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Sample records for acetaminophen acetylsalicylic acid

  1. Influence of combinations of acetylsalicylic acid, acetaminophen, and diclofenac on platelet aggregation.

    PubMed

    Galliard-Grigioni, Katja S; Fehr, Martin; Reinhart, Walter H

    2008-10-24

    Acetylsalicylic acid (aspirin) is often given together with other nonsteroidal anti-inflammatory drugs and acetaminophen. The latter have been accused in epidemiologic studies to cause an increased cardiovascular risk. We have, therefore, analysed the influence of various such drug combinations on platelet aggregation in vitro. Citrated blood was incubated with either 25 microg/ml acetaminophen, 0.5 microg/ml aspirin, 0.04 microg/ml diclofenac, or buffer; followed by a second of the above-mentioned solutions. After a 20 min incubation, platelet aggregation was assessed with a platelet function analyser (PFA-100), which measures the pore closure time (CT) by aggregating platelets. The length of CT reflects the degree of platelet inhibition. Acetaminophen alone did not affect platelet aggregation. Aspirin and diclofenac both increased CT (184+/-69 s, P<0.01 and 196+/-54 s, P<0.001; control 120+/-13 s). Combinations of either aspirin and diclofenac, aspirin and acetaminophen, or diclofenac and acetaminophen increased CT further (290+/-22 s, 281+/-36 s, 288+/-25 s, respectively, P<0.001). The time sequence of drug application was important: when diclofenac or acetaminophen was added before aspirin, platelet aggregation was less inhibited than when given in opposite order, i.e. aspirin prior to diclofenac or acetaminophen. We conclude that acetaminophen by itself does not affect platelet aggregation, but potentiates the antiaggregatory effect of aspirin or diclofenac. Aspirin given before acetaminophen or diclofenac had a more potent antiaggregatory effect than vice versa. These observations may have clinical implications.

  2. Identification and Quantitative Analysis of Acetaminophen, Acetylsalicylic Acid, and Caffeine in Commercial Analgesic Tablets by LC-MS

    ERIC Educational Resources Information Center

    Fenk, Christopher J.; Hickman, Nicole M.; Fincke, Melissa A.; Motry, Douglas H.; Lavine, Barry

    2010-01-01

    An undergraduate LC-MS experiment is described for the identification and quantitative determination of acetaminophen, acetylsalicylic acid, and caffeine in commercial analgesic tablets. This inquiry-based experimental procedure requires minimal sample preparation and provides good analytical results. Students are provided sufficient background…

  3. A safety assessment of fixed combinations of acetaminophen and acetylsalicylic acid, coformulated with caffeine.

    PubMed

    Bach, P H; Berndt, W O; Delzell, E; Dubach, U; Finn, W F; Fox, J M; Hess, R; Michielsen, P; Sandler, D P; Trump, B; Williams, G

    1998-11-01

    Overuse and abuse of phenacetin-containing mixed analgesics has contributed to end-stage renal disease. Combination analgesics, especially those coformulated with caffeine, have been implicated as imparting a greater risk of analgesic-associated nephropathy (AAN) than single or coformulated analgesics without caffeine. This has led to a recommendation that the sale of "two plus caffeine" analgesic mixtures be reclassified from over-the-counter to prescription only availability. There is a rational basis for coformulating acetylsalicylic acid (ASA) and acetaminophen (paracetamol) as this reduces the dose of each, without altering efficacy. The coformulation of caffeine with these analgesics has a significant adjuvant effect and increases analgesic efficacy 1.4-1.6-fold. Currently available animal and human data do not support the notion that the nephrotoxic risk from coformulated ASA and acetaminophen is higher than the risk from either ASA or acetaminophen alone, in equivalent analgesic doses. There are no epidemiological data that implicate caffeine in AAN, and only limited evidence that links excessive acetaminophen usage to renal disease. There is no evidence that caffeine increases analgesics papillotoxicity directly. The presence of caffeine in mixtures of analgesics are no more addictive than other sources of caffeine. There is no evidence to suggest that adding caffeine to analgesic mixtures enhances the potential for promoting analgesic misuse in the general population. Thus distinct therapeutic benefits of ASA, acetaminophen and caffeine appear to outweigh any known risk. It is doubtful if preventing the availability of these products will significantly affect the role of analgesic abuse/overuse in end-stage renal disease. Better risk management would come from a focused educational program, developed in a close collaboration between industry, healthcare professionals and consumer organizations, such a program must warn against the potential dangers of

  4. [Interaction between NSAIDs and acetylsalicylic acid disregarded].

    PubMed

    Vollaard, E J; Kramers, C; Brouwers, J R B J

    2014-01-01

    In 2013 the European Medicines Agency declared that diclofenac is contraindicated in patients with arterial thrombotic complications, based on a meta-analysis of randomised controlled trials on the adverse reactions of NSAIDs. The same decision was taken for coxibs some years earlier. The Dutch authorities (CBG/MEB) informed physicians and pharmacists about this decision without taking into account whether these patients were using prophylactic acetylsalicylic acid or not. It has been shown that NSAIDs with high COX-1 affinity like ibuprofen and naproxen cause a pharmacodynamic interaction with the inhibition of thromboxane synthesis by acetylsalicylic acid. This interaction does not occur with relatively COX-2-selective NSAIDs such as coxibs and diclofenac. Therefore, in patients who use acetylsalicylic acid for thromboprophylaxis, contraindicating coxibs or diclofenac is not justified, on the contrary: they are preferable.

  5. [The forensic chemical investigation of acetylsalicylic acid].

    PubMed

    Shormanov, V K; Chupak, V V; Pobedonstseva, M N; Maslov, S V; Kibets, N A; Tikhopoeva, N N

    2015-01-01

    The objective of the present study was to develop the universal approach to the quantitative determination of acetylsalicylic acid in biological tissues and fluids to be applied in the practice of forensic chemical expertise with the use of thin-layer chromatography, gas chromatography and mass spectrometry, low-pressure column chromatography, and spectrophotometry. A system of solvents consisting of acetone and ethyl acetate (7:3) was proposed as a universal agent for extracting acetylsalicylic acid from the cadaveric tissues and blood. It was shown that acetylsalicylic acid and its principal metabolite, salicylic acid, can be purified from the endogenous admixtures present in the biological materials by column chromatography on silica gel L 40/100 mcm. Salicylic acid in extracts from biological materials was identified and quantified with the use of thin-layer chromatography, gas chromatography/mass spectrometry, and electronic spectrophotometry. The method for forensic chemical investigation of acetylsalicylic acid has been developed and applied in the analysis of the material provided for expertise.

  6. The evaluation method for antiplatelet effect of acetylsalicylic acid.

    PubMed

    Yokoyama, Haruko; Mastumura, Takashi; Soeda, Shinji; Suzuki, Yuji; Watanabe, Masayuki; Kashiwakura, Emiko; Saso, Takayuki; Ikeda, Noriyuki; Tokuoka, Kentaro; Kitagawa, Yasuhisa; Yamada, Yasuhiko

    2014-12-01

    Reduced platelet aggregation by acetylsalicylic acid administration has been associated with adverse outcomes in patients with thrombotic diseases, thus it is important to determine aspirin resistance in those cases. The antiplatelet effect of acetylsalicylic acid is rarely measured, but it has many problems. The aim of this study was to find the evaluation method for antiplatelet effect after administration of acetylsalicylic acid. We developed a particle counting method based upon laser light scattering, and utilized the platelet aggregation agonists, collagen, at 0.25, 0.5 and 1.0 μg/mL, and adenosine diphosphate (ADP), at 0.5, 1.0 and 2.0 μM, to determine their effective concentrations. Seventeen healthy volunteers were administered acetylsalicylic acid at 162 mg/day, with platelet aggregation determined before and 20 min after administration. In all subjects, the rate of platelet aggregation induced by 1.0 μg/mL of collagen before taking acetylsalicylic acid was the highest value obtained, while 20 min after acetylsalicylic acid administration, aggregation induced by collagen at 1.0 μg/mL was significantly decreased as compared to before administration. As for the other concentrations of collagen and all those of ADP tested, platelet aggregation was either not significantly induced before taking acetylsalicylic acid or the rate of aggregation was not significantly decreased after taking acetylsalicylic acid. Our results indicate that collagen at 1.0 μg/mL is appropriate as a platelet aggregation agonist for evaluating the antiplatelet effect of acetylsalicylic acid. Thus, it is useful that the measurement is performed only once.

  7. Inhibitory effects of acetylsalicylic acid on exocrine pancreatic carcinogenesis.

    PubMed

    Yıldız, H; Oztas, H; Yıldız, D; Koc, A; Kalipci, E

    2013-05-01

    We investigated short (6 months) and long (12 months) term inhibitory effects of low (200 ppm) and high (400 ppm) dosages of acetylsalicylic acid (aspirin) on exocrine pancreatic carcinogenesis. It is known that exocrine pancreatic carcinogenesis can be detected by the presence of atypical acinar cell foci (AACF) in pancreas. We investigated possible inhibitory effects of acetylsalicylic acid in an azaserine-treated rat model. AACF were produced in rats by injection with azaserine according to previous studies. Our findings showed that the number, volume and diameter of pancreatic AACF were reduced after acetylsalicylic acid application. These observations suggest that acetylsalicylic acid may exert a protective effect against neoplastic development of pancreatic acinar cells in azaserine injected rats. Our findings corroborate reports in the literature concerning the effects of aspirin in reducing neoplastic development.

  8. Electrochemical Sensors for Detection of Acetylsalicylic Acid

    PubMed Central

    Supalkova, Veronika; Petrek, Jiri; Havel, Ladislav; Krizkova, Sona; Petrlova, Jitka; Adam, Vojtech; Potesil, David; Babula, Petr; Beklova, Miroslava; Horna, Ales; Kizek, Rene

    2006-01-01

    Acetylsalicylic acid (AcSA), or aspirin, was introduced in the late 1890s and has been used to treat a variety of inflammatory conditions. The aim of this work was to suggest electrochemical sensor for acetylsalicylic detection. Primarily, we utilized square wave voltammetry (SWV) using both carbon paste electrode (CPE) and of graphite pencil electrode (GPE) as working ones to indirect determination of AcSA. The principle of indirect determination of AcSA bases in its hydrolysis on salicylic acid (SA), which is consequently detected. Thus, we optimized both determination of SA and conditions for AcSA hydrolysis and found out that the most suitable frequency, amplitude, step potential and the composition and pH of the supporting electrolyte for the determination of SA was 260 Hz, 50 mV, 10 mV and Britton-Robinson buffer (pH 1.81), respectively. The detection limit (S/N = 3) of the SA was 1.3 ng/ml. After that, we aimed on indirect determination of AcSA by SWV CPE. We tested the influence of pH of Britton-Robinson buffer and temperature on yield of hydrolysis, and found out that 100% hydrolysis of AcSA was reached after 80 minutes at pH 1.81 and 90°C. The method for indirect determination of AcSA has been utilized to analyse pharmaceutical drug. The determined amount of AcSA in the pharmaceutical drug was in good agreement with the declared amounts. Moreover, we used GPE for determination of AcSA in a pharmaceutical drug. Base of the results obtained from stationary electrochemical instrument we used flow injection analysis with electrochemical detection to determine of salicylates (SA, AcSA, thiosalicylic acid, 3,5-dinitrosalicylic acid and 5-sulfosalicylic acid – SuSA). We found out that we are able to determine all of detected salicylates directly without any pre-treatment, hydrolysis and so on at units of femtomoles per injection (5 μl).

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

    PubMed Central

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

    2015-01-01

    Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury. PMID:26208104

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

    PubMed

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

    2015-01-01

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

  11. An acetylsalicylic acid-sensitive aggregation phenomenon in Dipodascopsis uninucleata.

    PubMed

    Kock, J L; van Wyk, P W; Venter, P; Coetzee, D J; Smith, D P; Viljoen, B C; Nigam, S

    1999-04-01

    Aggregation of ascospores has been discovered in the yeast Dipodascopsis uninucleata. When this yeast is cultivated to reach the sexual reproductive stage, small ascospores are individually released from the tip of a sac-like ascus which then aggregate in orderly clusters. Acetylsalicylic acid (ASA) inhibited ascospore release and subsequent ordered aggregation process. We suggest that novel ASA-sensitive oxidised fatty acids (3R-hydroxy-oxylipins) and small hooks located on the surface of these ascospores, are involved.

  12. Acetaminophen

    MedlinePlus

    Backprin® (as a combination product containing Acetaminophen, Caffeine, Magnesium Salicylate) ... Forte® (as a combination product containing Acetaminophen, Caffeine, Magnesium Salicylate, Phenyltoloxamine)

  13. Effects of microgravity on the binding of acetylsalicylic acid by Rhizobium leguminosarum bv. trifolii

    NASA Astrophysics Data System (ADS)

    Urban, James E.; Gerren, Richard; Zoelle, Jeffery

    1995-07-01

    Bacteroids can be induced in vitro by treating growing Rhizobium leguminosarum bv. trifolii with succinic acid or succinic acid structural analogs like acetylsalicylic acid. Quantitating bacteroid induction by measuring acetylsalicylic binding under normal (1 g) conditions showed two forms of binding to occur. In one form of binding cells immediately bound comparatively high levels of acetylsalicylic acid, but the binding was quickly reversed. The second form of binding increased with time by first-order kinetics, and reached saturation in 40 s. Similar experiments performed in the microgravity environment aboard the NASA 930 aircraft showed only one form of binding and total acetylsalicylic acid bound was 32% higher than at 1 g.

  14. Superiority of zinc complex of acetylsalicylic acid to acetylsalicylic acid in preventing postischemic myocardial dysfunction.

    PubMed

    Korkmaz, Sevil; Atmanli, Ayhan; Li, Shiliang; Radovits, Tamás; Hegedűs, Peter; Barnucz, Enikő; Hirschberg, Kristóf; Loganathan, Sivakkanan; Yoshikawa, Yutaka; Yasui, Hiroyuki; Karck, Matthias; Szabó, Gábor

    2015-09-01

    The pathophysiology of ischemic myocardial injury involves cellular events, reactive oxygen species, and an inflammatory reaction cascade. The zinc complex of acetylsalicylic acid (Zn(ASA)2) has been found to possess higher anti-inflammatory and lower ulcerogenic activities than acetylsalicylic acid (ASA). Herein, we studied the effects of both ASA and Zn(ASA)2 against acute myocardial ischemia. Rats were pretreated with ASA (75 mg/kg) or Zn(ASA)2 (100 mg/kg) orally for five consecutive days. Isoproterenol (85 mg/kg, subcutaneously [s.c.]) was applied to produce myocardial infarction. After 17-22 h, animals were anesthetized with sodium pentobarbital (60 mg/kg, intraperitoneally [i.p.]) and both electrical and mechanical parameters of cardiac function were evaluated in vivo. Myocardial histological and gene expression analyses were performed. In isoproterenol-treated rats, Zn(ASA)2 treatment normalized significantly impaired left-ventricular contractility index (Emax 2.6 ± 0.7 mmHg/µL vs. 4.6 ± 0.5 mmHg/µL, P < 0.05), increased stroke volume (30 ± 3 µL vs. 50 ± 6 µL, P < 0.05), decreased systemic vascular resistance (7.2 ± 0.7 mmHg/min/mL vs. 4.2 ± 0.5 mmHg/min/mL, P < 0.05) and reduced inflammatory infiltrate into the myocardial tissues. ECG revealed a restoration of elevated ST-segment (0.21 ± 0.03 mV vs. 0.09 ± 0.02 mV, P < 0.05) and prolonged QT-interval (79.2 ± 3.2 ms vs. 69.5 ± 2.5 ms, P < 0.05) by Zn(ASA)2. ASA treatment did not result in an improvement of these parameters. Additionally, Zn(ASA)2 significantly increased the mRNA-expression of superoxide dismutase 1 (+73 ± 15%), glutathione peroxidase 4 (+44 ± 12%), and transforming growth factor (TGF)-β1 (+102 ± 22%). In conclusion, our data demonstrate that oral administration of zinc and ASA in the form of bis(aspirinato)zinc(II) complex is superior to ASA in preventing electrical

  15. THE EFFECT OF ACETYLSALICYLIC ACID ON PLATELET FUNCTION

    PubMed Central

    Evans, Geoffrey; Packham, Marian A.; Nishizawa, Edward E.; Mustard, James F.; Murphy, Edmund A.

    1968-01-01

    Acetylsalicylic acid (ASA, aspirin) and sodium salicylate inhibit platelet aggregation induced by collagen, antigen-antibody complexes, gamma globulin-coated particles or thrombin. These compounds suppress the release of platelet constituents, such as adenosine diphosphate (ADP) and serotonin, induced by such stimuli. Since ASA and sodium salicylate do not inhibit ADP-induced platelet aggregation, it appears that their effect on the action of the other stimuli is due to a decrease in the amount of ADP released. The administration of ASA to rabbits (in doses which inhibited collagen-induced platelet aggregation) impaired hemostasis, prolonged platelet survival, and diminished the amount of deposit formed in an extracorporeal shunt. PMID:4176225

  16. [Clarification on publications concerning the synthesis of acetylsalicylic acid].

    PubMed

    Lafont, O

    1996-01-01

    Charles Frédéric Gerhardt (1816-1856) mentioned in his Traité de chimie Organique (1854) a publication, in French (realized in 1852 but published in 1853) entitled "Researches on anhydrous organic acids" in which, was reported the reaction of sodium salicylate with acetyl chloride. He thought that the reaction product was an acid anhydride, but obtained really crude acetylsalicylic acid. Later on, but also in 1853, a publication in german, by the same author related the same experiments. Surprisingly only the second publication has been mentioned in most of the historical studies on the subject. Acetyl salicylic acid was identified and synthesised in 1859 by von Gilm by another method and the product obtained by Gerhardt was identified to it in 1869.

  17. Acidosis, magnesium and acetylsalicylic acid: Effects on thrombin

    NASA Astrophysics Data System (ADS)

    Borisevich, Nikolaj; Loznikova, Svetlana; Sukhodola, Aleksandr; Halets, Inessa; Bryszewska, Maria; Shcharbin, Dzmitry

    2013-03-01

    Thrombin, an enzyme from the hydrolase family, is the main component of the blood coagulation system. In ischemic stroke it acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin forming blood clots in the brain. It has been found to phosphoresce at room temperature in the millisecond and microsecond ranges. The phosphorescence of thrombin was studied under physiological conditions, in acidosis (decrease of pH from 8.0 to 5.0) and on the addition of salts (magnesium sulfate and sodium chloride) and of acetylsalicylic acid, and its connection with thrombin function is discussed. Acidosis significantly increased the internal dynamics of thrombin. We propose that lactate-acidosis plays a protective role in stroke, preventing the formation of clots. The addition of NaCl and MgSO4 in different concentrations increased the internal dynamics of thrombin. Also, the addition of MgSO4 decreased thrombin-induced platelet aggregation. However, magnesium sulfate and acetylsalicylic acid in the therapeutic concentrations used for treatment of ischemic stroke had no effect on thrombin internal dynamics. The data obtained will help to elucidate the conformational stability of thrombin under conditions modulating lactate-acidosis and in the presence of magnesium sulfate.

  18. Infrared spectra of hydrogen-bonded salicylic acid and its derivatives : Salicylic acid and acetylsalicylic acid

    NASA Astrophysics Data System (ADS)

    Wójcik, Marek J.

    1981-11-01

    Infrared spectra of hydrogen-bonded salicylic acid, O-deutero-salicylic acid and acetylsalicylic acid crystals have been studied experimentally and theoretically. Interpretation of these spectra was based on the Witkowski-Maréchal model. Semi-quantitative agreement between experimental and theoretical spectra can be achieved with the simplest form of this model, with values of interaction parameters transferable for equivalent intermolecular hydrogen bonds.

  19. Flow-injection chemiluminescence determination of acetylsalicylic acid based on its enhancing effect on the lucigenin–hydrogen peroxide system.

    PubMed

    Wabaidur, S M; Alam, S M; Alothmana, Z A; Eldesokya, Gaber

    2014-09-01

    A sensitive flow-injection chemiluminescence method for the determination of acetylsalicylic acid is described. It is based on the enhanced chemiluminescent emission of the alkaline lucigenin–H2O2 system by acetylsalicylic acid. The difference in chemiluminescent intensity of alkaline lucigenin–H2O2 in the presence of acetylsalicylic acid from that in the absence of acetylsalicylic acid was linear at acetylsalicylic acid concentrations in the range of 0.0029–47.37 μg/mL, with detection and quantification limits of 0.0011 and 0.0029 μg/mL, respectively. The correlation coefficient of the working curve was 0.9983. The relative standard deviation (n = 10) for 25 μg/mL acetylsalicylic acid is 1.95%. All experimental parameters were optimized. The method was successfully applied to the determination of acetylsalicylic acid in pharmaceutical preparations. The recovery results obtained by the method were satisfactory.

  20. Treatment of endometriosis with local acetylsalicylic acid injection: experimental study in rabbits.

    PubMed

    Siqueira, Juliana Menezes; Barreto, Adriana Beatriz; Saad-Hossne, Rogério

    2011-01-01

    The objective of the present study was to estimate the effects of introduction of acetylsalicylic acid solution into peritoneal implants in autologous endometrium as a method for treating endometriosis. Forty adult female rabbits were subdivided into 4 groups of 10 rabbits each, and endometriosis was induced via autotransplantation of endometrial fragments into the peritoneal cavity. At 30 days after induction of endometriosis, all animals were randomly assigned to 1 of 2 protocols. In protocol 1, animals were evaluated at 24 hours after treatment; group 1 (control) received physiologic solution, and group 2 received acetylsalicylic acid. In protocol 2, animals were evaluated at 10 days after treatment, group 3 (control) and group 4 received acetylsalicylic acid. After measuring the lesion, the endometriotic focus was removed and prepared for mounting on slides for histologic analysis. Imaging software was used for analysis of the total remaining area of endometrial tissue. The affected area in acetylsalicylic acid-treated animals was smaller than that in control animals at 24 hours and 10 days after treatment; a significant difference was found between control and treated groups (p < .001). Statistical analysis comparing protocols 1 and 2 demonstrated no differences between controls groups or acetylsalicylic acid groups (p = .30), and no differences between times (p = .75). Acetylsalicylic acid solution led to less growth (or higher involution) of endometrial implants. Acetylsalicylic acid injected directly into endometriotic foci was effective in their destruction. This presents new perspectives for treatment of endometriosis and for clinical applications based on further clinical studies.

  1. Acetylsalicylic Acid Daily vs Acetylsalicylic Acid Every 3 Days in Healthy Volunteers: Effect on Platelet Aggregation, Gastric Mucosa, and Prostaglandin E2 Synthesis.

    PubMed

    Ferreira, Plinio Minghin Freitas; Gagliano-Jucá, Thiago; Zaminelli, Tiago; Sampaio, Marinalva Ferreira; Blackler, Rory Willian; Trevisan, Miriam da Silva; Novaes Magalhães, Antônio Frederico; De Nucci, Gilberto

    2016-07-01

    Substantial platelet inhibition was observed 3 days after a single administration of acetylsalicylic acid 81 mg to healthy volunteers. Here we investigate prostaglandin E2 (PGE2 ) antrum concentrations and gastrointestinal symptoms in two treatment groups: one receiving losartan and acetylsalicylic acid every day and the other receiving losartan every day and acetylsalicylic acid every 3 days. Twenty-eight healthy volunteers from both sexes received either 50 mg losartan and acetylsalicylic acid 81 mg daily or 50 mg losartan and acetylsalicylic acid 81 every 3 days with placebo on the other days. Therapy was delivered for 30 days for both groups. Gastric endoscopy was performed before and after treatment period. Biopsies were collected for PGE2 quantification. Platelet function tests were carried out before and during treatment and TXB2 release on platelet rich plasma was measured. The every 3 day low-dose acetylsalicylic acid regimen produced complete inhibition of platelet aggregation compared to the daily treatment. Thromboxane B2 release was substantially abolished for both groups during treatment. There was no significant difference on the endoscopic score of both treatment groups after the 30-day treatment (P = .215). There was over 50% suppression of antrum PGE2 content on volunteers receiving acetylsalicylic acid daily (P = .0016), while for the every 3 day dose regimen there was no significant difference between pre and post-treatment antrum PGE2 dosages (P = .4193). Since PGE2 is involved in gastric healing, we understand that this new approach could be safer and as efficient as the standard daily therapy on a long-term basis.

  2. High-pressure polymorphism of acetylsalicylic acid (aspirin): Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Crowell, Ethan L.; Dreger, Zbigniew A.; Gupta, Yogendra M.

    2015-02-01

    Micro-Raman spectroscopy was used to elucidate the high-pressure polymorphic behavior of acetylsalicylic acid (ASA), an important pharmaceutical compound known as aspirin. Using a diamond anvil cell (DAC), single crystals of the two polymorphic phases of aspirin existing at ambient conditions (ASA-I and ASA-II) were compressed to 10 GPa. We found that ASA-I does not transform to ASA-II, but instead transforms to a new phase (ASA-III) above ∼2 GPa. It is demonstrated that this transformation primarily introduces structural changes in the bonding and arrangement of the acetyl groups and is reversible upon the release of pressure. In contrast, a less dense ASA-II shows no transition in the pressure range studied, though it appears to exhibit a disordered structure above 7 GPa. Our results suggest that ASA-III is the most stable polymorph of aspirin at high pressures.

  3. [Comparative assessment of antiaggregant efficacy of acetylsalicylic acid and clopidogrel in peripheral atherosclerosis].

    PubMed

    Kuznetsov, M R; Sergeeva, N A; Koshkin, V M; Boldin, B V; Rodionov, S V; Virganskiĭ, A O; Kosykh, I V; Lisenkov, O P; Kuznetsova, V F

    2014-01-01

    Presented in the article are the results of studying antiaggregate activity of acetylsalicylic acid and clopidogrel in a total of 36 patients suffering from various-severity chronic arterial insufficiency of lower limbs on the background of atherosclerosis obliterans. The study was conducted prior to treatment for correct selection of a particular antiplatelet agent. The obtained results showed that clopidogrel was not always more efficient than acetylsalicylic acid, since there is individual sensitivity of each patients to a particular antiplatelet agent. Therefore, an individual approach is necessary to conservative therapy of arterial insufficiency of lower limbs. For some patients it is preferable to administer clopidogrel, for others - acetylsalicylic acid. In a series of cases combined treatment is justified, while some patients having low sensitivity to both acetylsalicylic acid and clopidogrel require careful selection of alternative agents influencing other thrombocyte receptors.

  4. [Identification of rat and human hemoglobin acetilation sites after its interaction with acetylsalicylic acid].

    PubMed

    Shreĭner, E V; Murashko, E A; Dubrovskiĭ, Ia D; Krasnov, N V; Podol'skaia, E P; Babakov, V N

    2012-01-01

    The possibility of interaction of 0.1 mg/mL acetylsalicylic acid with purified human and rat globin in vitro during 24 h at 37 degrees C was investigated. The rat globin can be modified with acetylsalicylic acid on aminoacid residues K-17, K-57, K-91, K-140 in alpha subunit as well as on K-18, K-77 in beta subunit. The human globin can be modified with acetylsalicylic acid on aminoacid residues K-17, K-41, K-57 and K-91 in alpha subunit as well as on K-18, K-96 and K- 133 in beta subunit. We identified of acetetylated lysines K-17 and K-57 in alpha subunit of human hemoglobin after incubation whole blood with 0.1 mg/mL acetylsalicylic acid during 3 h.

  5. Acetylsalicylic acid as a potential pediatric health hazard: legislative aspects concerning accidental intoxications in the European Union.

