadol in combined pharmaceutical dosage forms without any interference from the excipients with good recovery, precision and accuracy.

  8. Electrogenerated chemiluminescence quenching of Ru(bpy){sub 3} {sup 2+} (bpy=2,2 Prime -bipyridine) in the presence of acetaminophen, salicylic acid and their metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Haslag, Catherine S. [Department of Chemistry, Missouri State University, Springfield, Missouri 65897 (United States); Richter, Mark M., E-mail: MarkRichter@missouristate.edu [Department of Chemistry, Missouri State University, Springfield, Missouri 65897 (United States)

    2012-03-15

    Quenching of Ru(bpy) {sub 3}{sup 2+} (bpy=2,2 Prime -bipyridine) coreactant electrogenerated chemiluminescence (ECL) has been observed in the presence of acetaminophen, salicylic acid and related complexes. However, no quenching is observed with the acetylsalicylic acid. In most instances, quenching is observed with 100-fold excess of quencher (compared to ECL luminophore) with complete quenching observed between 10,000 and 100,000 fold excess. Fluorescence and UV-vis experiments coupled with bulk electrolysis support the formation of benzoquinone products upon electrochemical oxidation. The mechanism of quenching may involve the interaction of the electrochemically generated benzoquinone species with (i) the {sup Low-Asterisk }Ru(bpy){sub 3}{sup 2+} excited state or (ii) highly energetic coreactant radicals. - Highlights: Black-Right-Pointing-Triangle Efficient quenching of the electrogenerated chemiluminescence is observed. Black-Right-Pointing-Triangle Acetaminophen, salicylic acid and related compounds can be detected. Black-Right-Pointing-Triangle The mechanism of quenching involves benzoquinones formed upon electrolysis.

  9. Remarks on Sasidharan et al. “Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage”. Molecules 2012, 17, 13937-13947

    Directory of Open Access Journals (Sweden)

    Manu Sharma

    2013-03-01

    Full Text Available An article by Sasidharan et al. recently published in the journal Molecules [1] claimed to show the hepatoprotective effects of lantadene A against acetaminophen-induced liver damage in mice. While reading this paper, I came across certain points that need to be clarified and taken up in the interest of science and other scientists working in this area.

  10. Human plasma concentrations of tolbutamide and acetaminophen extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances and simple physiologically based pharmacokinetic modeling for radio-labeled microdose clinical studies

    International Nuclear Information System (INIS)

    The aim of the current study was to extrapolate the pharmacokinetics of drug substances orally administered in humans from rat pharmacokinetic data using tolbutamide and acetaminophen as model compounds. Adjusted animal biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human biomonitoring equivalents using known species allometric scaling factors. In this extrapolation, in vitro metabolic clearance data were obtained using liver preparations. Rates of tolbutamide elimination were roughly similar in rat and human liver microsome experiments, but acetaminophen elimination by rat liver microsomes and cytosolic preparations showed a tendency to be faster than those in humans. Using a simple physiologically based pharmacokinetic (PBPK) model, estimated human plasma concentrations of tolbutamide and acetaminophen were consistent with reported concentrations. Tolbutamide cleared in a roughly similar manner in humans and rats, but medical-dose levels of acetaminophen cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in rats. The data presented here illustrate how pharmacokinetic data in combination with a simple PBPK model can be used to assist evaluations of the pharmacological/toxicological potential of new drug substances and for estimating human radiation exposures from radio-labeled drugs when planning human studies. (author)

  11. Diagnosis and Treatment of Six Acetaminophen Poisoning Patients and Lessons from It%对乙酰氨基酚中毒六例临床诊治经验与教训

    Institute of Scientific and Technical Information of China (English)

    马飞; 李毅; 于学忠

    2014-01-01

    目的:探讨对乙酰氨基酚中毒的诊治要点,以提高诊治水平。方法对2008年12月-2014年4月北京协和医院急诊科收治的6例对乙酰氨基酚中毒临床资料进行回顾性分析。结果本组因不同程度的意识障碍、烦躁不安、恶心、呕吐、头晕、头痛等就诊,实验室检查提示肝功能明显异常。结合患者或家属提供发病前大量用药史,血、尿毒物检测提示对乙酰氨基酚过量或中毒,确诊为对乙酰氨基酚中毒,予特效解毒剂N-乙酰半胱氨酸治疗,5例好转出院;1例因合并急性重症胰腺炎自动出院。结论对乙酰氨基酚中毒临床表现缺乏特异性,急诊医师应提高对其的认识,结合患者病史、临床表现及毒物检测结果,早期诊断与治疗,防止误漏诊,减少肝衰竭等严重并发症的发生。%Objective To improve the diagnosis and the treatment level of acetaminophen overdose. Methods Clin-ical data of six patients with acetaminophen poisoning from December 2008 to April 2014 was retrospectively analyzed. Results The major manifestations of six patients were confusion, malaise, nausea, vomiting, dizziness and headache. The laboratory examination showed obvious hepatotoxicity. All the patients were diagnosed as acetaminophen poisoning by medication history acquired from the patients or family members, blood screen and urinalysis. All patients received N-acetylcysteine treatment. Five patients were discharged with improvement. One patient gave up the therapy because of severe acute pancreatitis. Con-clusion Acetaminophen poisoning is easy to be misdiagnosed because of nonspecific features. The acetaminophen poisoning can be diagnosed based on medical history, clinical manifestations and medical examinations, and the final diagnosis can be made depending on the blood acetaminophen screen test. The emergency staff should improve the attention to acetaminophen poisoning so as to reduce the rate of liver failure.

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

    Directory of Open Access Journals (Sweden)

    Tomishima Yoshiro

    2013-01-01

    Full Text Available Abstract Background Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2 synthase inhibitor, on liver injury induced by APAP overdose in mice. Methods Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg. The effects of ozagrel (200 mg/kg treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL on cytochrome P450 2E1 (CYP2E1 activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1–100 muM were evaluated by the WST-1 cell viability assay. Results Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos and C/EBP homologous protein (chop, but did not suppress B-cell lymphoma 2-like protein11 (bim expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. Conclusions We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest

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

    Science.gov (United States)

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

    2002-02-01

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