    PubMed

    Mund, Menen E; Gyo, Christoph; Brüggmann, Dörthe; Quarcoo, David; Groneberg, David A

    2016-01-01

    Acetylsalicylic acid is a frequently used medication worldwide. It is not used in pediatrics due its association with Reye syndrome. However, in case of pediatric intoxication, children are more fragile to salicylate poisoning because of their reduced ability of buffer the acid stress. Intoxication leads to a decoupling of oxidative phosphorylation and subsequently to a loss in mitochondrial function. Symptoms of poisoning are diverse; eventually they can lead to the death of the patient. Governmental websites of various EU countries were searched for legal information on acetylsalicylic acid availability in pharmacies and non-pharmacy stores. Various EU countries permit prescription-free sales of acetylsalicylic acid in pharmacies and non-pharmacy stores. In Sweden acetylsalicylic acid 500 mg may be sold in a maximum package size of 20 tablets or effervescent tablets in a non-pharmacy. In the UK a maximum of 16 tablets of acetylsalicylic acid 325 mg is allowed to sell in non-pharmacies. In Ireland acetylsalicylic acid is classified as S2 medication. Subsequently, acetylsalicylic acid is allowed to be sold prescription-free in pharmacies and non-pharmacy stores. In the Netherlands acetylsalicylic acid may only be sold in drug stores or pharmacies. A maximum of 24 tablets of 500 mg is allowed to purchase in a drug store. Several countries in the European Union are permitted to offer acetylsalicylic acid prescription-free in pharmacies and non-pharmacy stores without legal guidance on the storage position within the store. Further research is needed to investigate whether acetylsalicylic acid is located directly accessible to young children within the stores in EU countries which permit prescription-free sales of acetylsalicylic acid.

  6. Prevention of small black spots on sugar-coated tablets containing aluminum acetylsalicylic acid.

    PubMed

    Tomida, Y; Makino, T

    1999-04-01

    Sugar-coated tablets containing aluminum acetylsalicylate gradually developed black spots on their surface. A factorial experiment was performed based on an L32 orthogonal array table in an attempt to halt this phenomenon. The factor responsible proved to be talc used to formulate the smooth coating layer over the subcoating layer containing aluminum acetylsalicylate. When HCl-treated talc was used as a filler for the smoothing layer, the black spots were markedly decreased. The spotting mechanism was considered to be due to hydrolysis of aluminum acetylsalicylate in the subcoating layer to salicylic acid and acetic acid, which sublimated into the pores of the smoothing layer. Then, ferrous ion substituted from magnesium ion in the talc molecule center was extracted by salicylic acid, acetic acid, and moisture. Finally, the ferrous ion was oxidized to ferric ion, and this produced an Fe3+ chelate compound together with salicylic acid.

  7. Effect of acetylsalicylic acid on microvascular thrombosis in autologous breast reconstruction.

    PubMed

    Enajat, Morteza; Aziz Mohammadi, Mujzgan; Debeij, Jan; van der Hulst, Rene R W J; Mureau, Marc A M

    2014-01-01

    Although advances in microsurgery have increased success rates of autologous breast reconstruction, microvascular thrombosis still remains a major concern as a cause of flap failure. At present, no evidence-based guidelines on pharmacological prevention of microvascular thrombosis exist. This study investigates the effect of acetylsalicylic acid on the incidence of microvascular complications in patients undergoing autologous breast reconstruction. Patients undergoing deep inferior epigastric artery perforator or free transverse rectus abdominis myocutaneous flap breast reconstruction at two academic centers in the Netherlands between 2005 and 2011 were included. Patients at one center received once daily 0.6 mL of nadroparine and 40 mg acetylsalicylic acid, while patients at the other center received 0.6 mL nadroparine only. A total of 430 consecutive patients underwent 592 breast reconstructions. No statistically significant differences were found between the two groups in the incidence of flap failure (2.8 and 2.5%), microvascular thromboembolic complications (2.6 and 3.8%), venous congestion (3.4 and 2.8%), or overall complications (28.0 and 32.3%). Hematoma tended to occur more often in the group receiving acetylsalicylic acid (9.2 and 4.7%).It was found that no protective effect of acetylsalicylic acid on microvascular complications was present. Given its known risks and the somewhat increased occurrence of hematoma in the present study, we stopped to routinely administer acetylsalicylic acid after autologous breast reconstruction.

  8. Acetylsalicylic Acid and Eflornithine in Treating Patients at High Risk for Colorectal Cancer | Division of Cancer Prevention

    Cancer.gov

    This phase II trial is studying how well giving acetylsalicylic acid together with eflornithine works in treating patients at high risk for colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of acetylsalicylic acid and eflornithine may prevent colorectal cancer. |

  9. Modified MCM-41 as a drug delivery system for acetylsalicylic acid

    NASA Astrophysics Data System (ADS)

    Vyskočilová, Eliška; Luštická, Ivana; Paterová, Iva; Machová, Libuše; Červený, Libor

    2014-12-01

    The modification of prepared MCM-41 by different groups (amino, chloro and oxo) was studied. Prepared materials were treated by acetylsalicylic acid and hybrid materials were characterized, compared from the point of view of immobilized amount of active substance. The highest amount of acetylsalicylic acid was detected using methyl-tert- butyl ether as a solvent and MCM-41 without modification after 1 h (0.35 g per 1 g of the support) or MCM modified by amino group after 5 h (0.37 g per 1 g of the support) as a support. Using amino modified MCM, the longer treatment by acetylsalicylic acid converged to the equilibrium and after 24 h the immobilized amount was 0.3 g per 1 g. A dissolution in vitro study was carried out, comparing the stability of formed interactions. The slowest dissolution was detected using non-modified MCM-41 and oxo modified material.

  10. Relaxation in the glass former acetylsalicylic acid studied by deuteron magnetic resonance and dielectric spectroscopy

    NASA Astrophysics Data System (ADS)

    Nath, R.; El Goresy, T.; Geil, B.; Zimmermann, H.; Böhmer, R.

    2006-08-01

    Supercooled liquid and glassy acetylsalicylic acid was studied using dielectric spectroscopy and deuteron relaxometry in a wide temperature range. The supercooled liquid is characterized by major deviations from thermally activated behavior. In the glass the secondary relaxation exhibits the typical features of a Johari-Goldstein process. Via measurements of spin-lattice relaxation times the selectively deuterated methyl group was used as a sensitive probe of its local environments. There is a large difference in the mean activation energy in the glass with respect to that in crystalline acetylsalicylic acid. This can be understood by taking into account the broad energy barrier distribution in the glass.

  11. Heat shock protein 70-dependent protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells.

    PubMed

    Qin, Ying; Naito, Yuji; Handa, Osamu; Hayashi, Natsuko; Kuki, Aiko; Mizushima, Katsura; Omatsu, Tatsushi; Tanimura, Yuko; Morita, Mayuko; Adachi, Satoko; Fukui, Akifumi; Hirata, Ikuhiro; Kishimoto, Etsuko; Nishikawa, Taichiro; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Takagi, Tomohisa; Yagi, Nobuaki; Kokura, Satoshi; Yoshikawa, Toshikazu

    2011-11-01

    Protection of the small intestine from mucosal injury induced by nonsteroidal anti-inflammatory drugs including acetylsalicylic acid is a critical issue in the field of gastroenterology. Polaprezinc an anti-ulcer drug, consisting of zinc and L-carnosine, provides gastric mucosal protection against various irritants. In this study, we investigated the protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of the RIE1 rat intestinal epithelial cell line. Confluent rat intestinal epithelial cells were incubated with 70 µM polaprezinc for 24 h, and then stimulated with or without 15 mM acetylsalicylic acid for a further 15 h. Subsequent cellular viability was quantified by fluorometric assay based on cell lysis and staining. Acetylsalicylic acid-induced cell death was also qualified by fluorescent microscopy of Hoechst33342 and propidium iodide. Heat shock proteins 70 protein expression after adding polaprezinc or acetylsalicylic acid was assessed by western blotting. To investigate the role of Heat shock protein 70, Heat shock protein 70-specific small interfering RNA was applied. Cell viability was quantified by fluorometric assay based on cell lysis and staining and apoptosis was analyzed by fluorescence-activated cell sorting. We found that acetylsalicylic acid significantly induced apoptosis of rat intestinal epithelial cells in a dose- and time-dependent manner. Polaprezinc significantly suppressed acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells at its late phase. At the same time, polaprezinc increased Heat shock protein 70 expressions of rat intestinal epithelial cells in a time-dependent manner. However, in Heat shock protein 70-silenced rat intestinal epithelial cells, polaprezinc could not suppress acetylsalicylic acid -induced apoptosis at its late phase. We conclude that polaprezinc-increased Heat shock protein 70 expression might be an important mechanism by which polaprezinc suppresses acetylsalicylic

  12. Determination of acetylsalicylic acid and its major metabolites in bovine urine using ultra performance liquid chromatography.

    PubMed

    Castillo-García, M L; Aguilar-Caballos, M P; Gómez-Hens, A

    2015-03-15

    A new method based on ultra high performance liquid chromatography (UPLC) with photometric and fluorometric detection for the determination of acetylsalicylic acid and its main metabolites, namely gentisic, salicylic and salicyluric acids, in bovine urine samples is reported. Photometric detection was used for acetylsalicylic acid determination, whereas the native fluorescence of the metabolites was monitored using fluorometric detection. The separation was performed under isocratic conditions, using acetonitrile-phosphate solution (3.5mM, pH 3.5) (26:74, v/v) as the mobile phase. The retention times of the four compounds were lower than 2min, which are shorter than those achieved using conventional HPLC. Under the optimum separation conditions, the dynamic ranges and detection limits (ngmL(-1)) were: 0.2-2500, 0.09 for gentisic acid; 0.2-2500, 0.08 for salicylic acid and 2.5-15,000, 1.1 for salicyluric acid, using fluorescence detection, and 10-25,000, 2.2 for acetylsalicylic acid, using UV detection. Intra-day and inter-day precision data were assessed at two levels of concentration of each analyte using both detection systems. The selectivity of the method was checked by assaying different drugs of veterinary use showing that most of them did not interfere with the determination of the analytes. The method has been applied to the analysis of bovine urine samples, which only required a simple clean up step of the samples prior to injection in the UPLC system. A recovery study was performed, which provided values in the range of 80-100%. This fact proves the practical usefulness of this method as an ultrafast analytical tool for the therapeutic control of acetylsalicylic acid administration in bovine animals intended for food production.

  13. Acetylsalicylic Acid Compared to Placebo in Treating High-Risk Patients With Subsolid Lung Nodules | Division of Cancer Prevention

    Cancer.gov

    This randomized phase II trial studies acetylsalicylic acid compared to placebo in treating high-risk patients with subsolid lung nodules. A nodule is a growth or lump that may be malignant (cancer) or benign (not cancer). Chemoprevention is the use of drugs to keep cancer from forming or coming back. The use of acetylsalicylic acid may keep cancer from forming in patients with subsolid lung nodules. |

  14. Preparation of acetylsalicylic acid-acylated chitosan as a novel polymeric drug for drug controlled release.

    PubMed

    Liu, Changkun; Wu, Yiguang; Zhao, Liyan; Huang, Xinzheng

    2015-01-01

    The acetylsalicylic acid-acylated chitosan (ASACTS) with high degree of substitution (DS) was successfully synthesized, and characterized with FTIR, (1)H NMR and elemental analysis methods. The optimum synthesis conditions were obtained which gave the highest DS (about 60%) for ASACTS. Its drug release experiments were carried out in simulated gastric and intestine fluids. The results show that the drugs in the form of acetylsalicylic acid (ASA) and salicylic acid (SA) were released in a controlled manner from ASACTS only in simulated gastric fluid. The release profile can be best fitted with logistic and Weibull model. The research results reveal that ASACTS can be a potential polymeric drug for the controlled release of ASA and SA in the targeted gastric environment.

  15. Acetaminophen hepatotoxicity and sterile inflammation: The mechanism of protection of Chlorogenic acid.

    PubMed

    Jaeschke, Hartmut

    2016-01-05

    Acetaminophen hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response. A recent report suggested that a therapeutic intervention with chlorogenic acid, a dietary polyphenolic compound, protects against acetaminophen-induced liver injury by inhibiting the inflammatory injury. The purpose of this letter is to discuss a number of reasons why the protective mechanism of chlorogenic acid against acetaminophen hepatotoxicity does not involve an anti-inflammatory effect and provides an alternative explanation for the observed protection.

  16. [Acetylsalicylic acid desensitization in the new era of percutaneous coronary intervention].

    PubMed

    Fuertes Ferre, Georgina; Ferrer Gracia, Maria Cruz; Calvo Cebollero, Isabel

    2015-09-21

    Dual antiplatelet therapy is essential in patients undergoing percutaneous coronary intervention with stent implantation. Hypersensitivity to acetylsalicylic acid (ASA) limits treatment options. Desensitization to ASA has classically been studied in patients with respiratory tract disease. Over the last years, many protocols have been described about ASA desensitization in patients with ischemic heart disease, including acute coronary syndrome and the need for coronary stent implantation. It is important to know the efficacy and safety of ASA desensitization in these patients.

  17. Application of hydroalcoholic solutions of formaldehyde in preparation of acetylsalicylic acid gastro-resistant capsules.

    PubMed

    Pina, M E; Sousa, A T

    2002-04-01

    Enteric coating of hard gelatin capsules by application of hydroalcoholic solutions of formaldehyde was studied and developed in accordance with previous publications. It is possible to affirm that this coating constitutes a simple, stable, reproducible, and inexpensive method, being a valid alternative to those which have been proposed. The aim of the present investigation is the preparation of acetylsalicylic acid gelatin capsules with good conditions of gastro-resistance and enteros solubility.

  18. Activity ratio between antiprostacyclin and antiaggregating effects of acetylsalicylic acid, indometacin and ditazole.

    PubMed

    Caprino, L; Togna, G; Antonetti, F; Borrelli, F

    1980-01-01

    The effects of acetylsalicylic acid (ASA) indometacin and ditazole on prostacyclin production from rabbit aortic rings were studied in comparison to their inhibiting activity on platelet aggregation. The result were expressed as the ratio between the drug dose inhibiting by 50% prostacycline production and the minimum oral antiaggregating dose. The following ratios were found: 2.4 for ASA, 7.3 for indometacin and 20.4 for ditazole.

  19. The effects of acetylsalicylic acid on the pituitary prolactin of the lizard, Uromastix hardwickii.

    PubMed

    Ahmad, Mahmood; Hasan, Ruqaiya; Ahmad, Mansoor; Qureshi, Anila; Masroor, Shama

    2005-07-01

    This study deals with the intravenous administration of 7 mg acetylsalicylic acid (ASA) solution to Uromastix hardwickii for 4 days. It enhances the activity of anterior pituitary lactotrophs, when 0.1 ml of pituitary homogenate of ASA treated was injected hypodermically to crop-sac showed a greater diametric response and increased activity with milk like secretion than that of the injections of 0.1 ml homogenate of control pituitary. The present study indicated that ASA induces hyperprolactinemia.

  20. Acetylsalicylic acid combined with diclofenac inhibits cartilage degradation in rabbit models of osteoarthritis.

    PubMed

    Liu, Jianqiang; Wu, Changshun; Wang, Dong; Wang, Laicheng; Sun, Shui

    2016-10-01

    The present study aimed to investigate the effect of different concentrations of acetylsalicylic acid combined with diclofenac on the articular cartilage of a rabbit model of osteoarthritis (OA). A total of 40 New Zealand white rabbits were divided into 5 groups. Group A was a sham-operated control group, which was treated with normal saline. Groups B-E were OA models and were treated with normal saline and acetylsalicylic acid combined with diclofenac at concentrations of 5, 10 and 20 mg/kg, respectively. A cartilage macroscopic examination and a pathological observation were performed to analyze the structure of the articular cartilage in all of the treated groups. The nitric oxide (NO) content and interleukin 1β (IL-1β) levels were detected by an enzyme-linked immunosorbent assay. In addition, the protein expression of matrix metalloproteinase 3 (MMP)-3 and MMP-13 were detected by western blot analysis. The mRNA expression of tissue inhibitor of metalloproteinases 1 (TIMP1) was detected by polymerase chain reaction (PCR). The results revealed that different concentrations of the drugs significantly reduced the scores of cartilago articularis, the NO and IL-1β levels and the protein expression of MMP-3 and MMP-13. Furthermore, PCR revealed that the mRNA expression of TIMP1 was significantly upregulated, and the effects increased with increasing drug concentration. Thus, the administration of different concentrations of acetylsalicylic acid combined with diclofenac demonstrates preventive or therapeutic effects against OA progression.

  1. DNA damage and oxidative stress induced by acetylsalicylic acid in Daphnia magna.

    PubMed

    Gómez-Oliván, Leobardo Manuel; Galar-Martínez, Marcela; Islas-Flores, Hariz; García-Medina, Sandra; SanJuan-Reyes, Nely

    2014-08-01

    Acetylsalicylic acid is a nonsteroidal anti-inflammatory widely used due to its low cost and high effectiveness. This compound has been found in water bodies worldwide and is toxic to aquatic organisms; nevertheless its capacity to induce oxidative stress in bioindicators like Daphnia magna remains unknown. This study aimed to evaluate toxicity in D. magna induced by acetylsalicylic acid in water, using oxidative stress and DNA damage biomarkers. An acute toxicity test was conducted in order to determine the median lethal concentration (48-h LC50) and the concentrations to be used in the subsequent subacute toxicity test in which the following biomarkers were evaluated: lipid peroxidation, oxidized protein content, activity of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, and level of DNA damage. Lipid peroxidation level and oxidized protein content were significantly increased (p<0.05), and antioxidant enzymes significantly altered with respect to controls; while the DNA damage were significantly increased (p<0.05) too. In conclusion, acetylsalicylic acid induces oxidative stress and DNA damage in D. magna.

  2. Successful living donor liver transplantation for acute liver failure after acetylsalicylic acid overdose.

    PubMed

    Shirota, Tomoki; Ikegami, Toshihiko; Sugiyama, Satoshi; Kubota, Kouji; Shimizu, Akira; Ohno, Yasunari; Mita, Atsuyoshi; Urata, Koichi; Nakazawa, Yuichi; Kobayashi, Akira; Iwaya, Mai; Miyagawa, Shinichi

    2015-04-01

    A 20-year-old woman was admitted to an emergency hospital after ingesting 66 g of acetylsalicylic acid in a suicide attempt. Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. Steroid pulse therapy, plasma exchange, and continuous hemodiafiltration did not yield any improvement in her hepatic or renal function, and she was transferred to our hospital for living donor liver transplantation. Nine days after drug ingestion, she developed hepatic encephalopathy: thus, we diagnosed the patient with acute liver failure with hepatic coma accompanied by acute pancreatitis due to the overdose of acetylsalicylic acid. Living donor liver transplantation was immediately performed using a left lobe graft from the patient's mother. Following transplantation, the patient's renal and hepatic function and consciousness improved, and she was discharged. In this report, we describe a rare case of acetylsalicylic acid-induced acute liver failure with acute hepatic coma and concomitant acute pancreatitis and acute renal failure, which were treated successfully with emergency living donor liver transplantation.

  3. Determination of acetylsalicylic acid in commercial tablets by SERS using silver nanoparticle-coated filter paper.

    PubMed

    Sallum, Loriz Francisco; Soares, Frederico Luis Felipe; Ardila, Jorge Armando; Carneiro, Renato Lajarim

    2014-12-10

    In this work, filter paper was used as a low cost substrate for silver nanoparticles in order to perform the detection and quantification of acetylsalicylic acid by SERS in a commercial tablet. The reaction conditions were 150mM of ammonium hydroxide, 50mM of silver nitrate, 500mM of glucose, 12min of the reaction time, 45°C temperature, pretreatment with ammonium hydroxide and quantitative filter paper (1-2μm). The average size of silver nanoparticles deposited on the paper substrate was 180nm. Adsorption time of acetylsalicylic acid on the surface of the silver-coated filter paper was studied and an adsorption time of 80min was used to build the analytical curve. It was possible to obtain a calibration curve with good precision with a coefficient of determination of 0.933. The method proposed in this work was capable to quantify acetylsalicylic acid in commercial tablets, at low concentration levels, with relative error of 2.06% compared to the HPLC. The preparation of filter paper coated with silver nanoparticles using Tollen's reagent presents several advantages such as low cost of synthesis, support and reagents; minimum amount of residuals, which are easily treated, despite the SERS spectroscopy presenting fast analysis, with low sample preparation and low amount of reactants as in HPLC analysis.

  4. Determination of acetylsalicylic acid in commercial tablets by SERS using silver nanoparticle-coated filter paper

    NASA Astrophysics Data System (ADS)

    Sallum, Loriz Francisco; Soares, Frederico Luis Felipe; Ardila, Jorge Armando; Carneiro, Renato Lajarim

    2014-12-01

    In this work, filter paper was used as a low cost substrate for silver nanoparticles in order to perform the detection and quantification of acetylsalicylic acid by SERS in a commercial tablet. The reaction conditions were 150 mM of ammonium hydroxide, 50 mM of silver nitrate, 500 mM of glucose, 12 min of the reaction time, 45 °C temperature, pretreatment with ammonium hydroxide and quantitative filter paper (1-2 μm). The average size of silver nanoparticles deposited on the paper substrate was 180 nm. Adsorption time of acetylsalicylic acid on the surface of the silver-coated filter paper was studied and an adsorption time of 80 min was used to build the analytical curve. It was possible to obtain a calibration curve with good precision with a coefficient of determination of 0.933. The method proposed in this work was capable to quantify acetylsalicylic acid in commercial tablets, at low concentration levels, with relative error of 2.06% compared to the HPLC. The preparation of filter paper coated with silver nanoparticles using Tollen's reagent presents several advantages such as low cost of synthesis, support and reagents; minimum amount of residuals, which are easily treated, despite the SERS spectroscopy presenting fast analysis, with low sample preparation and low amount of reactants as in HPLC analysis.

  5. Acetylsalicylic acid combined with diclofenac inhibits cartilage degradation in rabbit models of osteoarthritis

    PubMed Central

    Liu, Jianqiang; Wu, Changshun; Wang, Dong; Wang, Laicheng; Sun, Shui

    2016-01-01

    The present study aimed to investigate the effect of different concentrations of acetylsalicylic acid combined with diclofenac on the articular cartilage of a rabbit model of osteoarthritis (OA). A total of 40 New Zealand white rabbits were divided into 5 groups. Group A was a sham-operated control group, which was treated with normal saline. Groups B-E were OA models and were treated with normal saline and acetylsalicylic acid combined with diclofenac at concentrations of 5, 10 and 20 mg/kg, respectively. A cartilage macroscopic examination and a pathological observation were performed to analyze the structure of the articular cartilage in all of the treated groups. The nitric oxide (NO) content and interleukin 1β (IL-1β) levels were detected by an enzyme-linked immunosorbent assay. In addition, the protein expression of matrix metalloproteinase 3 (MMP)-3 and MMP-13 were detected by western blot analysis. The mRNA expression of tissue inhibitor of metalloproteinases 1 (TIMP1) was detected by polymerase chain reaction (PCR). The results revealed that different concentrations of the drugs significantly reduced the scores of cartilago articularis, the NO and IL-1β levels and the protein expression of MMP-3 and MMP-13. Furthermore, PCR revealed that the mRNA expression of TIMP1 was significantly upregulated, and the effects increased with increasing drug concentration. Thus, the administration of different concentrations of acetylsalicylic acid combined with diclofenac demonstrates preventive or therapeutic effects against OA progression. PMID:27698707

  6. Peristalsis in the Guinea pig small intestine in vitro is impaired by acetaminophen but not aspirin and dipyrone.

    PubMed

    Herbert, Michael K; Weis, Rebecca; Holzer, Peter; Roewer, Norbert

    2005-01-01

    Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. It is unknown whether non-opioid analgesics, such as acetaminophen, acetylsalicylic acid, and dipyrone, exert any effect on intestinal motility. In the current in vitro study we examined the effect of these analgesics on intestinal peristalsis and analyzed some of their mechanisms of action. In isolated segments of the guinea pig small intestine peristalsis was triggered by a perfusion-induced increase of the intraluminal pressure. The peristaltic pressure threshold (PPT) at which peristaltic waves were elicited was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), acetaminophen (0.01-100 microM), acetylsalicylic acid (100-300 microM), and dipyrone (10-100 microM) were added extraserosally to the organ bath. Acetaminophen concentration-dependently increased PPT and abolished peristalsis in four of six segments at the concentration of 10 microM and in all segments tested at 100 microM (EC50=6.0 microM). The increase in PPT resulting from 3 microM acetaminophen was reduced by naloxone and apamin but not changed by L-nitro-arginine methylester (L-NAME), its inactive enantiomer D-NAME, acetylsalicylic acid, methysergide, or tropisetron. Acetylsalicylic acid and dipyrone did not affect peristalsis. The results reveal, for the first time, that acetaminophen concentration-dependently impairs intestinal peristalsis, whereas acetylsalicylic acid and dipyrone lacked such an effect. The inhibition caused by acetaminophen involves transmitters acting via small conductance Ca2+-activated potassium channels, endogenous opioidergic pathways, and presumably inhibition of cyclooxygenase-3.

  7. Inhibitory effect of acetylsalicylic acid on matrix metalloproteinase - 2 activity in human endothelial cells exposed to high glucose.

    PubMed

    Nicolae, Manuela; Tircol, Magdalena; Alexandru, Dorin

    2005-01-01

    Matrix metalloproteinases play a major role in the process of angiogenesis, an important feature of diabetes complications, cancer or rheumatoid arthritis. High glucose concentrations were reported to augment metalloproteinase-2 secretion in some cell types. In the present study we investigated the influence of acetylsalicylic acid on metalloproteinase- 2 secretion and expression in endothelial cells cultured for one week in high glucose conditions (25 mM and 33 mM). Metalloproteinase-2 activity was evidenced by gel zymography, the protein was identified by Western blotting, and the gene expression was quantitated by RT-PCR. The results indicated a marked inhibitory effect of acetylsalicylic acid at gene expression level (approximately 43%) and also at secretion level in samples of conditioned media (approximately 30%) and cellular homogenates (approximately 70%). This may suggest that acetylsalicylic acid could have a beneficial effect in preventing the angiogenic process that appears in diabetes complications.

  8. Simultaneous determination of acetylsalicylic and salicylic acids by first derivative spectrometry in pharmaceutical preparations

    NASA Astrophysics Data System (ADS)

    Rogić, Dunja

    1993-03-01

    A multicomponent first derivative UV spectrometric procedure for determination of acetylsalicylic acid (aspirin) and salicylic acid in the solution containing 1 % (w/v) of citric acid in some pharmaceutical preparations is presented. The method is based on the use of the first derivative minimum spectrometric measurements at 286 nm for aspirin and at 318 nm for salicylic acid. Four kinds of cmmercial Aspirin tablets were assayed without a long pretreatment of the pharmaceuticals from the tablet additives. Beer's law is obeyed from 13.62-68.1 μg ml -1 of aspirin and from 2.723-13.616 μg ml -1 of salicylic acid. Detection limits at the 0.05 level of significance were calculated to be 1.24 and 0.25 μg ml -1 with relative standard deviations of 1.09 % and 1.2 % of aspirin and salicylic acid, respectively.

  9. DFT studies on the vibrational and electronic spectra of acetylsalicylic acid

    NASA Astrophysics Data System (ADS)

    Ye, Yunfeng; Tang, Guodong; Han, Yonghong; Culnane, Lance F.; Zhao, Jianyin; Zhang, Yu

    2016-05-01

    The following is a theoretical and experimental study on the vibrational and electronic properties of acetylsalicylic acid (ASA). Vibrational information was obtained by FT-IR and Raman spectroscopy which agree well with harmonic vibrational frequency calculations. The calculations were carried out using density functional theory B3LYP methods with 6-311G** and LANL2DZ basis sets. The vibrational assignments were calculated by Gaussview. Absorption UV-Vis experiments of ASA reveal three maximum peaks at 203, 224 and 277 nm, which are in agreement with calculated electronic transitions using TD-B3LYP/6-311G**.

  10. Enteric coating can lead to reduced antiplatelet effect of low-dose acetylsalicylic acid.

    PubMed

    Haastrup, Peter Fentz; Grønlykke, Thor; Jarbøl, Dorte Ejg

    2015-03-01

    Low-dose acetylsalicylic acid (ASA) is widely used as antithrombotic prophylaxis. Enteric-coated ASA has been developed to decrease the risk of gastrointestinal side effects. The consequences of enteric coating on pharmacokinetics and antiplatelet effect of ASA have not systematically been assessed. This MiniReview demonstrates that data from clinical trials indicate that enteric coating can reduce the antiplatelet effect of ASA compared to plain ASA. This is possibly due to decreased bioavailability of ASA caused by prolonged solvation and absorption of the enteric-coated formulations. Therefore, low-dose enteric-coated ASA might not be bioequivalent to plain ASA, entailing the risk of insufficient cardiovascular prophylaxis.

  11. [Effect of acetylsalicylic acid in complex with lipid nanostructures of various compositions on human platelet aggregation].

    PubMed

    Suslina, Z A; Prokhorov, D I; Shilova, A G; Kaplun, A P; Ionova, V G; Seĭfulla, R D

    2011-01-01

    The effect of lipid nanocomplexes loaded with acetylsalicylic acid (aspirin) on platelet aggregation in vitro was investigated. The antithrombotic effect of aspirin in complex with liposomes prepared from pig brain glycosphingolipids is not only significantly higher compared to control, but also accompanied by leveling of the development of proaggregant effects. It was shown that ADP-induced platelet aggregation is reduced by the introduction of electrostatic charge in the structure of lipid bilayer of liposomes. The effect achieved for the liposomes possessing a negative charge was more pronounced in comparison to the effect of positively charged liposomes.

  12. Medications Containing Aspirin (Acetylsalicylate) and Aspirin-Like Products

    MedlinePlus

    ... Some medication labels may use the words acetylsalicylate, acetylsalicylic acid, salicylic, salicylamide, phenyl salicylate, etc., instead of the word aspirin. There is not data as to other forms ...

  13. IR spectroscopic investigation of the inhibition of the glycation process by acetylsalicylic acid

    NASA Astrophysics Data System (ADS)

    Otero de Joshi, Virginia; Gil, Herminia; Contreras, Silvia; Velasquez, William; Joshi, Narahari V.

    2000-05-01

    An IR spectroscopic study was carried out at room temperature for Human Serum albumin (HSA) glycated with fructose and glucose and inhibited with acetylsalicylic acid. The glycation process was carried out in our laboratory by a conventional method to confirm earlier reported observation of the effect of glycation on the intensity variation of the IR spectra, particularly, in the range 1500 cm-1 to 1700 cm-1 and around 3300 cm-1. IR spectra reveal that the effects of glycation of HSA by fructose are more intense than with glucose, which is the expected. Bovine serum albumin was also glycated using Glucose-6-phosphate disodium salt, and gamma-globulin was glycate with glucose, As expected, the glycation process was more intense with glucose-t-phosphate disodium salt. Acetyl salicylic acid was also used and its inhibitor effects could be observed in both cases, with glucose and with glucose-6-phosphate disodium salt even though, to a smaller extent with the latter. This is consistent with the earlier data and is explained on the basis of the attachment of macromolecules to (epsilon) -NH2 groups of lysines. The experimental results confirm that acetylsalicylic acid, indeed, acts as an inhibitor by acetylation of the (epsilon) -NG2 group where the sugars are supposed to be attached.

  14. Does the use of acetylsalicylic acid have an influence on our vision?

    PubMed Central

    Michalska-Małecka, Katarzyna; Regucka, Agnieszka; Śpiewak, Dorota; Sosnowska-Pońska, Magdalena; Niewiem, Alfred

    2016-01-01

    Purpose Acetylsalicylic acid (ASA) is one of the most commonly used drugs in the world due to its anti-inflammatory, analgesic, and antipyretic properties. This review aims to describe the relationship between acetylsalicylic acid and age-related macular degeneration (AMD) – a chronic disease that causes deterioration of visual acuity and is one of the most common ophthalmological diseases these days. Methods Data presented in this review were collected from both research and review articles concerning ophthalmology and pharmacology. Results The results of the studies analyzed in this review are not unambiguous. Moreover, the studies are not homogenous. They differed from one another in terms of the number of patients, the age criteria, the ASA dose, and the duration of control period. The reviewed studies revealed that ASA therapy, which is applied as a protection in cardiovascular diseases in patients with early forms of AMD and geographic atrophy, should not be discontinued. Conclusion On the basis of the present studies, it cannot be unequivocally said whether ASA influences people’s vision and if people endangered with AMD progression or who are diagnosed with AMD should use this drug. It may increase the risk of AMD, but it can also reduce the risk of life-threatening conditions. The authors suggest that in order to avoid possible risks of AMD development, people who frequently take ASA should have their vision checked regularly. PMID:27843305

  15. Comparison of intravenous acetylsalicylic acid and dipyrone in postoperative pain

    PubMed Central

    Blendinger, I.; Eberlein, H. J.

    1980-01-01

    1 In 17 gynaecological patients with postoperative pain the analgesic efficacy of intravenous lysine salicylate 1.8 g (corresponding to acetylsalicyclic acid (ASA) 1.0 g) and dipyrone 1.0 g were compared in a double-blind randomized study. 2 In the ASA group, mean pain relief and pain intensity difference scores reached a maximum 30 min after drug administration and remained at this level for the next 90 minutes. 3 In the dipyrone group, these scores reached their peak 60 min after drug administration and seemed to fall off during the next hour. 4 The mean pain relief and intensity difference scores were greater following aspirin than dipyrone. However, firm conclusions cannot be drawn from the results of this small study. PMID:7437274

  16. Numerical simulation of the solvate structures of acetylsalicylic acid in supercritical carbon dioxide containing polar co-solvents

    NASA Astrophysics Data System (ADS)

    Petrenko, V. E.; Antipova, M. L.; Gurina, D. L.; Odintsova, E. G.; Kumeev, R. S.; Golubev, V. A.

    2016-07-01

    Hydrogen-bonded complexes of acetylsalicylic acid with polar co-solvents in supercritical carbon dioxide, modified by methanol, ethanol, and acetone of 0.03 mole fraction concentration, are studied by numerical methods of classical molecular dynamics simulation and quantum chemical calculations. The structure, energy of formation, and lifetime of hydrogen-bonded complexes are determined, along with their temperature dependences (from 318 to 388 K at constant density of 0.7 g cm-3). It is shown that the hydrogen bonds between acetylsalicylic acid and methanol are most stable at 318 K and are characterized by the highest value of absolute energy. At higher supercritical temperatures, however, the longest lifetime is observed for acetylsalicylic acid-ethanol complexes. These results correlate with the known literature experimental data showing that the maximum solubility of acetylsalicylic acid at density values close to those considered in this work and at temperatures of 318 and 328 K is achieved when using methanol and ethanol as co-solvents, respectively.

  17. Quality and antioxidant properties on sweet cherries as affected by preharvest salicylic and acetylsalicylic acids treatments.

    PubMed

    Giménez, María José; Valverde, Juan Miguel; Valero, Daniel; Guillén, Fabián; Martínez-Romero, Domingo; Serrano, María; Castillo, Salvador

    2014-10-01

    The effects of salicylic acid (SA) or acetylsalicylic acid (ASA) treatments during on-tree cherry growth and ripening on fruit quality attributes, especially those related with the content on bioactive compounds and antioxidant activity were analysed in this research. For this purpose, two sweet cherry cultivars, 'Sweet Heart' and 'Sweet Late', were used and SA or ASA treatments, at 0.5, 1.0 and 2.0mM concentrations, were applied at three key points of fruit development (pit hardening, initial colour changes and onset of ripening). These treatments increased fruit weight and ameliorated quality attributes at commercial harvest, and led to cherries with higher concentration in total phenolics and in total anthocyanins, as well as higher antioxidant activity, in both hydrophilic and lipophilic fractions. Thus, preharvest treatments with SA or ASA could be promising tools to improve sweet cherry quality and health beneficial effects for consumers.

  18. Using Capillary Electrophoresis to Determine the Purity of Acetylsalicylic Acid Synthesized in the Undergraduate Laboratory

    NASA Astrophysics Data System (ADS)

    Welder, Frank; Colyer, Christa L.

    2001-11-01

    Capillary electrophoresis (CE), although a powerful analytical tool, has found only limited application in undergraduate laboratory study. In an effort to expose freshman and sophomore chemistry students to this technique, thereby giving them practical instrumental experience early in their careers, we propose to use CE in the analysis of student-synthesized acetylsalicylic acid (ASA). The synthesis of ASA from salicylic acid (SA) is a routine undergraduate laboratory, although students rarely have the opportunity to test the purity of their product. The CE method described herein provides students with a method to test purity and yield of their product and to determine the effect of aging on their sample. CE can accomplish this in a short period of time, with minimal disruption to the regular laboratory curriculum. Optimized separation conditions, limits of detection, and linear range for ASA and SA are also given.

  19. Drug delivery and therapeutic impact of extended-release acetylsalicylic acid.

    PubMed

    Bliden, Kevin P; Patrick, Jeff; Pennell, Andrew T; Tantry, Udaya S; Gurbel, Paul A

    2016-01-01

    Current treatment guidelines recommend once-daily, low-dose acetylsalicylic acid (ASA; aspirin) for secondary prevention of cardiovascular events. However, the anti-thrombotic benefits of traditional ASA formulations may not extend over a 24-h period, especially in patients at high risk for a recurrent cardiovascular event. A next-generation, extended-release ASA formulation (ER-ASA) has been developed to provide 24-h anti-thrombotic coverage with once-daily dosing. The pharmacokinetics of ER-ASA indicates slower absorption and prolonged ASA release versus immediate-release ASA, with a favorable safety profile. ER-ASA minimizes systemic ASA absorption and provides sustained antiplatelet effects over a 24-h period.

  20. Controlled release of acetylsalicylic acid from polythiophene/carrageenan hydrogel via electrical stimulation.

    PubMed

    Pairatwachapun, Sanita; Paradee, Nophawan; Sirivat, Anuvat

    2016-02-10

    Blends between polythiophene (PTh) and a carrageenan hydrogel were fabricated as the matrix for the electric field assisted drug release. The pristine carrageenan and the blend films were prepared by the solution casting using acetylsalicylic acid (ASA) as the anionic model drug and Mg(2+), Ca(2+), and Ba(2+) as the crosslinking agents. The ASA was released by the Fickian diffusion mechanism. The diffusion coefficient decreased with increasing crosslinking ratio or decreasing crosslinking ionic radii. The diffusion coefficients were greater with the applied electrical potentials by an order of magnitude relative to those without electric field. Moreover, the diffusion coefficients with PTh as the drug carrier were higher than those without PTh. Thus, the presence of the conductive polymer in the hydrogel blend coupled with applied electric field is shown here to drastically enhance the drug delivery rate.

  1. Origin of the low temperature excess heat capacity of isotopically substituted acetylsalicylic acid

    NASA Astrophysics Data System (ADS)

    Schröder, F.; Winkler, B.; Bauer, J. D.; Haussühl, E.; Rivera Escoto, B.; Tristan López, F.; Avalos Borja, M.; Richter, C.; Ferner, J.

    2011-09-01

    The low temperature heat capacities of single crystals of fully protonated acetylsalicylic acid, measured between 2 K < T < 80 K, have been compared to samples in which the methyl-group was replaced by CD3, CH2D and 13CH3. For the partially methyl-deuterated crystal (CH2D) a significant excess heat capacity was found below T < 40 K with a broad maximum around T ≈ 14 K. The thermodynamic data are explained on the basis of a Schottky model using results obtained in earlier NMR and neutron spectroscopic experiments. In contrast, the excess heat capacity of the fully deuterated compound can be explained by a change of the phonon density of states.

  2. Synthesis, characterisation and biological evaluation of copper and silver complexes based on acetylsalicylic acid.

    PubMed

    Rubner, Gerhard; Bensdorf, Kerstin; Wellner, Anja; Bergemann, Silke; Gust, Ronald

    2011-10-01

    Metalcarbonyl complexes with ligands derived from acetylsalicylic acid demonstrated high cytotoxic potential against various tumor cell lines and strong inhibition of the cyclooxygenase enzymes COX-1 and 2. In this study we tried to achieve comparable effects with [alkyne]silver or copper trifluoromethanesulfonate complexes which are more hydrophilic then the uncharged metalcarbonyl derivatives. All compounds were evaluated for growth inhibition against breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1 and COX-2 inhibitory effects at isolated isoenzymes. Pure ligands showed neither cytotoxic nor COX-inhibitory effects. While the silver complexes of (but-2-ynyl)-2-acetoxybenzoate (But-ASS-Ag) and (but-2-yne-1,4-diyl)-bis(2-acetoxybenzoate) (Di-ASS-But-Ag) were strong cytostatics, only the copper complex Di-ASS-But-Cu was active. At the COX enzymes the complexes were more effective than their ligands and aspirin.

  3. Acetylsalicylic-acid-containing drugs and nonsteroidal anti-inflammatory drugs available in Canada.

    PubMed

    Brigden, M; Smith, R E

    1997-04-01

    A large number of drugs containing acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are available by prescription and over the counter in Canada. The possibility of serious side effects and drug interactions is therefore high. The authors have compiled a comprehensive list of products containing these drugs from information supplied by pharmaceutical databases, independent marketing researchers and Health Canada's Drug Directorate. Physicians should ensure that additional ASA-containing drugs or NSAIDs are not inadvertently taken by patients, especially those receiving oral anticoagulant therapy or those with a qualitative platelet defect. Patients at risk should be cautioned to check with their physician before taking any new medication, even over-the-counter products.

  4. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis.

    PubMed

    Kristensen, D M; Lesné, L; Le Fol, V; Desdoits-Lethimonier, C; Dejucq-Rainsford, N; Leffers, H; Jégou, B

    2012-06-01

    More than half the pregnant women in the Western world report taking mild analgesics. These pharmaceutical compounds have been associated with congenital cryptorchidism in humans, the best-known risk factor for low semen quality and testicular germ cell cancer. Furthermore, some of these mild analgesics exert potent anti-androgenic effects in the male rat and several endocrine-disrupting compounds, known to alter masculinization, have also been shown to be potent inhibitors of prostaglandin (PG) synthesis similar to mild analgesics. Using a 3-day ex vivo organotypic model system based on gestational day 14.5 rat testes, we herein show that testosterone production was inhibited by paracetamol, at doses of 0.1 μm to 100 μm. Similar results were obtained for aspirin (1-100 μm) and indomethacin (10 μm). The production of the other Leydig cell hormone, Insl3, was not disrupted by exposure to paracetamol. Investigations of the gross anatomy of the testis as well as Leydig cells number and rate of gonocyte apoptosis after the 3 days of ex vivo differentiation showed no significant effect of the analgesics tested compared with controls. These data indicate therefore that mild analgesics specifically inhibit testosterone production in rat foetal testes in vitro and that these compounds had no effect on gonocyte survival. Parallel determinations of prostaglandin D2 (PGD2) production indicated that the effects of paracetamol and aspirin on PGD2 and testosterone were not connected, whereas the effects of indomethacin were correlated. We conclude that mild analgesics exert direct and specific anti-androgenic effects in rat foetal testis in our experimental setup and that the mechanism of action is probably uncoupled from the inhibition of PG synthesis.

  5. Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men

    PubMed Central

    2014-01-01

    Background Previous studies have suggested that DNA methylation contributes to coronary artery disease (CAD) risk variability. DNA hypermethylation at the ATP-binding cassette transporter A1 (ABCA1) gene, an important modulator of high-density lipoprotein cholesterol and reverse cholesterol transport, has been previously associated with plasma lipid levels, aging and CAD, but the association with CAD has yet to be replicated. Results ABCA1 DNA methylation levels were measured in leucocytes of 88 men using bis-pyrosequencing. We first showed that DNA methylation at the ABCA1 gene promoter locus is associated with aging and CAD occurrence in men (P < 0.05). The latter association is stronger among older men with CAD (≥61 years old; n = 19), who showed at least 4.7% higher ABCA1 DNA methylation levels as compared to younger men with CAD (<61 years old; n = 19) or men without CAD (n = 50; P < 0.001). Higher ABCA1 DNA methylation levels in older men were also associated with higher total cholesterol (r = 0.34, P = 0.03), low-density lipoprotein cholesterol (r = 0.32, P = 0.04) and triglyceride levels (r = 0.26, P = 0.09). Furthermore, we showed that acetylsalicylic acid therapy is associated with 3.6% lower ABCA1 DNA methylation levels (P = 0.006), independent of aging and CAD status of patients. Conclusions This study provides new evidence that the ABCA1 epigenetic profile is associated with CAD and aging, and highlights that epigenetic modifications might be a significant molecular mechanism involved in the pathophysiological processes associated with CAD. Acetylsalicylic acid treatment for CAD prevention might involve epigenetic mechanisms. PMID:25093045

  6. Effect of tocopherol and acetylsalicylic acid on the biochemical indices of blood in dioxin-exposed rats.

    PubMed

    Rosińczuk, Joanna; Całkosiński, Ireneusz

    2015-07-01

    New sources of dioxins and increased dioxin concentrations in the environment, coupled with their increased bioavailability along the food chain and accumulation in adipose tissues, contribute to various adverse long-term biological effects. The purpose of the study was to determine whether tocopherol protects the CNS by decreasing the pro-inflammatory influence of free radicals generated by TCDD; whether acetylsalicylic acid inhibits the production of inflammatory mediators; and whether the combined administration of tocopherol and acetylsalicylic acid to TCDD-exposed rats has a potential CNS-protective effect. The study included 117 rats divided into 8 groups: 75 female and 12 male Buffalo rats aged 8-10 weeks, weighing 140-160 g; as well as 30 female rats aged 6 weeks and weighing 120 g, which were the offspring of females from each study group. In the experiment, the following substances were used: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dosed at 5 μg/kg BW and 12.5 μg/kg BW, diluted in a 1% DMSO solution at the concentration of 1 μg/ml; α-tocopherol acetate, dosed at 30 mg/kg BW, in 0.2 ml of oil solution; and acetylsalicylic acid, 50mg/kg BW, suspended in 0.5 ml of starch solution, administered orally using a feeding tube. Pleurisy was induced by an injection of 0.15 ml of 1% carrageenin solution. The use of tocopherol reduces the adverse effects of the inflammatory reaction induced by TCDD. Administering tocopherol improves protein metabolism by reducing protein catabolism, and raises γ-globulin fraction levels. Combined acetylsalicylic acid and tocopherol suppress catabolic processes accompanying inflammation.

  7. Acetylsalicylic Acid Inhibits IL-18-Induced Cardiac Fibroblast Migration Through the Induction of RECK

    PubMed Central

    SIDDESHA, JALAHALLI M.; VALENTE, ANTHONY J.; SAKAMURI, SIVA S.V.P.; GARDNER, JASON D.; DELAFONTAINE, PATRICE; NODA, MAKOTO; CHANDRASEKAR, BYSANI

    2015-01-01

    The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18 induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18 induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Spl-mediated RECK suppression, mechanisms that required Nox4-dependent H2O2 generation. Notably, forced expression of RECK attenuated IL-18 induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18 induced H2O2 generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18 induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms. PMID:24265116

  8. Acetylsalicylic acid regulates MMP-2 activity and inhibits colorectal invasion of murine B16F0 melanoma cells in C57BL/6J mice: effects of prostaglandin F(2)alpha.

    PubMed

    Tsai, Chin-Shaw Stella; Luo, Shue-Fen; Ning, Chung-Chu; Lin, Chien-Liang; Jiang, Ming-Chung; Liao, Ching-Fong

    2009-08-01

    Epidemiological studies indicate that acetylsalicylic acid may reduce the risk of mortality due to colon cancers. Metastasis is the major cause of cancer death. Matrix metalloproteinases (MMPs) play important roles in tumor invasion regulation, and prostaglandin F(2)alpha (PGF(2)alpha) is a key stimulator of MMP production. Thus, we investigated whether acetylsalicylic acid regulated MMP activity and the invasion of cancer cells and whether PGF(2)alpha attenuated acetylsalicylic acid-inhibited invasion of cancer cells. Gelatin-based zymography assays showed that acetylsalicylic acid inhibited the MMP-2 activity of B16F0 melanoma cells. Matrigel-based chemoinvasion assays showed that acetylsalicylic acid inhibited the invasion of B16F0 cells. Acetylsalicylic acid can inhibit PGF(2)alpha synthesis and PGF(2)alpha is a key stimulator of MMP-2 production. Our data showed that PGF(2)alpha treatment attenuated the acetylsalicylic acid-inhibited invasion of B16F0 cells. In animal experiments, acetylsalicylic acid reduced colorectal metastasis of B16F0 cells in C57BL/6J mice by 44%. Our results suggest that PGF(2)alpha is a therapeutic target for metastasis inhibition and acetylsalicylic acid may possess anti-metastasis ability.

  9. Local sustained delivery of acetylsalicylic acid via hybrid stent with biodegradable nanofibers reduces adhesion of blood cells and promotes reendothelialization of the denuded artery.

    PubMed

    Lee, Cheng-Hung; Lin, Yu-Huang; Chang, Shang-Hung; Tai, Chun-Der; Liu, Shih-Jung; Chu, Yen; Wang, Chao-Jan; Hsu, Ming-Yi; Chang, Hung; Chang, Gwo-Jyh; Hung, Kuo-Chun; Hsieh, Ming-Jer; Lin, Fen-Chiung; Hsieh, I-Chang; Wen, Ming-Shien; Huang, Yenlin

    2014-01-01

    Incomplete endothelialization, blood cell adhesion to vascular stents, and inflammation of arteries can result in acute stent thromboses. The systemic administration of acetylsalicylic acid decreases endothelial dysfunction, potentially reducing thrombus, enhancing vasodilatation, and inhibiting the progression of atherosclerosis; but, this is weakened by upper gastrointestinal bleeding. This study proposes a hybrid stent with biodegradable nanofibers, for the local, sustained delivery of acetylsalicylic acid to injured artery walls. Biodegradable nanofibers are prepared by first dissolving poly(D,L)-lactide-co-glycolide and acetylsalicylic acid in 1,1,1,3,3,3-hexafluoro-2-propanol. The solution is then electrospun into nanofibrous tubes, which are then mounted onto commercially available bare-metal stents. In vitro release rates of pharmaceuticals from nanofibers are characterized using an elution method, and a highperformance liquid chromatography assay. The experimental results suggest that biodegradable nanofibers release high concentrations of acetylsalicylic acid for three weeks. The in vivo efficacy of local delivery of acetylsalicylic acid in reducing platelet and monocyte adhesion, and the minimum tissue inflammatory reaction caused by the hybrid stents in treating denuded rabbit arteries, are documented. The proposed hybrid stent, with biodegradable acetylsalicylic acid-loaded nanofibers, substantially contributed to local, sustained delivery of drugs to promote re-endothelialization and reduce thrombogenicity in the injured artery. The stents may have potential applications in the local delivery of cardiovascular drugs. Furthermore, the use of hybrid stents with acetylsalicylic acid-loaded nanofibers that have high drug loadings may provide insight into the treatment of patients with high risk of acute stent thromboses.

  10. Dual effects of acetylsalicylic acid on ERK signaling and Mitf transcription lead to inhibition of melanogenesis.

    PubMed

    Nishio, Takashi; Usami, Mai; Awaji, Mizuki; Shinohara, Sumire; Sato, Kazuomi

    2016-01-01

    Acetylsalicylic acid (ASA) is widely used as an analgesic/antipyretic drug. It exhibits a wide range of biological effects, including preventative effects against heart attack and stroke, and the induction of apoptosis in various cancer cells. We previously found that ASA inhibits melanogenesis in B16 melanoma cells. However, the mechanisms of how ASA down-regulates melanin synthesis remain unclear. Here, we investigated the effect of ASA on melanogenic pathways, such as extracellular signal-regulated kinase (ERK) and microphthalmia-associated transcription factor (Mitf) transcription. ASA significantly inhibited melanin synthesis in a dose-dependent manner without oxidative stress and cell death. Semi-quantitative reverse transcription-polymerase chain reaction analysis showed that the inhibitory effect of ASA might be due to the inhibition of Mitf gene transcription. Interestingly, ASA also induced ERK phosphorylation. Additionally, treatment with PD98059, a specific ERK phosphorylation inhibitor, abolished the anti-melanogenic effect of ASA. These results suggest that the depigmenting effect of ASA results from down-regulation of Mitf, which is induced by both the induction of ERK phosphorylation and the inhibition of Mitf transcription.

  11. Effects of Acetylsalicylic Acid Usage on Inflammatory and Oxidative Stress Markers in Hemodialysis Patients.

    PubMed

    Maniglia, Fabíola Pansani; da Costa, José Abrão Cardeal

    2016-02-01

    The aims of this study were to determine the effects of acetylsalicylic acid (ASA) on inflammation and oxidative stress markers in hemodialysis (HD) patients and to examine the associations between these markers and the sociodemographic and clinical characteristics of participants. The study included 36 subjects who used 300 mg of ASA for 60 days. Inflammation and oxidative stress were assessed based on levels of biochemical markers. ASA usage promoted a decrease in high-sensitivity C-reactive protein (p = 0.01). The level of hydrogen peroxide increased after 30 days of use of ASA and subsequently decreased (p = 0.01). Reduced glutathione reduced at the end of the study (p < 0.01); the malondialdehyde level did not change and the levels of vitamins A and E were inverse to drug use (p = 0.01). ASA usage promoted reduced levels of inflammation, increased production of markers of oxidative stress, and reduced antioxidant defense.

  12. Low-dose acetylsalicylic acid and bleeding risks with ventriculoperitoneal shunt placement.

    PubMed

    Kamenova, Maria; Croci, Davide; Guzman, Raphael; Mariani, Luigi; Soleman, Jehuda

    2016-09-01

    OBJECTIVE Ventriculoperitoneal (VP) shunt placement is a common procedure for the treatment of hydrocephalus following diverse neurosurgical conditions. Most of the patients present with other comorbidities and receive antiplatelet therapy, usually acetylsalicylic acid (ASA). Despite its clinical relevance, the perioperative management of these patients has not been sufficiently investigated. The aim of this study was to compare the peri- and postoperative bleeding complication rates associated with ASA intake in patients undergoing VP shunt placement. METHODS Of 172 consecutive patients undergoing VP shunt placement between June 2009 and December 2015, 40 (23.3%) patients were receiving low-dose ASA treatment. The primary outcome measure was bleeding events in ASA users versus nonusers, whereas secondary outcome measures were postoperative cardiovascular events, hematological findings, morbidity, and mortality. A subgroup analysis was conducted in patients who discontinued ASA treatment for < 7 days (n = 4, ASA Group 1) and for ≥ 7 days (n = 36, ASA Group 2). RESULTS No statistically significant difference for bleeding events was observed between ASA users and nonusers (p = 0.30). Cardiovascular complications, surgical morbidity, and mortality did not differ significantly between the groups either. Moreover, there was no association between ASA discontinuation regimens (< 7 days and ≥ 7 days) and hemorrhagic events. CONCLUSIONS Given the lack of guidelines regarding perioperative management of neurosurgical patients with antiplatelet therapy, these findings elucidate one issue, showing comparable bleeding rates in ASA users and nonusers undergoing VP shunt placement.

  13. Simultaneous quantification of paracetamol, acetylsalicylic acid and papaverine with a validated HPLC method.

    PubMed

    Kalmár, Eva; Gyuricza, Anett; Kunos-Tóth, Erika; Szakonyi, Gerda; Dombi, György

    2014-01-01

    Combined drug products have the advantages of better patient compliance and possible synergic effects. The simultaneous application of several active ingredients at a time is therefore frequently chosen. However, the quantitative analysis of such medicines can be challenging. The aim of this study is to provide a validated method for the investigation of a multidose packed oral powder that contained acetylsalicylic acid, paracetamol and papaverine-HCl. Reversed-phase high-pressure liquid chromatography was used. The Agilent Zorbax SB-C18 column was found to be the most suitable of the three different stationary phases tested for the separation of the components of this sample. The key parameters in the method development (apart from the nature of the column) were the pH of the aqueous phase (set to 3.4) and the ratio of the organic (acetonitrile) and the aqueous (25 mM phosphate buffer) phases, which was varied from 7:93 (v/v) to 25:75 (v/v) in a linear gradient, preceded by an initial hold. The method was validated: linearity, precision (repeatability and intermediate precision), accuracy, specificity and robustness were all tested, and the results met the ICH guidelines.

  14. Biowaiver monograph for immediate-release solid oral dosage forms: acetylsalicylic acid.

    PubMed

    Dressman, Jennifer B; Nair, Anita; Abrahamsson, Bertil; Barends, Dirk M; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James E; Shah, Vinod P; Zimmer, Markus

    2012-08-01

    A biowaiver monograph for acetylsalicylic acid (ASA) is presented. Literature and experimental data indicate that ASA is a highly soluble and highly permeable drug, leading to assignment of this active pharmaceutical ingredient (API) to Class I of the Biopharmaceutics Classification System (BCS). Limited bioequivalence (BE) studies reported in the literature indicate that products that have been tested are bioequivalent. Most of the excipients used in products with a marketing authorization in Europe are not considered to have an impact on gastrointestinal motility or permeability. Furthermore, ASA has a wide therapeutic index. Thus, the risks to the patient that might occur if a nonbioequivalent product were to be incorrectly deemed bioequivalent according to the biowaiver procedure appear to be minimal. As a result, the BCS-based biowaiver procedure can be recommended for approval of new formulations of solid oral dosage forms containing ASA as the only API, including both multisource and reformulated products, under the following conditions: (1) excipients are chosen from those used in ASA products already registered in International Conference on Harmonization and associated countries and (2) the dissolution profiles of the test and the comparator products comply with the BE guidance.

  15. Water-soluble nitric-oxide-releasing acetylsalicylic acid (ASA) prodrugs.

    PubMed

    Rolando, Barbara; Lazzarato, Loretta; Donnola, Monica; Marini, Elisabetta; Joseph, Sony; Morini, Giuseppina; Pozzoli, Cristina; Fruttero, Roberta; Gasco, Alberto

    2013-07-01

    A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH 1) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO-donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. Simple NO-donor benzoic acids 3-hydroxy-4-(3-nitrooxypropoxy)benzoic acid (28) and 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoic acid (48) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300 μM. Only 28 displays quite potent NO-dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2-(acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3-(nitrooxy)propoxy]benzoate⋅HCl (38) and {[2-(acetyloxy)benzoyl]oxy}methyl 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoate oxalate (49), revealed that their anti-inflammatory activities are similar to that of ASA when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO-donor ASA prodrugs warrant further investigation for clinical application.

  16. Development and validation of a liquid chromatographic method for purity control of clopidogrel-acetylsalicylic acid in combined oral dosage forms.

    PubMed

    Kahsay, Getu; Van Schepdael, Ann; Adams, Erwin

    2012-03-05

    A reversed phase liquid chromatographic method with UV detection for the simultaneous determination of clopidogrel and acetylsalicylic acid and their related substances in combined oral formulations was developed and validated. Good separation was achieved on a Luna C18 column (150 mm × 4.6 mm, 3 μm) using gradient elution at a flow rate of 1 mL/min and a column temperature of 35 °C. UV detection was performed at 220 nm. The validation was performed according to the ICH guidelines. The method proved to be specific, sensitive (LOQ=0.975 μg/mL and 0.0384 μg/mL for clopidogrel and acetylsalicylic acid, respectively), linear in the concentration range from LOQ to 325 μg/mL for clopidogrel and from LOQ to 650 μg/mL for acetylsalicylic acid, precise (RSD values for intermediate precision <1%) and accurate with mean recovery values of 100.7% and 100.2% for clopidogrel and acetylsalicylic acid, respectively. Moreover, the solution stability and method robustness were examined. The method gives satisfactory separation of impurities of clopidogrel and acetylsalicylic acid and so it is suitable for quantification of the related substances as well as for the assay of the actives.

  17. Acetylsalicylic acid provides cerebrovascular protection from oxidant damage in salt-loaded stroke-prone rats.

    PubMed

    Ishizuka, Toshiaki; Niwa, Atsuko; Tabuchi, Masaki; Ooshima, Kana; Higashino, Hideaki

    2008-03-26

    Inflammatory processes may play a pivotal role in the pathogenesis of cerebrovascular injury in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Recent reports revealed that acetylsalicylic acid (aspirin) has anti-oxidative properties and elicits nitric oxide release by a direct activation of the endothelial NO synthase. The present study was designed to determine whether low-dose aspirin might prevent cerebrovascular injury in salt-loaded SHRSP by protecting oxidative damage. Nine-week-old SHRSP were fed a 0.4% NaCl or a 4% NaCl diet with or without treatment by naproxen (20 mg/kg/day), salicylic acid (5 mg/kg/day), or aspirin (5 mg/kg/day) for 5 weeks. Blood pressure, blood brain barrier impairment, mortality, and the parameters of cerebrovascular inflammation and damage were compared among them. High salt intake in SHRSP significantly increased blood brain barrier impairment and early mortality, which were suppressed by treatment with aspirin independent of changes in blood pressure. Salt loading significantly increased superoxide production in basilar arteries of SHRSP, which were significantly suppressed by treatment with aspirin. Salt loading also significantly decreased NOS activity in the basilar arteries of SHRSP, which were significantly improved by treatment with aspirin. At 5 weeks after salt loading, macrophage accumulation and matrix metalloproteinase-9 activity at the stroke-negative area in cerebral cortex of SHRSP were significantly reduced by treatment with aspirin. These results suggest that low-dose aspirin may exert protective effects against cerebrovascular inflammation and damage by salt loading through down-regulation of superoxide production and induction of nitric oxide synthesis.

  18. Impact of Acetylsalicylic Acid on the Clinicopathological Characteristics and Prognosis of Patients with Invasive Breast Cancer

    PubMed Central

    Sendur, Mehmet A.N.; Aksoy, Sercan; Ozdemir, Nuriye Y.; Zengin, Nurullah; Altundag, Kadri

    2014-01-01

    Summary Background The impact of acetylsalicylic acid (ASA) on the clinicopathological characteristics of breast cancer has not yet been elucidated in detail; we therefore aimed to investigate the effects of ASA on the clinicopathological characteristics of patients with breast cancer. Patients and Methods Patients diagnosed with breast cancer were retrospectively analyzed. Breast cancer patients who were taking ASA at the time of breast cancer diagnosis were enrolled as ASA users (n = 84); matching patients with the same age who were not taking ASA were included as control group (n = 890). Results The median age was 56 (range 34–82) years in both groups. ASA users had a significantly lower incidence of grade II–III tumors compared to non-users (P = 0.02). The other clinicopathological characteristics and treatment histories were similar in both groups. In patients using ASA, the disease-free survival (DFS) rate was 97.3%, 89.4%, and 79.9% and in non-users it was 94.1%, 81.8%, and 70.9% in the 1rst, 3rd, and 5th year, respectively (P = 0.01). In aspirin users, the overall survival rate was 95.0%, 90.6%, and 87.6% and in non-users it was 98.1%, 91.2%, and 85.5% in the 1rst, 3rd, and 5th year, respectively (P = 0.50). Conclusion Using ASA at the time of breast cancer diagnosis was associated with significantly improved DFS in breast cancer patients. PMID:25404885

  19. A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man.

    PubMed

    Raghoebar, M; Vrancx, F; Van Ginneken, C A

    1986-01-01

    Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were: Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic? Measurement of the kinetic parameters of ASA: first-pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half-lives, etc. Comparison of the formulations. Most of the formulations yield mean residence times for ASA of 0.3-1.0 h, which do not differ significantly (p greater than 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min-1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way. No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under 'artificial mistakes'.

  20. [Cost-effectiveness analysis of prevention of reinfarction using low-dose acetylsalicylic acid; model calculation].

    PubMed

    Schädlich, P K; Brecht, J G

    1997-01-01

    The purpose of this study is to estimate the potential of savings which can be achieved by prophylaxis of myocardial reinfarction with low-dose acetylsalicylic acid (ASA) at 75 mg per day over a treatment period of two years. After secondary analysis of published data, the effectiveness of low-dose ASA is compared to placebo by a model calculation. The difference in the effectiveness between the prophylaxis with ASA and placebo is taken from an international meta-analysis. The economic valuation of this difference is carried out by a cost-effectiveness analysis applying disease costs per case. According to the model calculation, 5535 DM can be saved per patient with a history of myocardial infarction with 75 mg ASA a day over a treatment period of two years. In 1991 there were around 740,000 patients with a history of myocardial infarction in the age group of 25-64 in the Old Bundesländer of the Federal Republic of Germany. The application of the results of the model calculation would lead to considerable savings. Even in the sensitivity analysis with different assumptions regarding costs incurred by hospital treatment and costs incurred by premature retirement, the cost advantage of the ASA-prophylaxis remains. Due to the cautious and conservative assumptions in the model calculation the potential of savings is likely underestimated. Nevertheless, there is a distinct advantage for the prophylaxis with low-dose ASA which already occurs in direct costs thus leading to advantages also for cost carriers.

  1. Succinate reverses in-vitro platelet inhibition by acetylsalicylic acid and P2Y receptor antagonists.

    PubMed

    Spath, Brigitte; Hansen, Arne; Bokemeyer, Carsten; Langer, Florian

    2012-01-01

    High on-treatment platelet reactivity has been associated with adverse cardiovascular events in patients receiving anti-platelet agents, but the molecular mechanisms underlying this phenomenon remain incompletely understood. Succinate, a citric acid cycle intermediate, is released into the circulation under conditions of mitochondrial dysfunction due to hypoxic organ damage, including sepsis, stroke, and myocardial infarction. Because the G protein-coupled receptor (GPCR) for succinate, SUCNR1 (GPR91), is present on human platelets, we hypothesized that succinate-mediated platelet stimulation may counteract the pharmacological effects of cyclooxygenase-1 and ADP receptor antagonists. To test this hypothesis in a controlled in-vitro study, washed platelets from healthy donors were treated with acetylsalicylic acid (ASA) or small-molecule P2Y(1) or P2Y(12) inhibitors and subsequently analyzed by light transmittance aggregometry using arachidonic acid (AA), ADP and succinate as platelet agonists. Aggregation in response to succinate alone was highly variable with only 29% of donors showing a (mostly delayed) platelet response. In contrast, succinate reproducibly and concentration-dependently (10-1000 µM) enhanced platelet aggregation in response to low concentrations of exogenous ADP. Furthermore, while succinate alone had no effect in the presence of platelet inhibitors, responsiveness of platelets to ADP after pretreatment with P2Y(1) or P2Y(12) antagonists was fully restored, when platelets were co-stimulated with 100 µM succinate. Similarly, succinate completely (at 1000 µM) or partially (at 100 µM) reversed the inhibitory effect of ASA on AA-induced platelet aggregation. In contrast, succinate failed to restore platelet responsiveness in the presence of both ASA and the P2Y(12) antagonist, suggesting that concomitant signaling via different GPCRs was required. Essentially identical results were obtained, when flow cytometric analysis of surface CD62P

  2. Effects of acetylsalicylic acid on fresh weight pigment and protein content of bean leaf discs (Phaseolus vulgaris L.).

    PubMed

    Canakçi, S

    2003-01-01

    The effects of 100, 250, and 500 ppm acetylsalicylic acid solutions treatments on weight alteration, pigment and protein amounts in discs from the primary leaves of one month old bean (Phaseolus vulgaris L.) seedlings produced tinder greenhouse conditions are presented. The experiments show that: 100 ppm ASA had no significant influence (P > 0.05) but 250 and 500 ppm ASA caused an increase on weight loss (P < 0.01); ASA at higher concentrations (250 and 500 ppm), generally, caused a decrease on pigment amounts (P < 0.05-P < 0.01) but 100 ppm ASA had no considerably significant influence on them (P > 0.05), none of the ASA treatments caused a statistically significant influence on carotenoid amount (P > 0.05); 100 and 250 ppm ASA treatments did not cause a significant influence on protein amount (P > 0.05). however 500 ppm ASA treatment caused an increase on protein injury (P < 0.05). Consequently, it is supposed that wet weight loss, pigment and protein injury have somewhat increased on leaf discs. depending on the toxic effect of high acetylsalicylic acid concentrations.

  3. Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism

    PubMed Central

    Welham, Simon J M; Sparrow, Alexander J; Gardner, David S; Elmes, Matthew J

    2017-01-01

    AIM To evaluate the effects of the non-selective, non-steroidal anti-inflammatory drug (NSAID) acetylsalicylic acid (ASA), on ex vivo embryonic kidney growth and development. METHODS Pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA (0.04-0.4 mg/mL) for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 μmol/L prostaglandin E2 (PGE2) for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous (PTGS2-/- and PTGS2-/+) embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal microscopy. RESULTS Increasing ASA concentration (0.1, 0.2 and 0.4 mg/mL) significantly inhibited metanephric growth (P < 0.05). After 7 d of culture, exposure to 0.2 mg/mL and 0.4 mg/mL reduced organ size to 53% and 23% of control organ size respectively (P < 0.01). Addition of 10 μmol/L PGE2 to culture media after exposure to 0.2 mg/mL ASA for 48 h resulted in a return of growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 μmol/L PGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% (0.2 mg/mL; P < 0.05) and 47% (0.4 mg/mL; P < 0.01). Finally, growth of PTGS2-/- and PTGS2+/- kidneys in organ culture showed no differences, indicating that PTGS2 derived PGE2 may at best have a minor role. CONCLUSION ASA reduces early renal growth and development but the

  4. Promoting endothelial recovery and reducing neointimal hyperplasia using sequential-like release of acetylsalicylic acid and paclitaxel-loaded biodegradable stents

    PubMed Central

    Lee, Cheng-Hung; Yu, Chia-Ying; Chang, Shang-Hung; Hung, Kuo-Chun; Liu, Shih-Jung; Wang, Chao-Jan; Hsu, Ming-Yi; Hsieh, I-Chang; Chen, Wei-Jan; Ko, Yu-Shien; Wen, Ming-Shien

    2014-01-01

    Introduction This work reports on the development of a biodegradable dual-drug-eluting stent with sequential-like and sustainable drug-release of anti-platelet acetylsalicylic acid and anti-smooth muscle cell (SMC) proliferative paclitaxel. Methods To fabricate the biodegradable stents, poly-L-lactide strips are first cut from a solvent-casted film. They are rolled onto the surface of a metal pin to form spiral stents. The stents are then consecutively covered by acetylsalicylic acid and paclitaxel-loaded polylactide-polyglycolide nanofibers via electrospinning. Results Biodegradable stents exhibit mechanical properties that are superior to those of metallic stents. Biodegradable stents sequentially release high concentrations of acetylsalicylic acid and paclitaxel for more than 30 and 60 days, respectively. In vitro, the eluted drugs promote endothelial cell numbers on days 3 and 7, and reduce the proliferation of SMCs in weeks 2, 4, and 8. The stents markedly inhibit the adhesion of platelets on days 3, 7, and 14 relative to a non-drug-eluting stent. In vivo, the implanted stent is intact, and no stent thrombosis is observed in the stent-implanted vessels without the administration of daily oral acetylsalicylic acid. Promotion of endothelial recovery and inhibition of neointimal hyperplasia are also observed on the stented vessels. Conclusion The work demonstrates the efficiency and safety of the biodegradable dual-drug-eluting stents with sequential and sustainable drug release to diseased arteries. PMID:25206303

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

    PubMed

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

    2013-04-01

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

  6. Simultaneous determination of acetylsalicylic acid, paracetamol and caffeine using solid-phase molecular fluorescence and parallel factor analysis.

    PubMed

    Alves, Julio Cesar L; Poppi, Ronei J

    2009-05-29

    This paper describes the determination of acetylsalicylic acid (ASA), paracetamol and caffeine in pharmaceutical formulations using solid-phase molecular fluorescence and second order multivariate calibration. This methodology is applicable even in the presence of unknown interferences and with spectral overlap of the components in the mixture. Parallel factor analysis (PARAFAC) was used for model development, whose effectiveness was demonstrated by analysis of variance (ANOVA). Errors below 10% were obtained for all compounds using an external validation set. Benefits of the new procedures not included in the reference methods such as low cost, no need of sample preparation, simple and fast analysis using fluorescence spectrometer and no generation of waste, make this method very attractive, allowing for the simultaneous determination of compounds with good reproducibility and accuracy.

  7. Simultaneous determination of acetylsalicylic acid and salicylic acid in human plasma by isocratic high-pressure liquid chromatography with post-column hydrolysis and fluorescence detection.

    PubMed

    Hobl, Eva-Luise; Jilma, Bernd; Ebner, Josef; Schmid, Rainer W

    2013-06-01

    A selective, sensitive and rapid high-performance liquid chromatography method with post-column hydrolysis and fluorescence detection was developed for the simultaneous quantification of acetylsalicylic acid and its metabolite salicylic acid in human plasma. Following the addition of 2-hydroxy-3-methoxybenzoic acid as internal standard and simple protein precipitation with acetonitrile, the analytes were separated on a ProntoSIL 120 C18 ace-EPS column (150 × 2 mm, 3 µm) protected by a C8 guard column (5 µm). The mobile phase, 10 mm formic acid in water (pH 2.9) and acetonitrile (70:30, v/v), was used at a flow rate of 0.35 mL/min. After on-line post-column hydrolysis of acetylsalicylic acid (ASA) to salicylic acid (SA) by addition of alkaline solution, the analytes were measured at 290 nm (λex ) and 400 nm (λem ). The method was linear in the concentration ranges between 0.05 and 20 ng/μL for both ASA and SA with a lower limit of quantification of 25 pg/μL for SA and 50 pg/μL for ASA. The limit of detection was 15 pg/μL for SA and 32.5 pg/μL for ASA. The analysis of ASA and SA can be carried out within 8 min; therefore this method is suitable for measuring plasma concentrations of salicylates in clinical routine.

  8. [Study of acetylsalicylic acid role in the potentiation of antiamnesic and neuroprotective properties of piracetam in rats with alloxan diabetes].

    PubMed

    Zhiliuk, V I; Levykh, A E; Mamchur, V I

    2013-01-01

    It has been established that prolonged alloxan-induced hyperglycemia in rats potentiates amnesic properties of scopolamine hydrobromide. It was characterized by shortening of the latent period by 44% (p<0,01) and by 47,7% (p<0,05) after 24 hours and on the 20th day of conditioned passive avoidance test. This effect was accompanied by increase in oxidative modification of proteins and nitric oxide synthesis in the cerebral cortex. Along with this, a significant enhancement of ADP- and collagen-induced platelet aggregation was observed. These processes may play the leading role in the development of cognitive deficit in diabetes. Meanwhile, co-administration of piracetam with acetylsalicylic acid was accompanied by an expressed antiamnetic potential - the reduction of early markers of proteins degradation (aldehydephenylhydrazones, APH) by 21,7% (p<0,05) and late markers of proteins degradation (ketonephenylhydrazones, KPH) by 23,8% (p<0,001) was noted. This combination was 15,7% (p<0,05) more active than piracetam according to the effect upon KPH. NO2-/NO3- level was also decreased by 30,3% (p<0,05) in comparison with alloxan-diabetic rats. The significant anti-platelet effect was observed: degree of collagen-induced platelet aggregation was reduced by 56,8% (p<0,01), ADP (5 μmol/l)-induced - by 31,7% (p<0,01), ADP (20 μmol/l)-induced - by 47,3% (p<0,01) as compared to the hyperglycemic rats. Such an increase in nootropic activity of piracetam may be assumed to be directly related to the ability of acetylsalicylic acid to improve microcirculation in the ischemic areas of the brain in diabetes and probably to its neuroprotective potential.

  9. Formation of molecular complexes of salicylic acid, acetylsalicylic acid, and methyl salicylate in a mixture of supercritical carbon dioxide with a polar cosolvent

    NASA Astrophysics Data System (ADS)

    Petrenko, V. E.; Antipova, M. L.; Gurina, D. L.; Odintsova, E. G.

    2015-08-01

    The solvate structures formed by salicylic acid, acetylsalicylic acid, and methyl salicylate in supercritical (SC) carbon dioxide with a polar cosolvent (methanol, 0.03 mole fractions) at a density of 0.7 g/cm3 and a temperature of 318 K were studied by the molecular dynamics method. Salicylic and acetylsalicylic acids were found to form highly stable hydrogen-bonded complexes with methanol via the hydrogen atom of the carboxyl group. For methyl salicylate in which the carboxyl hydrogen is substituted by a methyl radical, the formation of stable hydrogen bonds with methanol was not revealed. The contribution of other functional groups of the solute to the interactions with the cosolvent was much smaller. An analysis of correlations between the obtained data and the literature data on the cosolvent effect on the solubility of the compounds in SC CO2 showed that the dissolving ability of SC CO2 with respect to a polar organic substance in the presence of a cosolvent increased only when stable hydrogen-bonded complexes are formed between this substance and the cosolvent.

  10. Simultaneous quantitation of acetylsalicylic acid and clopidogrel along with their metabolites in human plasma using liquid chromatography tandem mass spectrometry.

    PubMed

    Chhonker, Yashpal S; Pandey, Chandra P; Chandasana, Hardik; Laxman, Tulsankar Sachin; Prasad, Yarra Durga; Narain, V S; Dikshit, Madhu; Bhatta, Rabi S

    2016-03-01

    The interest in therapeutic drug monitoring has increased over the last few years. Inter- and intra-patient variability in pharmacokinetics, plasma concentration related toxicity and success of therapy have stressed the need of frequent therapeutic drug monitoring of the drugs. A sensitive, selective and rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetylsalicylic acid (aspirin), salicylic acid, clopidogrel and carboxylic acid metabolite of clopidogrel in human plasma. The chromatographic separations were achieved on Waters Symmetry Shield(TM) C18 column (150 × 4.6 mm, 5 µm) using 3.5 mm ammonium acetate (pH 3.5)-acetonitrile (10:90, v/v) as mobile phase at a flow rate of 0.75 mL/min. The present method was successfully applied for therapeutic drug monitoring of aspirin and clopidogrel in 67 patients with coronary artery disease.

  11. Preharvest treatments with malic, oxalic, and acetylsalicylic acids affect the phenolic composition and antioxidant capacity of coriander, dill and parsley.

    PubMed

    El-Zaeddi, Hussein; Calín-Sánchez, Ángel; Nowicka, Paulina; Martínez-Tomé, Juan; Noguera-Artiaga, Luis; Burló, Francisco; Wojdyło, Aneta; Carbonell-Barrachina, Ángel A

    2017-07-01

    The effects of a preharvest treatment with malic (MA), oxalic (OA), or acetylsalicylic (ASA) acid at three concentrations (1, 2 and 3mM) on the bioactivity and antioxidant capacity of coriander, dill, and parsley were investigated. The antioxidant capacity of the herbs extracts was assayed by spectrophotometric methods by using three different analytical methods: ORAC, FRAP, and ABTS; the effects of treatments were very positive in coriander, produced intermediate results in dill, and no effects were found in parsley plants. Polyphenol compounds were identified by LC-MS-QTof and quantified by UPLC-PDA-FL. Thirty phenolic compounds were identified in these three herbs. The major compounds were (i) coriander: dimethoxycinnamoyl hexoside and quercetin-3-O-rutinoside, (ii) dill: neochlorogenic acid and quercetin glucuronide, and (iii) parsley: apigenin-7-apiosylglucoside (apiin) and isorhamnetin-3-O-hexoside. The application of these three organic acids favored the accumulation of phenolic compounds in coriander plants, but had no significant positive effects on dill and parsley. The treatments leading to the best results in all three plants were the application of MA or OA at 1mM.

  12. Acetylsalicylic acid-induced changes in the chemical coding of extrinsic sensory neurons supplying the prepyloric area of the porcine stomach.

    PubMed

    Rytel, L; Calka, J

    2016-03-23

    Acetylsalicylic acid is a popular drug that is commonly used to treat fever and inflammation, but which can also negativity affect the mucosal layer of the stomach, although knowledge concerning its influence on gastric innervation is very scarce. Thus, the aim of the present study was to study the influence of prolonged acetylsalicylic acid supplementation on the extrinsic primary sensory neurons supplying the porcine stomach prepyloric region. Fast Blue (FB) was injected into the above-mentioned region of the stomach. Acetylsalicylic acid was then given orally to the experimental gilts from the seventh day after FB injection to the 27th day of the experiment. After euthanasia, the nodose ganglia (NG) and dorsal root ganglia (DRG) were collected. Sections of these ganglia were processed for routine double-labelling immunofluorescence technique for substance P (SP), calcitonine gene related peptide (CGRP), galanin (GAL), neuronal isoform of nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP). Under physiological conditions within the nodose ganglia, the percentage of the FB-labeled neurons immunoreactive to particular substances ranged between 17.9 ± 2.7% (VIP-like immunoreactive (LI) neurons in the right NG) and 60.4 ± 1.7% (SP-LI cells within the left NG). Acetylsalicylic acid supplementation caused a considerable increase in the expression of all active substances studied within both left and right NG and the percentage of neurons positive to particular substances fluctuated from 47.2 ± 3.6% (GAL-LI neurons in the right NG) to 67.2 ± 2.0% (cells immunoreactive to SP in the left NG). All studied substances were also observed in DRG neurons supplying the prepyloric region of the stomach, but the number of immunoreactive neurons was too small to conduct a statistical analysis. The obtained results show that ASA may influence chemical coding of the sensory neurons supplying the porcine stomach, but the exact mechanisms of this action still

  13. A Prevention of Pre-eclampsia with the Use of Acetylsalicylic Acid and Low-molecular Weight Heparin - Molecular Mechanisms.

    PubMed

    Darmochwal-Kolarz, Dorota; Kolarz, Bogdan; Korzeniewski, Michal; Kimber-Trojnar, Zaneta; Patro-Malysza, Jolanta; Mierzynski, Radzisław; Przegalinska-Kałamucka, Monika; Oleszczuk, Jan

    Pre-eclampsia appears to be the main cause for the maternal and fetal morbidity and mortality. Pregnant women with pre-eclampsia are more likely to be threatened with conditions which potentially may be lethal, such as: disseminated intravascular coagulation, cerebral hemorrhage, liver and renal failure. Pregnancy complicated with pre-eclampsia is also associated with a greater risk for iatrogenic prematurity, intrauterine growth retardation, premature abruption of placenta, and even intrauterine fetal death. In the majority of cases the reasons for arterial hypertension among pregnant women remain obscure. For the past decades, there were many abortive attempts in the use of some microelements, vitamins or specific diets, such as polyunsaturated fatty acids, for the prophylaxis of pre-eclampsia. Recently, it has been shown that a prevention of pre-eclampsia with the use of a lowmolecular- weight heparins (LMWHs) and acetylsalicylic acid (ASA) could considerably reduce the frequency of preeclampsia. In this review, we present the studies concerning the applications of LMWHs and aspirin in the prophylaxis of pre-eclampsia and some important data about the mechanisms of anti-inflammatory actions of LMWHs and ASA.

  14. On the origin of surface imposed anisotropic growth of salicylic and acetylsalicylic acids crystals during droplet evaporation.

    PubMed

    Przybyłek, Maciej; Cysewski, Piotr; Pawelec, Maciej; Ziółkowska, Dorota; Kobierski, Mirosław

    2015-03-01

    In this paper droplet evaporative crystallization of salicylic acid (SA) and acetylsalicylic acid (ASA) crystals on different surfaces, such as glass, polyvinyl alcohol (PVA), and paraffin was studied. The obtained crystals were analyzed using powder X-ray diffraction (PXRD) technique. In order to better understand the effect of the surface on evaporative crystallization, crystals deposited on glass were scraped off. Moreover, evaporative crystallization of a large volume of solution was performed. As we found, paraffin which is non-polar surface promotes formation of crystals morphologically similar to those obtained via bulk evaporative crystallization. On the other hand, when crystallization is carried out on the polar surfaces (glass and PVA), there is a significant orientation effect. This phenomenon is manifested by the reduction of the number of peaks in PXRD spectrum recorded for deposited on the surface crystals. Noteworthy, reduction of PXRD signals is not observed for powder samples obtained after scraping crystals off the glass. In order to explain the mechanism of carboxylic crystals growth on the polar surfaces, quantum-chemical computations were performed. It has been found that crystal faces of the strongest orientation effect can be characterized by the highest surface densities of intermolecular interactions energy (IIE). In case of SA and ASA crystals formed on the polar surfaces the most dominant faces are characterized by the highest adhesive and cohesive properties. This suggests that the selection rules of the orientation effect comes directly from surface IIE densities.

  15. Hydrogen atoms in acetylsalicylic acid (Aspirin): the librating methyl group and probing the potential well in the hydrogen-bonded dimer

    NASA Astrophysics Data System (ADS)

    Wilson, Chick C.

    2001-02-01

    The structure of acetylsalicylic acid (2-(acetoyloxy)benzoic acid; Aspirin) has been studied by variable temperature single crystal neutron diffraction. The usual large torsional librational motion of the terminal methyl group is observed and its temperature dependence analysed using a simple model for the potential, yielding the force constant and barrier height for this motion. In addition, asymmetry of the scattering density of the proton involved in the hydrogen bond forming the carboxylic acid dimer motif is observed at temperatures above 200 K. This asymmetry is discussed in terms of its possible implications for the shape of the hydrogen bonding potential well.

  16. Inhibition of Radiation-Induced Oxidative Damage in the Lung Tissue: May Acetylsalicylic Acid Have a Positive Role?

    PubMed

    Demirel, Can; Kilciksiz, Sevil Cagiran; Gurgul, Serkan; Erdal, Nurten; Yigit, Seyran; Tamer, Lulufer; Ayaz, Lokman

    2016-02-01

    The lung is relatively sensitive to irradiation. It is shown that acetylsalicylic acid (ASA) might reduce oxidative injury and that it has a place in protection from cancer. The aim of this study is to evaluate the potential radioprotective effects of ASA. Whole-body irradiation (6 Gy, single dose) was applied to the rats. Glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels in the lung tissue were measured. Control (C), Radiation (R), Radiation + ASA (R + ASA; received irradiation and 25 mg/kg of ASA intraperitoneally (i.p.)), and Radiation + Amifostine (R + WR-2721; received irradiation and 200 mg/kg of WR-2721 i.p.) groups were used. The MPO levels decreased statistically significantly in the group administered ASA. Histopathologically, a radioprotective effect of ASA was more evident in the R + ASA group. ASA is an agent which has not been used as a radioprotector in the clinic yet, and it is worth supporting with more advanced studies.

  17. The infrared spectra and structure of acetylsalicylic acid (aspirin) and its oxyanion: an ab initio force field treatment

    NASA Astrophysics Data System (ADS)

    Binev, I. G.; Stamboliyska, B. A.; Binev, Y. I.

    1996-05-01

    The structures of acetylsalicylic acid (aspirin) (I) and its oxyanion (II) have been studied by means of infrared spectra and ab initio 3-21 G force field calculations. The 3100-1100 cm -1 region bands of both the aspirin molecule and its oxyanion have been assigned. The theoretical infrared data for the free aspirin anion are in good agreement with the experimental data for aspirin alkali-metal salts in dimethyl sulfoxide- d6. The theoretical geometrical parameters for the isolated aspirin molecule are close to the literature X-ray diffraction data for its dimer in the solid state, except for those of the carboxy group, which participates directly in hydrogen bond formation. The changes in both the spectral and geometrical parameters, caused by the conversion of the aspirin molecule into the anion, are essential, but they are localized mainly within the carboxy group and the adjacent C-Ph bond. This is also true for the changes in the corresponding bond indices and electronic charges.

  18. Increased blood plasma hydrolysis of acetylsalicylic acid in type 2 diabetic patients: a role of plasma esterases.

    PubMed

    Gresner, Peter; Dolník, Martin; Waczulíková, Iveta; Bryszewska, Maria; Sikurová, Libusa; Watala, Cezary

    2006-02-01

    Hydrolysis of acetylsalicylic acid (ASA, aspirin), an antiplatelet drug commonly used in the prevention of stroke and myocardial infarction, seems to play a crucial role in its pharmacological action. Thirty-eight healthy volunteers and 38 type 2 diabetic patients were enrolled to test the hypothesis that the enhanced plasma degradation and lowered bioavailability of ASA in diabetic patients is associated with the attenuation of platelet response. Aspirin esterase activities were tested at pH 7.4 and 5.5. A significantly higher overall aspirin esterase activity was noted at pH 7.4 in the diabetic patients (P<0.003), corresponding to faster ASA hydrolysis (P<0.006). This increased activity was attributable to butyrylcholinesterase and probably to albumin, because it was effectively inhibited by eserine and 4-bis-nitrophenyl phosphate (P<0.01). No significant differences between control and diabetic subjects were found at pH 5.5 in either enzymatic activities or ASA hydrolysis rates. The enhanced plasma ASA degradation in diabetic subjects was significantly associated with the refractoriness of blood platelets to ASA (P<0.05) and modulated by plasma cholesterol (P<0.01). No direct effects of plasma pH or albumin were observed. In conclusion, higher aspirin esterase activity contributes to the lowered response of diabetic platelets to ASA-mediated antiplatelet therapy.

  19. The role of trefoil factor family in apparently healthy subjects administrated gastroprotective agents for the primary prevention of gastrointestinal injuries from low-dose acetylsalicylic acid: a preliminary study.

    PubMed

    Kawai, Takashi; Takagi, Yu; Fukuzawa, Mari; Yamagishi, Tetsuya; Goto, Shinya

    2011-09-01

    It is well-known that acetylsalicylic acid induces gastrointestinal complication. Recently, trefoil factor family has been reported as a mucosal protective factor. We focused on trefoil factor family as one of defensive system for gastrointestinal injuries. The aim of this trial was to evaluate trefoil factor family levels in the serum of healthy subjects with low-dose acetylsalicylic acid. Low-dose acetylsalicylic acid with placebo or proton pump inhibitor or rebamipide were administered in 30 healthy subjects. Transnasal endoscopy was performed at 0, 24 h, 3 and 7 day. Changing of trefoil factor family (1,2,3) and numbers of gastric injuries were evaluated. The numbers of gastric injuries were significantly increased in the placebo group at 3 and 7 days. Injuries in the proton pump inhibitor group were not induced, in the rebamipide group were slightly induced. Trefoil factor family level in the placebo group were decreased in 3 and 7 days compared with prior to starting the trial. Trefoil factor family may have an important association with acetylsalicylic acid-induced gastrointestinal damage. Proton pump inhibitor and rebamipide prevented low-dose acetylsalicylic acid-induced gastrointestinal complications compared with the placebo group.

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

    SciTech Connect

    Blazquez, Alba G.; Briz, Oscar; Gonzalez-Sanchez, Ester; Perez, Maria J.; Ghanem, Carolina I.; Marin, Jose J.G.

    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.

  1. The effect of ethanol on spermatogenesis and fertility in male Sprague-Dawley rats pretreated with acetylsalicylic acid.

    PubMed

    Dare, W N; Noronha, C C; Kusemiju, O T; Okanlawon, O A

    2002-12-01

    Prenatal alcohol is associated with a variety of developmental abnormalies, including neuroanatomical, physical and behavioural features. This study was designed to determine the effects of administration of alcohol, exemplified mostly by ethanol (15 ml/kg, 25%, v/v) and acetylsalicylic acid (ASA, 15 mg/kg) as a representative of nonsteroidal anti-inflammatory drugs, individually and their combination (ethanol 15 ml/kg, 25%, v/v ASA 15 mg/kg) on semen quality and fertility after paternal intraperitoneal administration in Sprague-Dawley rats. In the combination study, the rats received ASA about 1 hour before ethanol administration. The combination experiments were conducted to determine if the effects of ethanol can be prevented by pre-treatment with acetyl salicylic acid (ASA) which has been reported to antagonise the rate-depressant effects of ethanol. All animals received this treatment for ten weeks. Semen parameters were determined and compared with controls. The result showed that when given alone, ethanol significantly reduced the sperm density and percentage of motile spermatozoa relative to controls. Pre-treatment with ASA failed to stop the decrease in sperm density and percentage motility caused by ethanol. Moreover none of the experimental male rats was able to fertilize the females exposed to them despite successful mating demonstrated by the presence of sperm plug. The present study demonstrates that chronic consumption of ethanol or ingestion of ASA has toxic effect on spermatozoa and impairs fertility in male Sprague-Dawley rats. Moreover, pre-treatment with ASA has no effect on the deleterious effects caused by ethanol.

  2. Dissolution testing of acetylsalicylic acid by a channel flow method-correlation to USP basket and intrinsic dissolution methods.

    PubMed

    Peltonen, Leena; Liljeroth, Peter; Heikkilä, Tiina; Kontturi, Kyösti; Hirvonen, Jouni

    2003-08-01

    A new modification of the channel flow dissolution method is introduced together with the theoretical basis to extract the solubility and mass transfer parameters from the dissolution experiments. Correlation of drug dissolution profiles in the channel flow apparatus was evaluated with respect to USP basket and intrinsic dissolution methods at pH 1.2 or 6.8. Acetylsalicylic acid (ASA) was studied as a pure drug substance and as three simple tablet compositions with microcrystalline cellulose (MCC) and/or lactose as excipients. The channel flow measurements of 100% ASA tablets correlated well with the results of intrinsic dissolution tests. In the channel flow method as well as in the USP basket method the release of ASA was fastest from the tablet compositions containing lactose, while the slowest dissolution rate was observed with the composition containing MCC as the only excipient. As presumed, the dissolution rate of the weak acid was decreased as the pH of the medium was lowered, which was clearly confirmed also by the three dissolution methods. MCC forms matrix tablets and in the USP basket method the dissolution profiles followed square root of time kinetics indicating that diffusion was the rate-controlling step of ASA dissolution. Also the channel flow results indicated that the dissolution of ASA was controlled by mass transfer. The swelling behaviour of the tablets is different in the channel flow method as compared to the basket method: only one tablet surface is exposed to the dissolution medium in the channel flow system. The contact between the tablet surface and the dissolution medium is more similar between the channel flow and intrinsic dissolution methods.

  3. Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers.

    PubMed

    Viganò, G; Garagiola, U; Gaspari, F

    1991-01-01

    A single-blind, randomized, crossover pharmacokinetic study was carried out to investigate the bioavailability of a new oral buffered 325 mg acetylsalicylic acid (ASA) formulation (ASPIRINA 03) in comparison with a 325 mg plain tablet. Twelve healthy volunteers of both sexes, aged between 20 and 37 years, received buffered or plain ASA on two separate occasions with a wash-out interval of at least two weeks. ASA and salicylic acid (SA) plasma levels were determined by a chromatographic method. The results showed no difference between the area under concentration time curve (AUC0-infinity) ASA values of both formulations (p = 0.19), and buffered ASA relative bioavailability was 102.49% (= bioequivalence). A significant difference was found between the AUC0-30 min ASA values: 90.5 micrograms. min/ml with buffered and 67.7 micrograms. min/ml with the plain tablet (p less than 0.05). The buffered ASA time of maximum concentration was shorter (28 +/- 8 min) than the plain one (38 +/- 19 min, p less than 0.05). The plasma concentrations and pharmacokinetic parameters of SA were not significantly different after the administration of the two ASA formulations. The plain ASA tablet had a significantly lower (p less than 0.05) dissolution rate than buffered ASA tablet. Moreover, the buffered ASA tablet significantly (p less than 0.01) increased the pH by 0.5 units. In conclusion, the bioavailability of the new oral buffered ASA was equivalent to that of plain ASA, but the plasma concentration peak was reached in a shorter time.

  4. Next-generation re-sequencing of genes involved in increased platelet reactivity in diabetic patients on acetylsalicylic acid.

    PubMed

    Postula, Marek; Janicki, Piotr K; Eyileten, Ceren; Rosiak, Marek; Kaplon-Cieslicka, Agnieszka; Sugino, Shigekazu; Wilimski, Radosław; Kosior, Dariusz A; Opolski, Grzegorz; Filipiak, Krzysztof J; Mirowska-Guzel, Dagmara

    2016-06-01

    The objective of this study was to investigate whether rare missense genetic variants in several genes related to platelet functions and acetylsalicylic acid (ASA) response are associated with the platelet reactivity in patients with diabetes type 2 (T2D) on ASA therapy. Fifty eight exons and corresponding introns of eight selected genes, including PTGS1, PTGS2, TXBAS1, PTGIS, ADRA2A, ADRA2B, TXBA2R, and P2RY1 were re-sequenced in 230 DNA samples from T2D patients by using a pooled PCR amplification and next-generation sequencing by Illumina HiSeq2000. The observed non-synonymous variants were confirmed by individual genotyping of 384 DNA samples comprising of the individuals from the original discovery pools and additional verification cohort of 154 ASA-treated T2DM patients. The association between investigated phenotypes (ASA induced changes in platelets reactivity by PFA-100, VerifyNow and serum thromboxane B2 level [sTxB2]), and accumulation of rare missense variants (genetic burden) in investigated genes was tested using statistical collapsing tests. We identified a total of 35 exonic variants, including 3 common missense variants, 15 rare missense variants, and 17 synonymous variants in 8 investigated genes. The rare missense variants exhibited statistically significant difference in the accumulation pattern between a group of patients with increased and normal platelet reactivity based on PFA-100 assay. Our study suggests that genetic burden of the rare functional variants in eight genes may contribute to differences in the platelet reactivity measured with the PFA-100 assay in the T2DM patients treated with ASA.

  5. Effects of nimesulide, acetylsalicylic acid, ibuprofen and nabumetone on cyclooxygenase-1- and cyclooxygenase-2-mediated prostanoid production in healthy volunteers ex vivo.

    PubMed

    Kerola, Markku; Vuolteenaho, Katriina; Kosonen, Outi; Kankaanranta, Hannu; Sarna, Seppo; Moilanen, Eeva

    2009-01-01

    : The beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with inhibition of cyclooxygenase-2 (COX-2), whereas some of their adverse effects are associated mainly with inhibition of COX-1. Selective COX-2 inhibitors reduce the risk of gastrointestinal adverse events, but increase the risk of thromboembolic events pointing to importance of optimal COX-1/COX-2 inhibition in drug safety. We compared the effects of acetylsalicylic acid, ibuprofen, nabumetone and nimesulide on COX-1 and COX-2 pathways in healthy volunteers in an ex vivo set-up using single oral doses commonly used to treat acute pain. In a randomized, double-blind four-phase cross-over study, 15 healthy volunteers were given orally a single dose of either acetylsalicylic acid 500 mg, ibuprofen 400 mg, nabumetone 1 g or nimesulide 100 mg. Blood samples were drawn before and 1, 3, 6, 24 and 48 hr after the drug for the assessment of COX-1 and COX-2 activity. COX-1 activity was measured as thromboxane(2) production during blood clotting and COX-2 activity as endotoxin-induced prostaglandin E(2) synthesis in blood leucocytes. The data show that after a single oral dose these four NSAIDs have different profiles of action on COX-1 and COX-2. As expected, acetylsalicylic acid appeared to be COX-1-selective and ibuprofen effectively inhibited both COX-1 and COX-2. Nabumetone showed only a slight inhibitory effect on COX-1 and COX-2. Nimesulide caused almost complete suppression of COX-2 activity and a partial reduction of COX-1 activity. This confirms the relative COX-2 selectivity of nimesulide.

  6. Quantification of ascorbic acid and acetylsalicylic acid in effervescent tablets by CZE-UV and identification of related degradation products by heart-cut CZE-CZE-MS.

    PubMed

    Neuberger, Sabine; Jooß, Kevin; Ressel, Christian; Neusüß, Christian

    2016-12-01

    Capillary electrophoresis is commonly applied for the analysis of pharmaceutical products due to its high separation efficiency and selectivity. For this purpose, electrospray-ionization-(ESI)-interfering additives or electrolytes are often required, which complicates the identification of impurities and degradation products by mass spectrometry (MS). Here, a capillary zone electrophoresis (CZE) method with ultraviolet (UV) absorption detection for the simultaneous determination and quantification of ascorbic acid and acetylsalicylic acid in effervescent tablets was developed. Related degradation products were identified via CZE-CZE-MS. Systematic optimization yielded 100 mM tricine (pH = 8.8) as appropriate background electrolyte, resulting in baseline separation of ascorbic acid, acetylsalicylic acid, and related anionic UV-active degradation products. The CZE-UV method was successfully validated regarding the guidelines of the Food and Drug Administration. The validated method was applied to trace the degradation rate of the active pharmaceutical ingredients at defined ambient conditions. A heart-cut CZE-CZE-MS approach, including a 4-port-nL-valve, was performed for the identification of the observed degradation products. This 2D setup enables a precise cutting of accurate sample volumes (20 nL) and the independent operation of two physically separated CZE dimensions, which is especially beneficial regarding MS detection. Hence, the ESI-interfering tricine electrolyte components were separated from the analytes in a second electrophoretic dimension prior to ESI-MS detection. The degradation products were identified as salicylic acid and mono- and diacetylated ascorbic acid. This setup is expected to be generally applicable for the mass spectrometric characterization of CZE separated analytes in highly ESI-interfering electrolyte systems. Graphical Abstract A CZE-UV method for the quantification of effervescent tablet ingredients and degradation products

  7. Application of gas-liquid chromatography and high-performance liquid chromatography to the analysis of trace amounts of salicylic acid, acetylsalicylic anhydride and acetylsalicylsalicylic acid in aspirin samples and aspirin formulations.

    PubMed

    Ali, S L

    1976-11-03

    The gas-liquid chromatographic (GLC) determination of salicylic acid (SA) in 12 commercial acetylsalicylic acid (aspirin, ASA) samples and 12 ASA formulations is reported. The GLC determination of SA as an impurity in ASA, utilising methylation with methyl iodide in the presence of potassium carbonate, requires a column chromatographic separation of SA prior to derivatization. Trace amounts of SA in ASA have also been determined by high-performance liquid chromatography (HPLC) on a Sil-X-I adsorption column using light petroleum-ethyl acetate-acetic acid as the mobile phase. Acetylsalicylic anhydride (ASN) and acetylsalicylsalicylic acid (ASSA) were determined by HPLC on a reversed-phase C18 column with water-methanol mixtures as the mobile phase. GLC was also applied to the determination of ASN as an impurity in ASA formulations.

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

    PubMed

    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.

  9. Rapid and sensitive determination of acetylsalicylic acid and salicylic acid in plasma using liquid chromatography-tandem mass spectrometry: application to pharmacokinetic study.

    PubMed

    Xu, Xiangrong; Koetzner, Lee; Boulet, Jamie; Maselli, Harry; Beyenhof, Jessica; Grover, Gary

    2009-09-01

    A simple and sensitive analytical method using liquid chromatography-tandem mass spectrometry (LC/MS/MS) for determination of acetylsalicylic acid (aspirin, ASA) and its major metabolite, salicylic acid (SA), in animal plasma has been developed and validated. Both ASA and SA in plasma samples containing potassium fluoride were extracted using acetonitrile (protein precipitation) with 0.1% formic acid in it. 6-Methoxysalicylic acid was used as the internal standard (IS). The compounds were separated on a reversed-phase column. The multiple reaction monitoring mode was used with ion transitions of m/z 178.9 --> 136.8, 137.0 --> 93.0 and 167.0 --> 123.0 for ASA, SA and IS, respectively. The lower limits of quantification for ASA and SA were 3 and 30 ng/mL, respectively. The developed method was successfully applied for the evaluation of pharmacokinetics of ASA and SA after p.o. and i.v. administration of 1 mg/kg to rats.

  10. Efficacy of fixed combinations of acetylsalicyclic acid, acetaminophen and caffeine in the treatment of idiopathic headache: a review.

    PubMed

    Anneken, K; Evers, S; Husstedt, I W

    2010-04-01

    Headache is one of the most common reasons for patients to visit their general practitioner. Most of these patients suffer from migraine, tension-type headache, or a combination of the two; they tend to self-medicate using over the counter combination headache preparations, particularly acetylsalicyclic acid (ASA) and acetaminophen coformulated with caffeine, which is one of the most commonly used combination analgesics in these patients worldwide. We reviewed studies on the efficacy and safety of this combination. In the treatment of migraine and tension-type headache, the combination of ASA, acetaminophen, and caffeine has been shown to be more efficacious and superior to monotherapy with the single substances of the combination. According to literature, there is no evidence for higher prevalence of undesirable side-effects of combination analgesics in comparison to monotherapy.

  11. Administration of zinc complex of acetylsalicylic acid after the onset of myocardial injury protects the heart by upregulation of antioxidant enzymes.

    PubMed

    Korkmaz-Icöz, Sevil; Atmanli, Ayhan; Radovits, Tamás; Li, Shiliang; Hegedüs, Peter; Ruppert, Mihály; Brlecic, Paige; Yoshikawa, Yutaka; Yasui, Hiroyuki; Karck, Matthias; Szabó, Gábor

    2016-03-01

    We recently demonstrated that the pre-treatment of rats with zinc and acetylsalicylic acid complex in the form of bis(aspirinato)zinc(II) [Zn(ASA)2] is superior to acetylsalicylic acid in protecting the heart from acute myocardial ischemia. Herein, we hypothesized that Zn(ASA)2 treatment after the onset of an acute myocardial injury could protect the heart. The rats were treated with a vehicle or Zn(ASA)2 after an isoproterenol injection. Isoproterenol-induced cardiac damage [inflammatory infiltration into myocardial tissue, DNA-strand breakage evidenced by TUNEL-assay, increased 11-dehydro thromboxane (TX)B2-levels, elevated ST-segment, widened QRS complex and prolonged QT-interval] was prevented by the Zn(ASA)2 treatment. In isoproterenol-treated rats, load-independent left ventricular contractility parameters were significantly improved after Zn(ASA)2. Furthermore, Zn(ASA)2 significantly increased the myocardial mRNA-expression of superoxide dismutase-1, glutathione peroxidase-4 and decreased the level of Na(+)/K(+)/ATPase. Postconditioning with Zn(ASA)2 protects the heart from acute myocardial ischemia. Its mechanisms of action might involve inhibition of pro-inflammatory prostanoids and upregulation of antioxidant enzymes.

  12. [Ability to Overcome the Thrombocyte Resistance to Acetylsalicylic Acid in Patients With Coronary Artery Disease After Myocardial Revascularization With Coronary Stenting].

    PubMed

    Pershukov, I V; Ostaschenko, S L; Kuznetsova, T N; Scherbo, S N; Karben, Z A; Sokryukina, E V; Omarov, A A; Ramazanov, D M; Bosak, N V; Shulzhenko, L V; Kalmatov, R K; Batyraliev, T A; Sidorenko, B A

    2016-07-01

    Resistance to acetylsalicylic acid (ASA) in patients with coronary artery disease is a poor predictor for the development of atherothrombotic complications. In 277 patients with coronary artery disease suffered uncomplicated coronary angioplasty with stent implantation, we was estimated arachidon-induced platelet aggregation during treatment with acetylsalicylic acid by bedside VerifyNow Assay test at 28-90 days after the intervention. It was found that 18.9% of the 144 patients receiving a combination of ASA 75 mg with 15.2 mg of magnesium hydroxide had true (laboratory) resistance to ASA. At the same time on the original enteric coated ASA 100 mg, we can found only 0.8% resistance to ASA among 129 patients. We made switch from combination of ASA 75 mg with 15.2 mg of magnesium hydroxide to original enteric coated ASA 100 mg and repeat VerifyNow Assay test at 2-4 days and found lost of resistance in 92% of 28 patients. Thus, resistance to the ASA is not constant, it depends on the form and the applied dose of ASA, and eliminating more than 92% when ASA changes from ineffective to effective form.

  13. Acetylsalicylic acid (aspirin) and salicylic acid interaction with the human erythrocyte membrane bilayer induce in vitro changes in the morphology of erythrocytes.

    PubMed

    Suwalsky, Mario; Belmar, Jessica; Villena, Fernando; Gallardo, María José; Jemiola-Rzeminska, Malgorzata; Strzalka, Kazimierz

    2013-11-01

    Despite the well-documented information, there are insufficient reports concerning the effects of salicylate compounds on the structure and functions of cell membranes, particularly those of human erythrocytes. With the aim to better understand the molecular mechanisms of the interaction of acetylsalicylic acid (ASA) and salicylic acid (SA) with cell membranes, human erythrocyte membranes and molecular models were utilized. These consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. The capacity of ASA and SA to perturb the multibilayer structures of DMPC and DMPE was evaluated by X-ray diffraction while DMPC unilamellar vesicles (LUV) were studied by fluorescence spectroscopy. Moreover, we took advantage of the capability of differential scanning calorimetry (DSC) to detect the changes in the thermotropic phase behavior of lipid bilayers resulting from ASA and SA interaction with PC and PE molecules. In an attempt to further elucidate their effects on cell membranes, the present work also examined their influence on the morphology of intact human erythrocytes by means of defocusing and scanning electron microscopy, while isolated unsealed human erythrocyte membranes (IUM) were studied by fluorescence spectroscopy. Results indicated that both salicylates interact with human erythrocytes and their molecular models in a concentration-dependent manner perturbing their bilayer structures.

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

    PubMed

    Zhu, Wencai; Huang, Hui; Gao, Xiaochun; Ma, Houyi

    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.

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

    SciTech Connect

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

    2008-11-01

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

  16. Raman spectroscopy and capillary zone electrophoresis for the analysis of degradation processes in commercial effervescent tablets containing acetylsalicylic acid and ascorbic acid.

    PubMed

    Neuberger, Sabine; Jooß, Kevin; Flottmann, Dirk; Scriba, Gerhard; Neusüß, Christian

    2017-02-05

    In order to ensure the stability of pharmaceutical products appropriate manufacturing and storage conditions are required. In general, the degradation of active pharmaceutical ingredients (APIs) and subsequent formation of degradation products affect the pharmaceutical quality. Thus, a fast and effective detection and characterization of these substances is mandatory. Here, the applicability of Raman spectroscopy and CZE for the characterization of the degradation of effervescent tablets containing acetylsalicylic acid (ASA) and ascorbic acid (AA) was evaluated. Therefore, a degradation study was performed analyzing tablets from two different manufacturers at varying conditions (relative humidity (RH) 33%, 52% and 75% at 30°C). Raman spectroscopy combined with principal component analysis could be successfully applied for the fast and easy discrimination of non-degraded and degraded effervescent tablets after a storage period of approximately 24h (RH 52%). Nevertheless, a clear identification or quantification of APIs and degradation products within the analyzed tablets was not possible, i.a. due to missing reference materials. CZE-UV enabled the quantification of the APIs (ASA, AA) and related degradation products (salicylic acid (SA); semi-quantitative also mono- and diacetylated AA) within the complex tablet mixtures. The higher the RH, the faster the degradation of ASA and AA as well as the formation of the degradation products. Mono- and diacetylated AA are major primary degradation products of AA for the applied effervescent tablets. A significant degradation of the APIs was detected earlier by CZE (6-12h, RH 52%) than by Raman spectroscopy. Summarized, Raman spectroscopy is well-suited as quick test to detect degradation of these tablets and CZE can be utilized for further detailed characterization and quantification of specific APIs and related degradation products.

  17. Antiplatelet Effect Durability of a Novel, 24-Hour, Extended-Release Prescription Formulation of Acetylsalicylic Acid in Patients With Type 2 Diabetes Mellitus.

    PubMed

    Gurbel, Paul A; Bliden, Kevin P; Chaudhary, Rahul; Patrick, Jeff; Liu, Fang; Chen, Gailing; McLeod, Christopher; Tantry, Udaya S

    2016-12-15

    High platelet reactivity and high platelet turnover have been implicated in incomplete platelet inhibition during immediate-release acetylsalicylic acid therapy in patients with type 2 diabetes mellitus (DM). An extended-release acetylsalicylic acid (ER-ASA; Durlaza) formulation was developed to provide 24-hour antithrombotic effects with once-daily dosing. The objective of the study was to evaluate the antiplatelet effects of ER-ASA in patients with DM. In this open-label, single-center study, patients with DM (n = 40) and multiple cardiovascular risk factors received ER-ASA 162.5 mg/day for 14 ± 4 days. Multiple platelet function tests, serum and urinary thromboxane B2 metabolites, prostacyclin metabolite, and high-sensitive C-reactive protein levels were assessed at 1, 12, 16, and 24 hours post-dose. Patients with high platelet turnover and/or high platelet reactivity were treated with ER-ASA 325 mg/day for 14 ± 4 days, and laboratory analyses were repeated. All patients responded to ER-ASA 162.5 mg/day as measured by arachidonic acid-induced aggregation, and there was no loss of the platelet inhibitory effect of ER-ASA 162.5 mg/day over 24 hours post-dose (p = not significant). The antiplatelet effect was sustained over 24 hours for all platelet function measurements. Mean 1- to 24-hour serum thromboxane B2 levels were low with both doses and were lower with ER-ASA 325 mg/day compared with 162.5 mg/day therapy (p = 0.002). In conclusion, ER-ASA 162.5 mg daily dose provided sustained antiplatelet effects over 24 hours in patients with type 2 DM and multiple cardiovascular risk factors and had a favorable tolerability profile.

  18. Dissolution difference between acidic and neutral media of acetaminophen tablets containing a super disintegrant and a soluble excipient. II.

    PubMed

    Chen, C R; Cho, S L; Lin, C K; Lin, Y H; Chiang, S T; Wu, H L

    1998-03-01

    The disintegration and dissolution of acetaminophen tablets containing sucrose and Ac-Di-Sol/Primojel was significantly different between acidic and neutral media. The purpose of this study was to investigate the mechanism of this phenomenon and to propose a way of reducing the dissolution difference between the two media. Tablets of different combinations of active ingredient, sucrose, and Ac-Di-Sol/Primojel were prepared and their dissolution in various media was evaluated. The dissolution differences were found to be largely related to the hydrophobicity of the active ingredient and pH difference of the two media. This difference was even more evident under the condition where acetaminophen, sucrose, and Primojel were combined. The dissolution difference was therefore attributed to the depressed function of Primojel in the acidic medium, the stronger binding of sucrose, the hydrophobicity of the active ingredient and pH difference of the two media. Increasing the concentration of Primojel or incorporating the surfactant in the tablet can thus greatly decrease the dissolution difference between acidic and neutral media.

  19. Dielectric study of equimolar acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone molecular alloys in the glass and ultraviscous states and their relevance to solubility and stability.

    PubMed

    Johari, G P; Kim, S; Shanker, Ravi M

    2010-03-01

    Equimolar mixtures of acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20 K/min heating rate, their T(g)s are 266, 330, and 263 K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel-Fulcher-Tammann equation, log(10)(tau(0)) = A(VFT) + [B(VFT)/(T - T(0))], where A(VFT), B(VFT), and T(0) are empirical constants. The equilibrium permittivity is highest for the aspirin-acetaminophen and lowest for the benzoic acid-progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid-progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its alpha-relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery.

  20. A rapid method for the simultaneous determination of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet by ultra performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Wabaidur, Saikh Mohammad; Alothman, Zeid Abdullah; Khan, Mohammad Rizwan

    2013-05-01

    In present study, a rapid and sensitive method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet. The optimum chromatographic separation was carried out on a reversed phase Waters® Acquity UPLC BEH C18 column (1.7 μm particle size, 100 mm × 2.1 mm ID) with an isocratic elution profile and mobile phase consisting of 0.1% formic acid in water and acetonitrile (75:25, v/v, pH 3.5) at flow rate of 0.5 mL min(-1). The influences of mobile phase composition, flow rate and pH on chromatographic resolution were investigated. The total chromatographic analysis time was as short as 2 min with excellent resolution. Detection and quantification of the target compounds were carried out with a triple quadrupole mass spectrometer using negative electrospray ionization (ESI) and multiple reaction monitoring (MRM) modes. The performance of the method was evaluated and very low limits of detection less than 0.09 μg g(-1), excellent coefficient correlation (r(2)>0.999) with liner range over a concentration range of 0.1-1.0 μg g(-1) for both L-ascorbic acid and acetylsalicylic acid, and good intraday and interday precisions (relative standard deviations (R.S.D.) <3%), were obtained. Comparison of system performance with traditional liquid chromatography-photo diode array detector (HPLC-PDA) was made with respect to analysis time, sensitivity, linearity and precisions. The proposed UPLC-MS/MS method was found to be reproducible and appropriate for quantitative analysis of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet.

  1. A rapid method for the simultaneous determination of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet by ultra performance liquid chromatography-tandem mass spectrometry

    NASA Astrophysics Data System (ADS)

    Wabaidur, Saikh Mohammad; Alothman, Zeid Abdullah; Khan, Mohammad Rizwan

    2013-05-01

    In present study, a rapid and sensitive method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet. The optimum chromatographic separation was carried out on a reversed phase Waters® Acquity UPLC BEH C18 column (1.7 μm particle size, 100 mm × 2.1 mm ID) with an isocratic elution profile and mobile phase consisting of 0.1% formic acid in water and acetonitrile (75:25, v/v, pH 3.5) at flow rate of 0.5 mL min-1. The influences of mobile phase composition, flow rate and pH on chromatographic resolution were investigated. The total chromatographic analysis time was as short as 2 min with excellent resolution. Detection and quantification of the target compounds were carried out with a triple quadrupole mass spectrometer using negative electrospray ionization (ESI) and multiple reaction monitoring (MRM) modes. The performance of the method was evaluated and very low limits of detection less than 0.09 μg g-1, excellent coefficient correlation (r2 > 0.999) with liner range over a concentration range of 0.1-1.0 μg g-1 for both L-ascorbic acid and acetylsalicylic acid, and good intraday and interday precisions (relative standard deviations (R.S.D.) <3%), were obtained. Comparison of system performance with traditional liquid chromatography-photo diode array detector (HPLC-PDA) was made with respect to analysis time, sensitivity, linearity and precisions. The proposed UPLC-MS/MS method was found to be reproducible and appropriate for quantitative analysis of L-ascorbic acid and acetylsalicylic acid in aspirin C effervescent tablet.

  2. Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease.

    PubMed

    Ibrahim, Naser H M; Gregoire, Melanie; Devassy, Jessay G; Wu, Yinhong; Yoshihara, Daisuke; Yamaguchi, Tamio; Nagao, Shizuko; Aukema, Harold M

    2015-01-01

    Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression.

  3. Ultra-fast determination of caffeine, dipyrone, and acetylsalicylic acid by capillary electrophoresis with capacitively coupled contactless conductivity detection and identification of degradation products.

    PubMed

    Marra, Mariana Cardoso; Cunha, Rafael Rodrigues; Vidal, Denis Tadeu Rajh; Munoz, Rodrigo Alejandro Abarza; do Lago, Claudimir Lucio; Richter, Eduardo Mathias

    2014-01-31

    Capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C(4)D) was used for fast, simultaneous determination of dipyrone (DIP), caffeine (CAF), and acetylsalicylic acid (ASA). In the same run and in less than 1min, the degradation products from DIP and ASA were also detected. In addition, the usage of the CE-C(4)D system allowed, for the first time, the detection of methylamine as a degradation product of DIP. Capillary electrophoresis with electrospray mass spectrometry experiments were carried out in order to confirm the formation of methylamine. The limits of detection by CE-C(4)D were 5, 5, and 6μmolL(-1) for CAF, DIP, and ASA, respectively. The proposed method was applied to the analysis of these compounds in pharmaceutical formulations with similar results to those achieved by HPLC (p<0.05).

  4. A retrospective study on IVF outcome in euthyroid patients with anti-thyroid antibodies: effects of levothyroxine, acetyl-salicylic acid and prednisolone adjuvant treatments

    PubMed Central

    2009-01-01

    Background Anti-thyroid antibodies (ATA), even if not associated with thyroid dysfunction, are suspected to cause poorer outcome of in vitro fertilization (IVF). Methods We retrospectively analyzed: (a) the prevalence of ATA in euthyroid infertile women, (b) IVF outcome in euthyroid, ATA+ patients, and (c) the effect of adjuvant treatments (levothyroxine alone or associated with acetylsalicylic acid and prednisolone) on IVF results in ATA+ patients. One hundred twenty-nine euthyroid, ATA+ women undergoing IVF were compared with 200 matched, ATA-controls. During IVF cycle, 38 ATA+ patients did not take any adjuvant treatment, 55 received levothyroxin (LT), and 38 received LT +acetylsalicylic acid (ASA)+prednisolone (P). Results The prevalence of ATA among euthyroid, infertile patients was 10.5%, similar to the one reported in euthyroid women between 18 and 45 years. ATA+ patients who did not receive any adjuvant treatment showed significantly poorer ovarian responsiveness to stimulation and IVF results than controls. ATA+ patients receiving LT responded better to ovarian stimulation, but had IVF results as poor as untreated ATA+ women. Patients receiving LT+ASA+P had significantly higher pregnancy and implantation rates than untreated ATA+ patients (PR/ET 25.6% and IR 17.7% vs. PR/ET 7.5% and IR 4.7%, respectively), and overall IVF results comparable to patients without ATA (PR/ET 32.8% and IR 19%). Conclusion These observations suggest that euthyroid ATA+ patients undergoing IVF could have better outcome if given LT+ASA+P as adjuvant treatment. This hypothesis must be verified in further randomized, prospective studies. PMID:19941670

  5. Acetylsalicylic Acid reduces the severity of dextran sodium sulfate-induced colitis and increases the formation of anti-inflammatory lipid mediators.

    PubMed

    Köhnke, Thomas; Gomolka, Beate; Bilal, Süleyman; Zhou, Xiangzhi; Sun, Yanping; Rothe, Michael; Baumgart, Daniel C; Weylandt, Karsten H

    2013-01-01

    The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore, in vitro experiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation.

  6. Effects of the precalving administration of omega-3 fatty acids alone or in combination with acetylsalicylic acid in periparturient dairy cows.

    PubMed

    Grossi, P; Bertoni, G; Cappelli, F Piccioli; Trevisi, E

    2013-06-01

    This study investigated the effects of the administration of long chain omega-3 fatty acids (ω-3 FA) and acetylsalicylic acid (ASA) on inflammation, performance, and fertility in periparturient dairy cows. Five weeks before calving, 26 multiparous dairy cows were randomly assigned to 1 of 3 treatments: ω-3 FA (n = 9; OME), ω-3 FA and ASA (n = 9; OMAS), or palm oil (n = 8; CTR). During the last 3 wk of pregnancy, OME and OMAS groups received daily 12.0 g of fish-derived ω-3 FA, whereas CTR cows received only SFA. In addition, OMAS cows received daily 6.0 mg ASA/kg BW starting at 7 d before calving. Only a few cows had health problems after calving, but those in OMAS were most affected (n = 3 vs. 1 in CTR). Inflammatory status around calving did not improve in OME cows, as confirmed by the patterns of concentration of acute-phase proteins (APP), which were similar to CTR. Compared with CTR and OME, the increase of the positive APP and the decrease of the negative APP (e.g., albumin; P < 0.01) observed in OMAS cows suggested a severe inflammatory status after calving. Compared with OMAS, postcalving energy metabolism was better in OME cows as shown by a lower degree of lipomobilization (smaller BCS drop, greater glucose) and milder ketogenesis (less β-hydroxybutyrate; P < 0.01). Cows in CTR had optimal fertility indices, whereas OMAS was the worst group. The severe inflammation and the more negative energy balance likely contributed to the poor fertility parameters in those cows. It is known that ASA exerts an inhibitory effect on cyclooxygenases, causing a possible decrease in the synthesis of PGF2α. A decreased concentration of PGF2α is connected with alterations in the physiologic processes related to labor and to uterine motility. Cows in OMAS had a longer pregnancy (P < 0.10 vs.OME) and a greater frequency of retained placenta, which may be attributed to decreased synthesis of PGF2α. The administration of ω-3 FA alone did not delay calving or the

  7. Simultaneous determination of salicylic, 3-methyl salicylic, 4-methyl salicylic, acetylsalicylic and benzoic acids in fruit, vegetables and derived beverages by SPME-LC-UV/DAD.

    PubMed

    Aresta, Antonella; Zambonin, Carlo

    2016-03-20

    Salicylic and benzoic acid are phenolic acids occurring in plant cells, thus they can be present in fruit and vegetables at various levels. They possess anti-inflammatory and antimicrobial properties, however they may induce symptoms and health problems in a small percentage of the population. Therefore, a low phenolic acid diet may be of clinical benefit to such individuals. In order to achieve this goal, the concentration of these substances in different food and beverages should be assessed. The present work describes for the first time a new method, based on solid phase microextraction (polydimethylsiloxane-divinylbenzene fiber) coupled to liquid chromatography with UV diode array detection, for the simultaneous determination of salicylic acid, 3-methyl salicylic acid, 4-methyl salicylic acid, acetylsalicylic acid and benzoic acid in selected fruit, vegetables and beverages. All the aspects influencing fiber adsorption (time, temperature, pH, salt addition) and desorption (desorption and injection time, desorption solvent mixture composition) of the analytes have been investigated. An isocratic separation was performed using an acetonitrile-phosphate buffer (pH 2.8; 2 mM) mixture (70:30, v/v) as the mobile phase. The estimated LOD and LOQ values (μg/mL) were in the range 0.002-0.028 and 0.007-0.095. The within-day and day-to-day precision values (RSD%) were between 4.7-6.1 and 6.6-9.4, respectively. The method has been successfully applied to the analysis of fava beans, blueberries, kiwi, tangerines, lemons, oranges and fruit juice (lemon and blueberry) samples. The major advantage of the method is that it only requires simple homogenization and/or centrifugation and dilution steps prior to SPME and injection in the LC system.

  8. Effect of 70-nm silica particles on the toxicity of acetaminophen, tetracycline, trazodone, and 5-aminosalicylic acid in mice.

    PubMed

    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.

  9. Acetaminophen overdose

    MedlinePlus

    ... measure and monitor the person's vital signs, including temperature, pulse, breathing rate, and blood pressure. Blood tests will be done to check how much acetaminophen is in the blood. The person may receive: Activated charcoal Airway support, including oxygen, breathing tube through the ...

  10. The Influence of Prolonged Acetylsalicylic Acid Supplementation-Induced Gastritis on the Neurochemistry of the Sympathetic Neurons Supplying Prepyloric Region of the Porcine Stomach

    PubMed Central

    Palus, Katarzyna; Całka, Jarosław

    2015-01-01

    This experiment was designed to establish the localization and neurochemical phenotyping of sympathetic neurons supplying prepyloric area of the porcine stomach in a physiological state and during acetylsalicylic acid (ASA) induced gastritis. In order to localize the sympathetic perikarya the stomachs of both control and acetylsalicylic acid treated (ASA group) animals were injected with neuronal retrograde tracer Fast Blue (FB). Seven days post FB injection, animals were divided into a control and ASA supplementation group. The ASA group was given 100 mg/kg of b.w. ASA orally for 21 days. On the 28th day all pigs were euthanized with gradual overdose of anesthetic. Then fourteen-micrometer-thick cryostat sections were processed for routine double-labeling immunofluorescence, using primary antisera directed towards tyrosine hydroxylase (TH), dopamine β-hydroxylase (DβH), neuropeptide Y (NPY), galanin (GAL), neuronal nitric oxide synthase (nNOS), leu 5-enkephalin (LENK), cocaine- and amphetamine- regulated transcript peptide (CART), calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP). The data obtained in this study indicate that postganglionic sympathetic nerve fibers supplying prepyloric area of the porcine stomach originate from the coeliac-cranial mesenteric ganglion complex (CCMG). In control animals, the FB-labelled neurons expressed TH (94.85 ± 1.01%), DβH (97.10 ± 0.97%), NPY (46.88 ± 2.53%) and GAL (8.40 ± 0.53%). In ASA group, TH- and DβH- positive nerve cells were reduced (85.78 ± 2.65% and 88.82 ± 1.63% respectively). Moreover, ASA- induced gastritis resulted in increased expression of NPY (76.59 ± 3.02%) and GAL (26.45 ± 2.75%) as well as the novo-synthesis of nNOS (6.13 ± 1.11%) and LENK (4.77 ± 0.42%) in traced CCMG neurons. Additionally, a network of CART-, CGRP-, SP-, VIP-, LENK-, nNOS- immunoreactive (IR) nerve fibers encircling the FB-positive perikarya were observed in both intact and ASA

  11. Non-enzymatic modifications of prostaglandin H synthase 1 affect bifunctional enzyme activity - Implications for the sensitivity of blood platelets to acetylsalicylic acid.

    PubMed

    Kassassir, Hassan; Siewiera, Karolina; Talar, Marcin; Stec-Martyna, Emilia; Pawlowska, Zofia; Watala, Cezary

    2016-06-25

    Due to its ability to inhibit the blood platelet PGHS-1, acetylsalicylic acid (ASA, Aspirin(®)) is widely used as a preventive agent in atherothrombotic diseases. However, its beneficial effects seem to be lower in diabetic patients, suggesting that protein glycation may impair effective ASA-mediated acetylation process. On the other hand, it is proposed that ASA can prevent some of the late complications of diabetes by lowering the extent of glycation at protein free amino groups. The aim of this work was to evaluate the extents of non-enzymatic N-glycosylation (glycation) and acetylation of blood platelet PGHS-1 (COX-1) and the competition between glycation and acetylation was investigated in order to demonstrate how these two reactions may compete against platelet PGHS-1. When PGHS-1 was incubated with glycating/acetylating agents (glucose, Glu; 1,6-bisphosphofructose, 1,6-BPF; methylglyoxal, MGO, acetylsalicylic acid, ASA), the enzyme was modified in 13.4 ± 1.6, 5.3 ± 0.5, 10.7 ± 1.2 and 6.4 ± 1.1 mol/mol protein, respectively, and its activity was significantly reduced. The prior glycation/carbonylation of PGHS-1 with Glu, 1,6-BPF or MGO decreased the extent of acetylation from 6.4 ± 1.1 down to 2.5 ± 0.2, 3.6 ± 0.3 and 5.2 ± 0.2 mol/mol protein, respectively, but the enzyme still remained susceptible to the subsequent inhibition of its activity with ASA. When PGHS-1 was first acetylated with ASA and then incubated with glycating/carbonylating agents, we observed the following reductions in the enzyme modifications: from 13.4 ± 1.6 to 8.7 ± 0.6 mol/mol protein for Glu, from 5.3 ± 0.5 to 3.9 ± 0.3 mol/mol protein for 1,6-BPF and from 10.7 ± 1.2 to 7.5 ± 0.5 mol/mol protein for MGO, however subsequent glycation/carbonylation did not significantly affect PGHS-1 function. Overall, our outcomes allow to better understand the structural aspects of the chemical competition between glycation and acetylation of PGHS-1.

  12. The Ability of PAS, Acetylsalicylic Acid and Calcium Disodium EDTA to Protect Against the Toxic Effects of Manganese on Mitochondrial Respiration in Gill of Crassostrea virginica

    PubMed Central

    Crawford, Sherine; Davis, Kiyya; Saddler, Claudette; Joseph, Jevaun; Catapane, Edward J.; Carroll, Margaret A.

    2011-01-01

    Manganese (Mn) is an essential metal that at excessive levels in brain causes Manganism, a condition similar to Parkinson's disease. Previously we showed that Mn had a neurotoxic effect on the dopaminergic, but not serotonergic, innervation of the lateral ciliated cells in the gill of the Eastern Oyster, Crassostrea virginica. While the mechanism of action of Mn toxicity is not completely understood, studies suggest that Mn toxicity may involve mitochondrial damage and resulting neural dysfunction in the brain’s dopaminergic system. In this study we utilized micro-batch chambers and oxygen probes to measure oyster gill mitochondrial respiration in the presence of Mn and potential Mn blockers. The addition of Mn to respiring mitochondria caused a dose dependent decrease in mitochondrial O2 consumption. Pretreating mitochondria with calcium disodium EDTA (caEDTA), p aminosalicylic acid (PAS) or acetylsalicylic acid (ASA) before Mn additions, provided full protection against the toxic effects of Mn. While mitochondrial pretreatment with any of the 3 drugs effectively blocked Mn toxicity, none of the drugs tested was able to reverse the decrease in mitochondrial O2 consumption seen in Mn treated mitochondria. The study found that high levels of Mn had a toxic effect on gill mitochondrial O2 consumption and that this effect could be blocked by the drugs caEDTA, PAS and ASA. C. virginica continues to be a good model with which to investigate the mechanism that underlies manganese neurotoxcity and in the pharmacological study of drugs to treat or prevent Manganism. PMID:21977482

  13. Probing of the combined effect of bisquaternary ammonium antimicrobial agents and acetylsalicylic acid on model phospholipid membranes: differential scanning calorimetry and mass spectrometry studies.

    PubMed

    Kasian, N A; Pashynska, V A; Vashchenko, O V; Krasnikova, A O; Gömöry, A; Kosevich, M V; Lisetski, L N

    2014-12-01

    A model molecular biosystem of hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers that mimics cell biomembranes is used to probe combined membranotropic effects of drugs by instrumental techniques of molecular biophysics. Differential scanning calorimetry reveals that doping of the DPPC model membrane with individual bisquaternary ammonium compounds (BQAC) decamethoxinum, ethonium, thionium and acetylsalicylic acid (ASA) leads to lowering of the membrane melting temperature (Tm) pointing to membrane fluidization. Combined application of the basic BQAC and acidic ASA causes an opposite effect on Tm (increase), corresponding to the membrane densification. Thus, modulation of the membranotropic effects upon combined use of the drugs studied can be revealed at the level of model membranes. Formation of noncovalent supramolecular complexes of the individual BQACs and ASA with DPPC molecules, which may be involved in the mechanism of the drug-membrane interaction at the molecular level, is demonstrated by electrospray ionization (ESI) mass spectrometry. In the ternary (DPPC + ASA + BQAC) model systems, the stable complexes of the BQAC dication with the ASA anion, which may be responsible for modulation of the membranotropic effects of the drugs, were recorded by ESI mass spectrometry. The proposed approach can be further developed for preliminary evaluation of the combined effects of the drugs at the level of model lipid membranes prior to tests on living organisms.

  14. [The prevention of thrombus formation and the improvement of the blood rheological properties during operations with a microsurgical technic. I. The possibilities for using acelysin--an acetylsalicylic acid derivative].

    PubMed

    Vabishchevich, A V; Smirnova, L A; Roĭtman, E V; Shibaev, E Iu; Mikhaĭlova, O M; Svetlov, V A

    1999-01-01

    Changes in the blood clotting system and rheology were studied in 39 patients during reconstructive operations making use of microsurgical methods. Effects of various doses of water soluble acelysine, an acetylsalicylic acid preparations (DL-lysine acetylsalicylate and glycine) have been evaluated during surgery and the immediate postoperative period. Clinical and laboratory changes in blood coagulation were determined at different doses (1000, 500, and 250 mg). Even in low doses (3.94 +/- 0.25 mg/kg) acelysine ensured chronometric and structural hypocoagulation as early as 1 h after dosed infusion and throughout the entire intervention, preventing thrombosis of microvascular anastomoses. Administration of acelysine in doses higher than 250 mg is not recommended, because higher doses involve the risk of hypocoagulation complications.

  15. Evaluation of platelet function using PFA-100® in patients treated with Acetylsalicylic acid and qualified for Trauma and Orthopedic surgery procedures.

    PubMed

    Kurak, J; Zając, P; Czyżewski, D; Kucharski, R; Grzanka, R; Kasperska-Zajac, A; Koczy, B

    2016-11-01

    The phenomenon of high on-acetylsalicylic acid (ASA) treatment platelet (PLT) reactivity - HATPR - and its clinical implications have not been fully understood. Little data is available on assessing PLT activity based on the severity of intra- and postoperative bleeding in a population of orthopedic patients with normal closure time (CT) measured by a PLT function analyzer PFA-100®, despite being given long-term ASA therapy. The aim is to assess PLT function using PFA-100® in patients with ASA therapy and qualified for trauma and orthopedic surgery procedures. The retrospective analysis covered 384 patients whose PLT reactivity was assessed using PFA-100®. Out of those, 198 had been taking ASA with a 75 mg dose until hospital admission. In addition, a group of 70 patients with a proximal femoral fracture surgically treated using the dynamic hip screw (DHS) was selected, in whom severity of bleeding was assessed by HIP ASA (+). The reference group comprised 52 patients (without ASA therapy) who were operated on due to the same indications. Normal CT was found in 37% of ASA-receiving patients. Patients with normal CT, despite ASA therapy, exhibited significantly more intense bleeding after DHS surgery. A similar number of patients required red blood cells (RBCs) transfusion in HIP ASA (+) and HIP ASA (-). Increased risk of complications in HIP ASA (+) group was not found.

  16. Effect of low dose acetylsalicylic acid on the frequency and hematologic activity of left ventricular thrombus in anterior wall acute myocardial infarction

    SciTech Connect

    Kuepper, A.J.V.; Verheugt, F.W.; Peels, C.H.; Galema, T.W.; den Hollander, W.; Roos, J.P.

    1989-04-15

    In this prospective, randomized, placebo-controlled trial the effect of 100 mg acetylsalicylic acid (ASA) once daily on the incidence, hematologic activity and embolic potential of left ventricular (LV) thrombosis was studied in 100 consecutive patients with a first anterior wall acute myocardial infarction (AMI). Patients were randomized to ASA or placebo less than 12 hours after onset of symptoms. Heparin, 5,000 IU subcutaneously twice daily, was given to all patients during immobilization. Echocardiography was performed less than 24 hours, 48 to 72 hours and 1, 2, and 12 weeks after AMI. LV thrombosis was detected by echocardiography in 30 (33%) of the 92 evaluable patients (15 patients given ASA and 15 given placebo). Indium-111 platelet scintigraphy was done in 17 of the 22 patients with an LV thrombus at the second week echocardiogram. Among 7 ASA-treated patients, 4 had positive images; among 10 placebo patients, 5 had positive images. LV thrombus resolution was noted in 3 of 9 patients with a positive scan and in 5 of 8 patients with a negative platelet scan. In 7 of 10 ASA-treated patients and 5 of 12 placebo-treated patients thrombus resolution was observed (difference not significant). Systemic embolism occurred in 2 patients, both given ASA, during the first week after AMI. Thus, low dose ASA has no effect on the incidence, hematologic activity and embolic potential of LV thrombosis in anterior wall AMI.

  17. Treatment with acetylsalicylic acid prevents short to mid-term radiographic progression of nontraumatic osteonecrosis of the femoral head: a pilot study

    PubMed Central

    Albers, Anthony; Carli, Alberto; Routy, Bertrand; Harvey, Edward J.; Séguin, Chantal

    2015-01-01

    Background Nontraumatic osteonecrosis of the femoral head (ONFH) is a progressive disease in young adults producing substantial morbidity and frequently resulting in total hip arthroplasty. Although hip-preserving surgical procedures represent the current mainstay of treatment for early disease, medical therapies targeting specific pathways in the ONFH pathogenesis could help prevent disease progression while producing less morbidity. Acetylsalicylic acid (ASA) is a promising alternative to other therapies for ONFH owing to its anti-inflammatory and antithrombotic mechanisms of action and its relatively benign side effect profile. Methods We followed a prospective cohort of 10 patients (12 hips) with precollapse ONFH who were given ASA to prevent disease progression. Their outcomes were compared with those of a historic control group taken from the literature. Results Progression occurred in 1 of 12 (8%) patients taking ASA compared with 30 of 45 (66.6%) controls (p = 0.002) at a mean follow-up of 3.7 years. Patients taking ASA also tended to exhibit decreased femoral head involvement at the end of therapy. Conclusion This hypothesis-generating study leads us to believe that ASA may be a simple and effective treatment option for delaying disease progression in patients with early-stage ONFH. PMID:26011853

  18. Histopathological, Ultrastructural, and Immunohistochemical Assessment of Hippocampus Structures of Rats Exposed to TCDD and High Doses of Tocopherol and Acetylsalicylic Acid

    PubMed Central

    Rosińczuk, Joanna; Całkosiński, Ireneusz

    2015-01-01

    The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on central nervous system consists of changing expression of estrogen receptors, whereas the result of chronic inflammatory reaction caused by dioxin is occurrence of destructive changes in various organs connected with disturbed metabolism of connective tissue and damage of cells. The aim of the study was to determine the effect of dioxins on function, ultrastructure, and cytological and histological structure of hippocampus, particularly on expression of estrogen receptors in central nervous system as well as to define protective influence of tocopherol (TCP) and acetylsalicylic acid (ASA) on the decrease in activity of proinflammatory effects in central nervous system. It was shown that TCDD contributes to destructive and inflammatory changes along with demyelization of myelin sheaths and atrophy of estrogen receptors in hippocampus. Dioxin contributes to atrophy of estrogen receptors in hippocampus, in which also destructive and inflammatory changes were found along with demyelination of myelin sheaths. Histopathological and ultrastructural image of hippocampus areas in rats, in which both TCP and ASA were used, is characterized by poorly expressed degenerative changes and smaller inflammatory reactivity. Using both TCP and ASA has a protective effect on functions of central nervous system. PMID:25879034

  19. The effect of microcrystalline cellulose crystallinity on the hydrophilic property of tablets and the hydrolysis of acetylsalicylic acid as active pharmaceutical ingredient inside tablets.

    PubMed

    Awa, Kimie; Shinzawa, Hideyuki; Ozaki, Yukihiro

    2015-08-01

    The crystal structures of active pharmaceutical ingredients and excipients should be strictly controlled because they influence pharmaceutical properties of products which cause the change in the quality or the bioavailability of the products. In this study, we investigated the effects of microcrystalline cellulose (MCC) crystallinity on the hydrophilic properties of tablets and the hydrolysis of active pharmaceutical ingredient, acetylsalicylic acid (ASA), inside tablets by using tablets containing 20% MCC as an excipient. Different levels of grinding were applied to MCC prior to tablet formulation, to intentionally cause structural variation in the MCC. The water penetration and moisture absorbability of the tablets increased with decreasing the crystallinity of MCC through higher level of grinding. More importantly, the hydrolysis of ASA inside tablets was also accelerated. These results indicate that the crystallinity of MCC has crucial effects on the pharmaceutical properties of tablets even when the tablets contain a relatively small amount of MCC. Therefore, controlling the crystal structure of excipients is important for controlling product qualities.

  20. Binary mixtures of diclofenac with paracetamol, ibuprofen, naproxen, and acetylsalicylic acid and these pharmaceuticals in isolated form induce oxidative stress on Hyalella azteca.

    PubMed

    Gómez-Oliván, Leobardo Manuel; Neri-Cruz, Nadia; Galar-Martínez, Marcela; Islas-Flores, Hariz; García-Medina, Sandra

    2014-11-01

    Toxicity in natural ecosystems is usually not due to exposure to a single substance, but is rather the result of exposure to mixtures of toxic substances. Knowing the effects of contaminants as a mixture compared to their effects in isolated form is therefore important. This study aimed to evaluate the oxidative stress induced by binary mixtures of diclofenac with paracetamol, ibuprofen, naproxen, and acetylsalicylic acid and by these nonsteroidal anti-inflammatory drugs (NSAIDs) in isolated form, using Hyalella azteca as a bioindicator. The median lethal concentration (LC50) and the lowest observed adverse effect level (LOAEL) of each NSAID were obtained. Amphipods were exposed for 72 h to the latter value in isolated form and as binary mixtures. The following biomarkers were evaluated: lipid peroxidation (LPX), protein carbonyl content (PCC), and activity of the antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Significant increases in LPX and PCC with respect to the control group (p ≤ 0.05) were induced by NSAIDs both in isolated form and as binary mixtures. Changes in SOD, CAT, and GPx activity likewise occurred with NSAIDs in isolated form and as binary mixtures. In conclusion, NSAIDs used in this study induce oxidative stress on H. azteca both in isolated form and as binary mixtures, and the interactions occurring between these pharmaceuticals are probably antagonistic in type.

  1. Au-Pd/reduced graphene oxide composite as a new sensing layer for electrochemical determination of ascorbic acid, acetaminophen and tyrosine.

    PubMed

    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.

  2. Modification of carbon paste electrode with Fe(III)-clinoptilolite nano-particles for simultaneous voltammetric determination of acetaminophen and ascorbic acid.

    PubMed

    Sharifian, Samira; Nezamzadeh-Ejhieh, Alireza

    2016-01-01

    A novel carbon paste electrode (CPE) modified with Fe(III)-exchanged clinoptilolite nano-particles (Fe(III)-NClino/CPE) was constructed and used for simultaneous voltammetric (CV, SqW and chronoamperometry) determination of ascorbic acid and acetaminophen. Raw and modified zeolites were characterized by X-ray diffraction (XRD) and transmission electron microscope (TEM). The square wave peak current was linearly increased in the concentration ranges of 1.0 × 10(-9)-1.0 × 10(-2) mol L(-1) for ascorbic acid and 1.0 × 10(-10-)1.0 × 10(-2) mol L(-1) for acetaminophen with detection limits of 1.8 × 10(-9) mol L(-1) and 9.9 × 10(-10) mol L(-1), respectively. The detection limits of 2.4 × 10(-10) mol L(-1) and 2.5 × 10(-11) mol L(-1) were also obtained for AA and AC in chronoamperometric measurements, respectively. The diffusion coefficients of 7.5 × 10(-5) cm(2) s(-1) and 2.4 × 10(-5) cm(2) s(-1) were respectively calculated for the oxidation of AC and AA by chronoamperometry. The proposed electrode exhibited high sensitivity and good stability, and would be valuable for the clinical assay of ascorbic acid and acetaminophen.

  3. Protective Role of Acetylsalicylic Acid in Experimental Trypanosoma cruzi Infection: Evidence of a 15-epi-Lipoxin A4-Mediated Effect

    PubMed Central

    Henriquez, Natalia; Faúndez, Mario; Torres, Gloria; Castillo, Christian; Escanilla, Sebastián; Kemmerling, Ulrike; Morello, Antonio; López-Muñoz, Rodrigo A.; Maya, Juan D.

    2013-01-01

    Chagas' disease, produced by Trypanosoma cruzi, affects more than 8 million people, producing approximately 10,000 deaths each year in Latin America. Migration of people from endemic regions to developed countries has expanded the risk of infection, transforming this disease into a globally emerging problem. PGE2 and other eicosanoids contribute to cardiac functional deficits after infection with T. cruzi. Thus, the inhibition of host cyclooxygenase (COX) enzyme emerges as a potential therapeutic target. In vivo studies about the effect of acetylsalicylic acid (ASA) upon T. cruzi infection are controversial, and always report the effect of ASA at a single dose. Therefore, we aimed to analyze the effect of ASA at different doses in an in vivo model of infection and correlate it with the production of arachidonic acid metabolites. ASA decreased mortality, parasitemia, and heart damage in T. cruzi (Dm28c) infected mice, at the low doses of 25 and 50 mg/Kg. However, this effect disappeared when the high ASA doses of 75 and 100 mg/Kg were used. We explored whether this observation was related to the metabolic shift toward the production of 5-lipoxygenase derivatives, and although we did not observe an increase in LTB4 production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA4 (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA4 in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA4 levels. Importantly, 15-epi-LXA4 prevented parasitemia, mortality, and cardiac changes in vivo and restored the protective role in the treatment with a high dose of ASA. This is the first report showing the production of ASA-triggered lipoxins in T. cruzi infected mice, which demonstrates the role of this lipid as an anti-inflammatory molecule in the acute phase of the disease. PMID:23638194

  4. How to Safely Give Acetaminophen

    MedlinePlus

    ... to 2-Year-Old How to Safely Give Acetaminophen KidsHealth > For Parents > How to Safely Give Acetaminophen ... without getting a doctor's OK first. What Is Acetaminophen Also Called? Acetaminophen is the generic name of ...

  5. A comparative study between conventional pan coater and quasi-continuous small batch coater on the stability of tablets containing acetylsalicylic acid.

    PubMed

    Cahyadi, Christine; Chan, Lai Wah; Heng, Paul Wan Sia

    2015-02-01

    The Supercell coater was developed as an in-line small batch tablet coater which uses air-fluidization for tablet coating. Coating time is very much reduced, with improved heat and mass transfer. It was hypothesized that the quasi-continuous Supercell coating process was more suitable for the aqueous coating of tablets containing moisture-sensitive drugs. Acetylsalicylic acid (ASA) was used as the model drug in this study. The extent of ASA degradation in Supercell coating was compared against that of tablets coated using the conventional pan coater. Less than 0.3% of ASA was degraded at the end of the coating process using either coater. The extent of ASA degradation was found to be more pronounced during storage. The Supercell coated tablets exhibited comparable or smaller percentage of ASA degradation than the pan coated tablets at the end of a storage period of 6 months under accelerated stability conditions (40°C/75% RH) and 3 years under ambient conditions (25°C/50% RH). The extent and rate of ASA degradation during storage were dependent on the processing conditions employed during Supercell coating. Increase in temperature generally led to a reduction in ASA degradation, while increase in spray rate and coating level caused more degradation. Greater extent of ASA degradation was observed on the surface of pan coated tablets compared with Supercell coated tablets due to greater moisture contact and the slower and wetter coating process. Changes to the processing conditions also influenced the residual moisture content (0.55-2.86%) of the tablets. However, no direct correlation between the residual moisture content of the tablets after coating and the extent of ASA degradation during storage was found.

  6. The effect of different doses and different routes of acetylsalicylic acid administration on platelet aggregation in healthy volunteers and ischemic stroke patients.

    PubMed

    Chýlová, Miroslava; Moťovská, Zuzana; Osmančík, Pavel; Procházka, Bohumír; Kalvach, Pavel

    2015-04-01

    The purpose was to assess the effect of different doses and different routes of acetylsalicylic acid (ASA) administration on platelet aggregation and the comparison between platelet aggregation after the single and the repetitive administration of ASA in healthy individuals and in patients after ischemic stroke. The study group consists of 22 healthy individuals and 30 patients with documented ischemic stroke. Platelet aggregation was measured in healthy individuals: (a) twice before ASA and (b) 2 h after different single doses and different routes of ASA administration-(b1) 500 mg orally, (b2) 500 mg intravenously, and (b3) 100 mg orally. We measured aggregability in healthy individuals after five consecutive days of 100 mg of ASA q.d. and in patients on chronic ASA 100 mg q.d. The VerifyNow was used with results expressed in aspirin reaction units (ARU). In healthy individuals, the dose-(b1) 500 mg orally-reduced the aggregability to mean (SD) 392 (36) ARU (p < 0.001), (b2) 500 mg intravenously to 428 (46) (p < 0.001) and (b3) 100 mg orally to 460 (76) (p < 0.001). The suppression of aggregation after 500 mg was (p = 0.029) higher after the oral compared to intravenous administration, and the same is true for the suppression after single dose of 500 mg orally and 100 mg orally (p = 0.011). Oral dose 100 mg for 5 days in healthy individuals reduced aggregation to 405 (37) and in post-stroke patients to 433 (54). All doses of ASA, both orally and intravenously, have produced a significant reduction of platelet aggregation. Preference of the parenteral to oral application has not been established.

  7. Toxicity of 50-nm polystyrene particles co-administered to mice with acetaminophen, 5-aminosalicylic acid or tetracycline.

    PubMed

    Isoda, K; Nozawa, T; Tezuka, M; Ishida, I

    2014-09-01

    We investigated whether nano-sized polystyrene particles affect drug-induced toxicity. The particles, which are widely used industrially, had diameters of 50 (NPP50), 200 (NPP200) or 1000 (NPP1000) nm. The toxic chemicals tested were acetaminophen (APAP), 5-aminosalicylic acid (5-ASA), tetracycline (TC), and sodium valproate (VPA). All treatments in the absence of the nanoparticles were non-lethal and did not result in severe toxicity. However, when mice were injected with APAP, 5-ASA or TC together with polystyrene particles, synergistic, enhanced toxicity was observed in mice injected with NPP50. These synergic effects were not observed in mice co-injected with NPP200 or NPP1000. On the other hand, co-administration of VPA and NPP50, NPP200 or NPP1000 did not elevate toxicity. The results show that NPP50 differs in hepatotoxicity depending on the drug co-administered. These findings suggest that further evaluation of the interactions between polystyrene nanoparticles and drugs is a critical prerequisite to the pharmaceutical application of nanotechnology.

  8. Homocysteine is a novel risk factor for suboptimal response of blood platelets to acetylsalicylic acid in coronary artery disease: a randomized multicenter study.

    PubMed

    Karolczak, Kamil; Kamysz, Wojciech; Karafova, Anna; Drzewoski, Jozef; Watala, Cezary

    2013-08-01

    The incomplete inhibition of platelet function by acetylsalicylic acid (ASA), despite the patients are receiving therapeutic doses of the drug ('aspirin-resistance'), is caused by numbers of risk factors. In this study we verified the idea that plasma homocysteine (Hcy) contributes to 'aspirin-resistance' in patients with coronary artery disease (CAD) and with or without type 2 diabetes mellitus (T2DM). A cross-designed randomized controlled intervention study has been performed (126 CAD pts incl. 26 with T2DM) to determine whether increasing ASA dose from 75mg to 150mg daily may result in the increased antiplatelet effect, in the course of four-week treatment. Platelet response to collagen (coll) or arachidonic acid (AA) was monitored with whole blood aggregometry, plasma thromboxane (Tx), and Hcy levels were determined immunochemically. The ASA-mediated reductions in platelet response to coll (by 12±3%) or AA (by 10±3%) and in plasma Tx (by 20±9%; p<0.02 or less) were significantly greater for higher ASA dose and significantly correlated with plasma Hcy, which was significantly lower in "good" ASA responders compared to "poor" responders (p<0.001). Higher plasma Hcy appeared a significant risk factor for blood platelet refractoriness to low ASA dose (OR=1.11; ±95%CI: 1.02-1.20, p<0.02, adjusted to age, sex and CAD risk factors). Hcy diminished in vitro antiplatelet effect of low ASA concentration and augmented platelet aggregation (by up to 62% (p<0.005) for coll and up to 15% (p<0.005) for AA), whereas its acetyl derivative acted oppositely. Otherwise, Hcy intensified antiplatelet action of high ASA. Hyperhomocysteinaemia may be a novel risk factor for the suppressed blood platelet response to ASA, and homocysteine may act as a specific sensitizer of blood platelets to some agonists. While homocysteine per se acts as a proaggregatory agent to blood platelets, its acetylated form is able to reverse this effect. Thus, these findings reveal a possibly new

  9. Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON)

    PubMed Central

    Devereaux, P J; Herlitz, Johan; Katelaris, Peter H; Lanas, Angel; Veldhuyzen van Zanten, Sander; Nauclér, Emma; Svedberg, Lars-Erik

    2011-01-01

    Objective To determine whether once-daily esomeprazole 40 mg or 20 mg compared with placebo reduces the incidence of peptic ulcers over 26 weeks of treatment in patients taking low-dose acetylsalicylic acid (ASA) and who are at risk for ulcer development. Design Multinational, randomised, blinded, parallel-group, placebo-controlled trial. Setting Cardiology, primary care and gastroenterology centres (n=240). Patients Helicobacter pylori-negative patients taking daily low-dose ASA (75–325 mg), who fulfilled one or more of the following criteria: age ≥18 years with history of uncomplicated peptic ulcer; age ≥60 years with either stable coronary artery disease, upper gastrointestinal symptoms and five or more gastric/duodenal erosions, or low-dose ASA treatment initiated within 1 month of randomisation; or age ≥65 years. All patients were ulcer-free at study entry. Interventions Once-daily, blinded treatment with esomeprazole 40 mg, 20 mg or placebo for 26 weeks. Main outcome measures The primary end point was the occurrence of endoscopy-confirmed peptic ulcer over 26 weeks. Results A total of 2426 patients (52% men; mean age 68 years) were randomised. After 26 weeks, esomeprazole 40 mg and 20 mg significantly reduced the cumulative proportion of patients developing peptic ulcers; 1.5% of esomeprazole 40 mg and 1.1% of esomeprazole 20 mg recipients, compared with 7.4% of placebo recipients, developed peptic ulcers (both p<0.0001 vs placebo). Esomeprazole was generally well tolerated. Conclusions Acid-suppressive treatment with once-daily esomeprazole 40 mg or 20 mg reduces the occurrence of peptic ulcers in patients at risk for ulcer development who are taking low-dose ASA. Clinical trial registration number ClinicalTrials.gov identifier: NCT00441727. PMID:21415072

  10. The role of hydrogen bonds in an aqueous solution of acetylsalicylic acid: a molecular dynamics simulation study.

    PubMed

    Donnamaria, Maria Cristina; de Xammar Oro, Juan Roberto

    2011-10-01

    This work focuses on the role of the dynamic hydrogen bonds (HB) formed in an aqueous solution of aspirin using molecular dynamics simulation. The statistics reveal the existence of internal HB that inhibit the rotational movements of the acetyl and the carboxylic acid groups, forcing the molecule to adopt a closed conformer structure in water, and playing an important role in stabilizing this conformation.

  11. Acetaminophen dosing for children

    MedlinePlus

    Tylenol ... Acetaminophen is used to help: Reduce aches, pain, sore throat, and fever in children with a cold ... Children's acetaminophen can be taken as liquid or chewable tablet. If your child is under 2 years old, check ...

  12. Determination of acetylsalicylic acid and its major metabolite, salicylic acid, in human plasma using liquid chromatography-tandem mass spectrometry: application to pharmacokinetic study of Astrix in Korean healthy volunteers.

    PubMed

    Bae, Soo Kyung; Seo, Kyung Ah; Jung, Eun Ji; Kim, Ho-Sook; Yeo, Chang-Woo; Shon, Ji-Hong; Park, Kyung-Mi; Liu, Kwang-Hyeon; Shin, Jae-Gook

    2008-06-01

    The first liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for determination of acetylsalicylic acid (aspirin, ASA) and one of its major metabolites, salicylic acid (SA), in human plasma using simvastatin as an internal standard has been developed and validated. For ASA analysis, a plasma sample containing potassium fluoride was extracted using a mixture of ethyl acetate and diethyl ether in the presence of 0.5% formic acid. SA, a major metabolite of ASA, was extracted from plasma using protein precipitation with acetonitrile. The compounds were separated on a reversed-phase column with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid (8:2, v/v). The ion transitions recorded in multiple reaction monitoring mode were m/z 179 --> 137, 137 --> 93 and 435 --> 319 for ASA, SA and IS, respectively. The coefficient of variation of the assay precision was less than 9.3%, and the accuracy exceeded 86.5%. The lower limits of quantification for ASA and SA were 5 and 50 ng/mL, respectively. The developed assay method was successfully applied for the evaluation of pharmacokinetics of ASA and SA after single oral administration of Astrix (entero-coated pellet, 100 mg of aspirin) to 10 Korean healthy male volunteers.

  13. Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid.

    PubMed

    Cuesta-Gragera, Ana; Navarro-Fontestad, Carmen; Mangas-Sanjuan, Victor; González-Álvarez, Isabel; García-Arieta, Alfredo; Trocóniz, Iñaki F; Casabó, Vicente G; Bermejo, Marival

    2015-07-10

    The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis-Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this model by comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000 mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000 mg) and with 6 test formulations with decreasing in vivo dissolution rate constants versus the reference formulation (kD 8-0.25 h (-1)). Finally, the third aim was to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in formulation performance. The validation results showed that the concentration-time curves obtained with the simulations reproduced closely the published experimental data, confirming model performance. The parent drug (ASA) was the analyte that showed to be more sensitive to the decrease in pharmaceutical quality, with the highest decrease in Cmax and AUC ratio between test and reference formulations.

  14. Prospective, randomised trial of the time dependent antiplatelet effects of 500 mg and 250 mg acetylsalicylic acid i. v. and 300 mg p. o. in ACS (ACUTE).

    PubMed

    Zeymer, Uwe; Hohlfeld, Thomas; Vom Dahl, Jürgen; Erbel, Raimund; Münzel, Thomas; Zahn, Ralf; Roitenberg, Alexander; Breitenstein, Stefanie; Pap, Ákos Ferenc; Trenk, Dietmar

    2017-02-28

    Little is known about the onset of action after intravenous or oral administration of acetylsalicylic acid (ASA) in patients with acute coronary syndromes (ACS). The aim of the study was to compare intravenous 250 or 500 mg acetylsalicylic acid (ASA) with oral 300 mg in ASA naïve patients with ACS concerning the onset of antiplatelet effects measured by time dependent thromboxane inhibition. A total of 270 patients with ACS < 24 hours were randomised into one of three treatment arms comprising administration of a single dose of ASA as soon as possible after admission. The primary endpoint was platelet inhibition assessed by measurement of arachidonic acid (AA)-induced platelet thromboxane release (TXB2) 5 minutes (min) after study drug administration. Both 250 mg and 500 mg ASA i. v. inhibited TXB2 formation nearly completely (geometric means: from 581.7 and 573.9 ng/ml at baseline to 3.9 and 3.1 ng/ml at 5 min, respectively) compared to 300 mg oral ASA (geometric means: from 652.0 to 223.7 ng/ml) (p-value, ANCOVA: < 0.0001). Similar results were obtained for inhibition of AA-induced platelet aggregation (Multiplate ASPItest; from means 86.41 and 85.72 U to 23.04 and 20.57 U at 5 min, respectively) compared to 300 mg oral ASA from mean 87.18 to 75.56 U (p-value, ANCOVA: <0.0001). The rate of bleedings was low and comparable between the groups. In summary, the administration of a single dose of 250 or 500 mg ASA IV compared to 300 mg orally is associated with a faster and more complete inhibition of thromboxane generation and platelet aggregation. Bleeding complications were comparable between the groups.

  15. An examination of binding motifs associated with inter-particle interactions between facetted nano-crystals of acetylsalicylic acid and ascorbic acid through the application of molecular grid-based search methods.

    PubMed

    Hammond, R B; Jeck, S; Ma, C Y; Pencheva, K; Roberts, K J; Auffret, T

    2009-12-01

    Grid-based intermolecular search methods using atom-atom force fields are used to assess the structural nature of potential crystal-crystal interfacial binding associated with the examination of representative pharmaceutical formulation components, viz acetylsalicylic acid (aspirin) and ascorbic acid (vitamin C). Molecular models of nano-sized molecular clusters for these two compounds, shaped in accordance with an attachment energy model of the respective particle morphologies, are constructed and used together with a grid-based search method to model the likely inter-particle interactions. The most-stable, mutual alignments of the respective nano-clusters based on their interaction energies are identified in the expectation that these are indicative of the most likely inter-particle binding configurations. The stable inter-particle binding configurations identified reveal that the number of interfacial hydrogen bonds formed between the binding particles is, potentially, an important factor in terms of the stability of inter-particle cohesion. All preferred inter-particle alignments are found to involve either the (1 0 0) or the (1 1 0) face of aspirin crystals interacting with a number of the growth forms of ascorbic acid. Four main types of interfacial hydrogen bonds are found to be associated with inter-particle binding and involve acceptor-donor interactions between hydroxyl, carbonyl, ester and lactone acceptor groups and hydroxyl donor groups. This hydrogen bonding network is found to be consistent with the surface chemistry of the interacting habit faces with, in general, the number of hydrogen bonds increasing for the more stable alignments. The likely usefulness of this approach for predicting solid-state formulation properties is reviewed.

  16. Simultaneous extraction of acetylsalicylic acid and salicylic acid from human plasma and simultaneous estimation by liquid chromatography and atmospheric pressure chemical ionization/tandem mass spectrometry detection. Application to a pharmacokinetic study.

    PubMed

    Nirogi, Ramakrishna; Kandikere, Vishwottam; Mudigonda, Koteshwara; Ajjala, Devender; Suraneni, Ramakrishna; Thoddi, Parthasarathi

    2011-01-01

    A simple analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in atmospheric chemical ionization mode (APCI) for the simultaneous estimation of acetylsalicylic acid (ASA, CAS 50-78-2) and its active metabolite salicylic acid (SA, CAS 69-72-7) in human plasma has been developed and validated. ASA and SA were analyzed simultaneously despite differences in plasma concentration ranges of ASA and SA after oral administration of ASA. In spite of having different chemical, ionization and chromatographic properties, ASA and SA were extracted simultaneously from the plasma sample using acetonitrile protein precipitation followed by liquid-liquid extraction. The analytes were separated on a reversed phase column with rapid gradient program using mobile phase consisting of ammonium acetate buffer and methanol. The structural analogue diclofenac was used as an internal standard. The multiple reaction monitoring (MRM) transitions m/z 179 --> 137 for ASA, m/z 137 --> 65 for SA and m/z 294 --> 250 for IS were used. The assay exhibited a linear dynamic range of 0.02-10 microg/mL for ASA and 0.1-50 microg/mL for SA. The between-batch precision (%CV) ranged from 2.1 to 7.9% for ASA and from 0.2 to 5.2% for SA. The between-batch accuracy ranged from 95.4 to 96.7% for ASA and from 94.6 to 111.3% for SA. The validated method was successfully applied for the evaluation of pharmacokinetics of ASA after single oral administration of 650 mg test formulation versus two 325 mg reference formulations of ASA in human subjects.

  17. Acetaminophen and Codeine

    MedlinePlus

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

  18. Acetylsalicylic acid and ascorbic acid combination improves cognition; via antioxidant effect or increased expression of NMDARs and nAChRs?

    PubMed

    Kara, Yusuf; Doguc, Duygu Kumbul; Kulac, Esin; Gultekin, Fatih

    2014-05-01

    Chronic inflammation occurs systematically in the central nervous system during ageing, it has been shown that neuroinflammation plays an important role in the pathogenesis of many neurodegenerative disorders. Aspirin, a nonselective COX inhibitor, as well as ascorbic acid, has been purported to protect cerebral tissue. We investigated the effects of subchronic aspirin and ascorbic acid usage on spatial learning, oxidative stress and expressions of NR2A, NR2B, nAChRα7, α4 and β2. Forty male rats (16-18 months) were divided into 4 groups, namely, control, aspirin-treated, ascorbic acid-treated, aspirin+ascorbic acid-treated groups. Following 10-weeks administration period, rats were trained and tested in the Morris water maze. 8-Hydroxy-2-deoxyguanosine and malondialdehyde were evaluated by ELISA and HPLC, respectively. Receptor expressions were assessed by western blotting of hippocampi. Spatial learning performance improved partially in the aspirin group, but significant improvement was seen in the aspirin+ascorbic acid group (p < 0.05). While 8-hydroxy-2-deoxyguanosine and malondialdehyde levels were significantly decreased, NR2B and nAChRα7 expressions were significantly increased in the aspirin+ascorbic acid group as compared to the control group (p < 0.05). Subchronic treatment with aspirin+ascorbic acid in aged rats was shown to enhance cognitive performance and increase the expressions of several receptors related to learning and memory process.

  19. Aspirin sensitivity: acetylsalicylate or excipients.

    PubMed

    Hebron, B S; Hebron, H J

    2009-08-01

    We present three patients who developed urticaria while taking an enteric formulation of aspirin, confirmed on a second exposure. Although hypersensitivity reactions to aspirin, especially in asthmatic patients or those with nasal polyps, are well reported, our patients did not exhibit any underlying history of atopy. Furthermore, two of the patients were able to tolerate a soluble formulation. We review the literature and discuss whether these symptoms might be caused by pharmaceutical excipients, present in very small amounts in the enteric coating, rather than the active ingredient acetylsalicylate. Adverse reactions to excipients are fortunately rare but are occasionally reported.

  20. Highly selective and sensitive voltammetric sensor based on modified multiwall carbon nanotube paste electrode for simultaneous determination of ascorbic acid, acetaminophen and tryptophan.

    PubMed

    Keyvanfard, Mohsen; Shakeri, Razieh; Karimi-Maleh, Hassan; Alizad, Khadijeh

    2013-03-01

    A carbon-paste electrode modified with multiwall carbon nanotubes (MWCNTs) was used for the sensitive and selective voltammetric determination of ascorbic acid (AA) in the presence of 3,4-dihydroxycinnamic acid (3,4-DHCA) as mediator. The mediated oxidation of AA at the modified electrode was investigated by cyclic voltammetry (CV), chronoamperommetry and electrochemical impedance spectroscopy (EIS). Also, the values of catalytic rate constant (k), and diffusion coefficient (D) for AA were calculated. Using square wave voltammetry (SWV), a highly selective and simultaneous determination of AA, acetaminophen (AC) and tryptophan (Trp) has been explored at the modified electrode. The modified electrode displayed strong function for resolving the overlapping voltammetric responses of AA, AC and Trp into three well-defined voltammetric peaks. In the mixture containing AA, AC and Trp, the three compounds can well separate from each other with potential differences of 200, 330 and 530 mV between AA and AC, AC and Trp and AA and Trp, respectively, which was large enough to determine AA, AC and Trp individually and simultaneously.

  1. Protective effects of levamisole, acetylsalicylic acid, and α-tocopherol against dioxin toxicity measured as the expression of AhR and COX-2 in a chicken embryo model.

    PubMed

    Gostomska-Pampuch, Kinga; Ostrowska, Alicja; Kuropka, Piotr; Dobrzyński, Maciej; Ziółkowski, Piotr; Kowalczyk, Artur; Łukaszewicz, Ewa; Gamian, Andrzej; Całkosiński, Ireneusz

    2017-04-01

    Polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are classed as persistent organic pollutants and have adverse effects on multiple functions within the body. Dioxins are known carcinogens, immunotoxins, and teratogens. Dioxins are transformed in vivo, and interactions between the products and the aryl hydrocarbon receptor (AhR) lead to the formation of proinflammatory and toxic metabolites. The aim of this study was to determine whether α-tocopherol (vitamin E), acetylsalicylic acid (ASA), and levamisole can decrease the amount of damage caused by dioxins. Fertile Hubbard Flex commercial line chicken eggs were injected with solutions containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or containing TCDD and the test compounds. The chicken embryos and organs were analyzed after 7 and 13 days. The levels at which AhR and cyclooxygenase-2 (COX-2) proteins (which are induced during inflammation) were expressed were evaluated by performing immunohistochemical analyses on embryos treated with TCDD alone or with TCDD and the test compounds. TCDD caused developmental disorders and increased AhR and COX-2 expression in the chicken embryo tissues. Vitamin E, levamisole, ASA, and ASA plus vitamin E inhibited AhR and COX-2 expression in embryos after 7 days and decreased AhR and COX-2 expression in embryos after 13 days. ASA, levamisole, and ASA plus vitamin E weakened the immune response and prevented multiple organ changes. Vitamin E was not fully protective against developmental changes in the embryos.

  2. Ferulic acid attenuated acetaminophen-induced hepatotoxicity though down-regulating the cytochrome P 2E1 and inhibiting toll-like receptor 4 signaling-mediated inflammation in mice

    PubMed Central

    Yuan, Junhui; Ge, Kuang; Mu, Junhuan; Rong, Jiang; Zhang, Li; Wang, Bin; Wan, Jingyuan; Xia, Gong

    2016-01-01

    Ferulic acid (FA), a phenolic acid which is abundant in vegetables and fruits, has been reported to exert anti-oxidative and anti-inflammatory activities. In the present study, the pharmacological effects and the underlying mechanisms of FA in mice with acetaminophen-induced hepatotoxicity were investigated. Our results revealed that FA pretreatment inhibited the augments of serum aminotransferases in a dose-dependent manner and attenuated the hepatic histopathological abnormalities and hepatocellular apoptosis in acetaminophen (APAP) exposed mice. Moreover, FA inhibited the expression of cytochrome P450 2E1 (CYP2E1), enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) as well as the contents of glutathione (GSH). Furthermore, FA markedly attenuated acetaminophen-induced serum tumor necrosis factor (TNF)-α and interleukin (IL)-1β production, suppressed Toll-like receptor (TLR) 4 expression and dampened p38 mitogen-activated (MAPK) and nuclear factor kappa (NF-κB) activation. These data suggested that FA could effectively protect against APAP-induced liver injury by down-regulated expression of CYP 2E1 and the suppression of TLR4-mediated inflammatory responses. PMID:27830004

  3. A randomized, controlled study on the influence of acetaminophen, diclofenac, or naproxen on aspirin-induced inhibition of platelet aggregation.

    PubMed

    Galliard-Grigioni, Katja S; Reinhart, Walter H

    2009-05-01

    Nonsteroidal anti-inflammatory drugs (NSAID) may interfere with aspirin (acetylsalicylic acid) and increase the risk for cardiovascular events. The clinical relevance is uncertain. The aim of this study was to analyse the influence of a co-administration of aspirin and NSAID on platelet aggregation. In a randomized, placebo controlled trial, eleven healthy volunteers were studied during 4 separate study periods of 4 days each. Individuals were treated on each occasion with 100 mg aspirin daily in combination with either 3 x 1 g acetaminophen, 3 x 50 mg diclofenac, 3 x 250 mg naproxen, or 3 x 1 placebo. Primary hemostasis was assessed with a platelet function analyser (PFA-100), which measures the closure time (CT) of a collagen- and epinephrine-coated pore by aggregating platelets in flowing blood. Naproxen enhanced the anti-aggregatory action of aspirin after 24 h (CT rising from 104+/-16 s at baseline to 212+/-69 s at 24 h, P<0.001), which was not seen with any other drug combination. Diclofenac reduced the anti-aggregatory action of aspirin in the first two days, since the CT did not rise significantly (109+/-19 s, 148+/-56 s, and 168+/-66 s at 0 h, 24 h, 48 h, respectively, P>0.05). Acetaminophen had no effect compared with placebo. After 4 days of treatment platelet aggregation was similarly inhibited by all combinations. We conclude that a co-administration of NSAID and aspirin may interfere with platelet inhibition at the beginning of a treatment with an increase of naproxen and a decrease of diclofenac. This effect is lost after 4 days, suggesting that a regular daily co-administration of NSAID does not have an influence on platelet inhibition by aspirin.

  4. Au/ZnO hybrid nanocatalysts impregnated in N-doped graphene for simultaneous determination of ascorbic acid, acetaminophen and dopamine.

    PubMed

    Chen, Xianlan; Zhang, Guowei; Shi, Ling; Pan, Shanqing; Liu, Wei; Pan, Hiabo

    2016-08-01

    The formation of nitrogen-doped (N-doped) graphene uses hydrothermal method with urea as reducing agent and nitrogen source. The surface elemental composition of the catalyst was analyzed through XPS, which showed a high content of a total N species (7.12at.%), indicative of the effective N-doping, present in the form of pyridinic N, pyrrolic N and graphitic N groups. Moreover, Au nanoparticles deposited on ZnO nanocrystals surface, forming Au/ZnO hybrid nanocatalysts, undergo a super-hydrophobic to super-hydrophilic conversion. Herein, we present Au/ZnO hybrid nanocatalysts impregnated in N-doped graphene sheets through sonication technique of the Au/ZnO/N-doped graphene hybrid nanostructures. The as-prepared Au/ZnO/N-doped graphene hybrid nanostructure modified glassy carbon electrode (Au/ZnO/N-doped graphene/GCE) was first employed for the simultaneous determination of ascorbic acid (AA), dopamine (DA) and acetaminophen (AC). The oxidation over-potentials of AA, DA and AC decreased dramatically, and their oxidation peak currents increased significantly at Au/ZnO/N-doped graphene/GCE compared to those obtained at the N-doped graphene/GCE and bare CCE. The peak separations between AA and DA, DA and AC, and AC and AA are large up to 195, 198 and 393mV, respectively. The calibration curves for AA, DA and AC were obtained in the range of 30.00-13.00×10(3), 2.00-0.18×10(3) and 5.00-3.10×10(3)μM, respectively. The detection limits (S/N=3) were 5.00, 0.40 and 0.80μM for AA, DA and AC, respectively.

  5. Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways.

    PubMed

    Lin, Musen; Zhai, Xiaohan; Wang, Guangzhi; Tian, Xiaofeng; Gao, Dongyan; Shi, Lei; Wu, Hang; Fan, Qing; Peng, Jinyong; Liu, Kexin; Yao, Jihong

    2015-02-01

    Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury.

  6. Characterization of niflumic acid as a selective inhibitor of human liver microsomal UDP-glucuronosyltransferase 1A9: application to the reaction phenotyping of acetaminophen glucuronidation.

    PubMed

    Miners, John O; Bowalgaha, Kushari; Elliot, David J; Baranczewski, Pawel; Knights, Kathleen M

    2011-04-01

    Enzyme selective inhibitors represent the most valuable experimental tool for reaction phenotyping. However, only a limited number of UDP-glucuronosyltransferase (UGT) enzyme-selective inhibitors have been identified to date. This study characterized the UGT enzyme selectivity of niflumic acid (NFA). It was demonstrated that 2.5 μM NFA is a highly selective inhibitor of recombinant and human liver microsomal UGT1A9 activity. Higher NFA concentrations (50-100 μM) inhibited UGT1A1 and UGT2B15 but had little effect on the activities of UGT1A3, UGT1A4, UGT1A6, UGT2B4, UGT2B7, and UGT2B17. NFA inhibited 4-methylumbelliferone and propofol (PRO) glucuronidation by recombinant UGT1A9 and PRO glucuronidation by human liver microsomes (HLM) according to a mixed (competitive-noncompetitive) mechanism, with K(i) values ranging from 0.10 to 0.40 μM. Likewise, NFA was a mixed or noncompetitive inhibitor of recombinant and human liver microsomal UGT1A1 (K(i) range 14-18 μM), whereas competitive inhibition (K(i) 62 μM) was observed with UGT2B15. NFA was subsequently applied to the reaction phenotyping of human liver microsomal acetaminophen (APAP) glucuronidation. Consistent with previous reports, APAP was glucuronidated by recombinant UGT1A1, UGT1A6, UGT1A9, and UGT2B15. NFA concentrations in the range of 2.5 to 100 μM inhibited APAP glucuronidation by UGT1A1, UGT1A9, and UGT2B15 but not by UGT1A6. The mean V(max) for APAP glucuronidation by HLM was reduced by 20, 35, and 40%, respectively, in the presence of 2.5, 50, and 100 μM NFA. Mean K(m) values decreased in parallel with V(max), although the magnitude of the decrease was smaller. Taken together, the NFA inhibition data suggest that UGT1A6 is the major enzyme involved in APAP glucuronidation.

  7. A double signal amplification platform for ultrasensitive and simultaneous detection of ascorbic acid, dopamine, uric acid and acetaminophen based on a nanocomposite of ferrocene thiolate stabilized Fe₃O₄@Au nanoparticles with graphene sheet.

    PubMed

    Liu, Meiling; Chen, Qiong; Lai, Cailang; Zhang, Youyu; Deng, Jianhui; Li, Haitao; Yao, Shouzhuo

    2013-10-15

    A double signal amplification platform for ultrasensitive and simultaneous detection of ascorbic acid (AA), dopamine (DA), uric acid (UA) and acetaminophen (AC) was fabricated by a nanocomposite of ferrocene thiolate stabilized Fe₃O₄@Au nanoparticles with graphene sheet. The platform was constructed by coating a newly synthesized phenylethynyl ferrocene thiolate (Fc-SAc) modified Fe₃O₄@Au NPs coupling with graphene sheet/chitosan (GS-chitosan) on a glassy carbon electrode (GCE) surface. The Fe₃O₄@Au-S-Fc/GS-chitosan modified GCE exhibits a synergistic catalytic and amplification effect toward AA, DA, UA and AC oxidation. The oxidation peak currents of the four compounds on the electrode were linearly dependent on AA, DA, UA and AC concentrations in the ranges of 4-400 μM, 0.5-50 μM, 1-300 μM and 0.3-250 μM in the individual detection of each component, respectively. By simultaneously changing the concentrations of AA, DA, UA and AC, their electrochemical oxidation peaks appeared at -0.03, 0.15, 0.24 and 0.35 V, and good linear current responses were obtained in the concentration ranges of 6-350, 0.5-50, 1-90 and 0.4-32 μM with the detection limits of 1, 0.1, 0.2 and 0.05 μM (S/N=3), respectively.

  8. [The action of the proton pump inhibitor pantoprazol against acetylsalicylic acid-induced gastroduodenopathy in comparison to ranitidine. An endoscopic controlled, double blind comparison].

    PubMed

    Müller, P; Simon, B

    1998-05-01

    In a randomised double-blind parallel study the gastroduodenal tolerability of 300 mg acetylsalicilic acid daily (ASA, CAS 50-78-2) has been evaluated in the presence of placebo (n = 8), 40 mg pantoprazole (CAS 102625-70-7) daily (8 a.m.) (n = 16) and 300 mg ranitidine (CAS 66357-35-5) daily (8 a.m.) (n = 16) in healthy volunteers using upper GI-endoscopy. The treatment period lasted 14 days, endoscopic controls were performed at entry and repeated at day 14. At entry, the mean endoscopic score averaged 1.0 +/- 0.0 (+/- SEM) in the ASA/placebo, in the ASA/pantoprazole and the ASA/ranitidine group. In the placebo experiments 300 mg ASA daily induced marked gastroduodenal lesions at day 14 (lesion score of 6.8 +/- 1.4 (+/- SEM). Concomitant administration of 40 mg pantoprazole daily offered significant protection against 300 mg ASS daily on day 14 (2.1 +/- 0.6) (+/- SEM) (p < 0.05) vs ASA/placebo. 300 mg ASA plus 300 mg ranitidine daily reduced the damaging score to 4.9 +/- 1.2 (+/- SEM) (n.s. vs ASA/ placebo). Our data suggest that coadministration of 40 mg pantoprazole daily reduces significantly gastroduodenal lesions evoked by 300 mg ASA daily.

  9. Effect of ultrasonic irradiation on the number of acetylsalicylic acid crystals produced under the supersaturated condition and the ability of controlling the final crystal size via primary nucleation

    NASA Astrophysics Data System (ADS)

    Miyasaka, Etsuko; Kato, Yumi; Hagisawa, Minoru; Hirasawa, Izumi

    2006-03-01

    The purposes of this study were to investigate the effects of ultrasound irradiation on the number of crystals formed in an acetylsalicyclic acid crystallization process and to assess the controllability of the final product size via the number of primary nuclei. The number of crystals present after primary nucleation was counted and the relationship between the final product size and the number of crystals was examined. Additionally, the growing ASA crystals were observed, since ultrasound energy not only may control primary nucleation but may also the perfection of the crystal shape. At a high level of ultrasonic energy, ultrasound irradiation increased the average number of crystals, an effect that has been reported often; however, at a low level of ultrasonic energy it decreased the average number of crystals, and moreover, these opposing ultrasonic effects on the number of crystals interchanged at a specific energy threshold. These results reveal two novel phenomena—that there is an energy region where ultrasonic irradiation inhibits primary nucleation, and that a specific amount of ultrasonic energy is needed to activate primary nucleation. On the other hand, the final product size almost depended upon the number of primary nuclei, indicating that the final product size could be controlled via the number of crystals influenced by ultrasound irradiation. According to the photographs of crystals, they were not destroyed by the process. Therefore, it was proposed that ultrasound energy does not destroy the perfection of the crystal shape but only controls primary nucleation under the condition: both short irradiation time and low supersaturated condition.

  10. Acetaminophen and meloxicam inhibit platelet aggregation and coagulation in blood samples from humans.

    PubMed

    Martini, Angela K; Rodriguez, Cassandra M; Cap, Andrew P; Martini, Wenjun Z; Dubick, Michael A

    2014-12-01

    Acetaminophen (Ace) and meloxicam (Mel) are the two types of analgesic and antipyretic medications. This study investigated the dose responses of acetaminophen and meloxicam on platelet aggregation and coagulation function in human blood samples. Blood samples were collected from six healthy humans and processed to make platelet-adjusted (100 × 10 cells/μl) blood samples. Acetaminophen (Tylenol, Q-PAP, 100 mg/ml) was added at the doses of 0 μg/ml (control), 214 μg/ml (the standard dose, 1 ×), 4 ×, 8 ×, 10 ×, 12 ×, 16 ×, and 20 ×. Similarly, meloxicam (Metacam, 5 mg/ml) was added at doses of 0 μg/ml (control), 2.85 μg/ml (the standard dose, 1 ×), 4 ×, 8 ×, 10 ×, 12 ×, 16 ×, and 20 ×. Fifteen minutes after the addition of acetaminophen and/or meloxicam, platelet aggregation was stimulated with collagen (2 μg/ml) or arachidonic acid (0.5 mmol/l) and assessed using a Chrono-Log 700 aggregometer. Coagulation function was assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT), and using Rotem thrombelastogram. A robust inhibition by acetaminophen and/or meloxicam was observed in arachidonic acid-stimulated platelet aggregation starting at 1 × dose. Collagen-stimulated platelet aggregation was inhibited by ACE starting at 1 × (78 ± 10% of control), and by meloxicam starting at 4 × (72 ± 5% of control, both P < 0.05). The inhibitions by acetaminophen and meloxicam combined were similar to those by acetaminophen or meloxicam. aPTT was prolonged by meloxicam starting at 4 ×. No changes were observed in PT or any of Rotem measurements by acetaminophen and/or meloxicam. Acetaminophen and meloxicam compromised platelet aggregation and aPTT. Further effort is warranted to characterize the effects of acetaminophen and meloxicam on bleeding in vivo.

  11. Acetaminophen and Children: Why Dosage Matters

    MedlinePlus

    Healthy Lifestyle Children's health An acetaminophen overdose is serious — and it can happen easier than you might think. ... 29, 2017 Original article: http://www.mayoclinic.org/healthy-lifestyle/childrens-health/in-depth/acetaminophen/art-20046721 . Mayo ...

  12. Intravenous paracetamol (acetaminophen).

    PubMed

    Duggan, Sean T; Scott, Lesley J

    2009-01-01

    Intravenous paracetamol (rINN)/intravenous acetaminophen (USAN) is an analgesic and antipyretic agent, recommended worldwide as a first-line agent for the treatment of pain and fever in adults and children. In double-blind clinical trials, single or multiple doses of intravenous paracetamol 1 g generally provided significantly better analgesic efficacy than placebo treatment (as determined by primary efficacy endpoints) in adult patients who had undergone dental, orthopaedic or gynaecological surgery. Furthermore, where evaluated, intravenous paracetamol 1 g generally showed similar analgesic efficacy to a bioequivalent dose of propacetamol, and a reduced need for opioid rescue medication. In paediatric surgical patients, recommended doses of intravenous paracetamol 15 mg/kg were not significantly different from propacetamol 30 mg/kg for the treatment of pain, and showed equivocal analgesic efficacy compared with intramuscular pethidine 1 mg/kg in several randomized, active comparator-controlled studies. In a randomized, noninferiority study in paediatric patients with an infection-induced fever, intravenous paracetamol 15 mg/kg treatment was shown to be no less effective than propacetamol 30 mg/kg in terms of antipyretic efficacy. Intravenous paracetamol was well tolerated in clinical trials, having a tolerability profile similar to placebo. Additionally, adverse reactions emerging from the use of the intravenous formulation of paracetamol are extremely rare (<1/10 000). [table: see text].

  13. Transcriptomic studies on liver toxicity of acetaminophen.

    PubMed

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

    2014-09-01

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

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

    PubMed

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

    2015-12-05

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

  15. [Clinical study on a new acetylsalicylic acid/paracetamol preparation with gastric acid resistant coating (Safapryn), and on two various phenylbutazone dosages in patients with primary chronic polyarthritis as based on a new evaluation method].

    PubMed

    Brooks, P M; Walker, J J; Lee, P; Bell, A M; Buchanan, W W; Fowler, P D; Anderson, J A

    1975-01-01

    The authors describe a simple non-crossover-blind test for the evaluation of subjective indices. A table for recording pains during the 14 days' study is described. The patient's satisfaction with the treatment and the number of days until withdrawal from the trial are recorded. The statistical procedure takes into consideration differences between the treatment groups and makes possible a valuable comparison with drugs tested in other clinical trials. The three dose schedules of antirheumatic treatment were tested on 122 patients and the results compared with those of 342 patients treated with the 6 other antirheumatic drugs (enteric-coated aspirin, paracetamol, indomethacin, flurbiprofen, mefenamic acid, and prednisolone) and those of 41 patients who received placebos. The results show that Safapryn (3,6 g aspirin + 3.0 g paracetamol daily) compared with 3.9 g enteric coated aspirin does not offer any advantage in its analgesic effect, although it gives rise to fewer side effects. Phenylbutazone (3000 mg) was almost as effective as 15 mg prednisolone daily. Between the effects of this dosage of phenylbutazone and other non-steroidal antirheumatic drugs, however, no significant difference could be detected. 50 mg phenylbutazone daily and placebo treatment could not be distinguished. The authors thank the Arthritis and Rheumatism Council for Research in Great Britain for its financial support. One of the authors (PL) was a Merck, Sharp, and Dohme Research Fellow and another one (PMB) received a Robins research scholarship.

  16. Acetaminophen use and asthma in children

    PubMed Central

    Sakulchit, Teeranai; Goldman, Ran D.

    2017-01-01

    Abstract Question A child with a history of asthma came to my clinic with acute fever. I have heard that acetaminophen might be associated with exacerbation of asthma. Is it safe if I recommend acetaminophen for this child? Answer Most studies suggest an association between acetaminophen use in children and development of asthma later in childhood. However, several confounding factors in study design might contribute to this positive correlation, and without a prospective controlled trial, confirming this finding is challenging. If children have a known history of asthma, it is likely safe to administer a single dose of acetaminophen without concern of precipitating adverse respiratory symptoms. Regular use of acetaminophen to relieve fever or pain does not seem to exacerbate asthma in children more than ibuprofen does. PMID:28292797

  17. Acetaminophen use and asthma in children.

    PubMed

    Sakulchit, Teeranai; Goldman, Ran D

    2017-03-01

    Question A child with a history of asthma came to my clinic with acute fever. I have heard that acetaminophen might be associated with exacerbation of asthma. Is it safe if I recommend acetaminophen for this child? Answer Most studies suggest an association between acetaminophen use in children and development of asthma later in childhood. However, several confounding factors in study design might contribute to this positive correlation, and without a prospective controlled trial, confirming this finding is challenging. If children have a known history of asthma, it is likely safe to administer a single dose of acetaminophen without concern of precipitating adverse respiratory symptoms. Regular use of acetaminophen to relieve fever or pain does not seem to exacerbate asthma in children more than ibuprofen does.

  18. Eucalyptus globulus extract protects upon acetaminophen-induced kidney damages in male rat

    PubMed Central

    Dhibi, Sabah; Mbarki, Sakhria; Elfeki, Abdelfettah; Hfaiedh, Najla

    2014-01-01

    Plants have historically been used in treating many diseases. Eucalyptus globules, a rich source of bioactive compounds, and have been shown to possess antioxidative properties. The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of Eucalyptus globulus extract upon acetaminophen-induced damages in kidney. Our study is realized in the Department of Biology, Faculty of Sciences of Sfax (Tunisia). 32 Wistar male rats; were divided into 4 batches: a control group (n=8), a group of rats treated with acetaminophen (goomg/kg) by intraperitoneal injection during 4 days (n=8), a group receiving Eucalyptus globulus extract (130 mg of dry leaves/kg/day) in drinking water during 42 days after 2 hours of acetaminophen administration (during 4 days) (n=8) and group received only Eucalyptus (n=8) during 42 days. After 6 weeks, animals from each group were rapidly sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, acetaminophen poisoning resulted in an oxidative stress evidenced by statistically significant losses in the activities of catalase (CAT), superoxide-dismutase (SOD), glutathione-peroxidase (GPX) activities and an increase in lipids peroxidation level in renal tissue of acetaminophen-treated group compared with the control group. Acetaminophen also caused kidney damage as evident by statistically significant (p<0.05) increase in levels of creatinine and urea and decreased levels of uric acid and proteins in blood. Histological analysis demonstrated alteration of proximal tubules, atrophy of the glomerule and dilatation of urinary space. Previous administration of plant extract is found to alleviate this acetaminophen-induced damage. PMID:24856382

  19. The Social Side Effects of Acetaminophen

    NASA Astrophysics Data System (ADS)

    Mischkowski, Dominik

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

  20. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.

    PubMed

    Stern, Stephan T; Bruno, Mary K; Horton, Robert A; Hill, Dennis W; Roberts, Jeanette C; Cohen, Steven D

    2005-01-15

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

  1. Acetaminophen toxicity with concomitant use of carbamazepine.

    PubMed

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

    2009-12-01

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

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

    PubMed Central

    Paul, Sudip; Islam, Md. Aminul; Tanvir, E. M.; Ahmed, Romana; Das, Sagarika; Rumpa, Nur-E-Noushin; Hossen, Md. Sakib; Parvez, Mashud; Gan, Siew Hua; Khalil, Md. Ibrahim

    2016-01-01

    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. PMID:27034701

  3. Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors.

    PubMed

    Kwan, D; Bartle, W R; Walker, S E

    1995-09-01

    J.M., a healthy, 25-year-old male, volunteered for a study involving warfarin and acetaminophen. Acetaminophen 1 g four times a day was started for 21 days. Liver function tests taken at regular intervals for the first 12 days were unremarkable. On day 18, however, aspartate aminotransferase (AST) was 527 IU/liter and alanine aminotransferase (ALT) was 166 IU/liter. Acetaminophen was discontinued and serum transaminase levels returned to baseline levels two weeks later (AST = 26, ALT = 20). Analysis of J.M.'s urine samples over the first 18 days showed excretion patterns of glucuronide, sulfate, and glutathione derived cysteine and mercapturic acid conjugates were similar to the other subjects in the study. Acetaminophen causes hepatotoxicity in overdose or malnourished or alcoholic patients, none of which applied to our subject. Differences in metabolic activation and capacity for glutathione synthesis can predispose individuals given therapeutic doses of acetaminophen to adverse effects. Failure to detoxify a highly reactive metabolite, formed by P-450 metabolism, via glutathione conjugation is responsible for the development of acute hepatic necrosis. Accumulation of the toxic metabolite due to depleted glutathione stores may have occurred with prolonged high dosing in our subject and been responsible for his abnormal rise in liver enzymes.

  4. Did acetaminophen provoke the autism epidemic?

    PubMed

    Good, Peter

    2009-12-01

    Schultz et al (2008) raised the question whether regression into autism is triggered, not by the measles-mumps-rubella (MMR) vaccine, but by acetaminophen (Tylenol) given for its fever and pain. Considerable evidence supports this contention, most notably the exponential rise in the incidence of autism since 1980, when acetaminophen began to replace aspirin for infants and young children. The impetus for this shift - a Centers for Disease Control and Prevention warning that aspirin was associated with Reye's syndrome - has since been compellingly debunked. If aspirin is not to be feared as a cause of Reyes syndrome, and acetaminophen is to be feared as a cause of autism, can the autism epidemic be reversed by replacing acetaminophen with aspirin or other remedies?

  5. Reversed-phase HPLC method for the estimation of acetaminophen, ibuprofen and chlorzoxazone in formulations.

    PubMed

    Ravisankar, S; Vasudevan, M; Gandhimathi, M; Suresh, B

    1998-08-01

    A simple, precise and rapid reversed-phase HPLC method was developed for the simultaneous estimation of acetaminophen, ibuprofen and chlorzoxazone in formulations. The method was carried out on a Kromasil(R) C(8) column using a mixture of 0.2% triethylamine:acetonitrile (adjusted to pH 3.2 using dilute orthophosphoric acid), and detection was carried out at 215 nm using ketoprofen as internal standard. All these drugs showed linearity in the range of 2-10 mug ml(-1), and limits of quantification was found to be 10, 50 and 20 ng ml(-1) for acetaminophen, ibuprofen and chlorzoxazone, respectively.

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

    PubMed

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

    2014-09-01

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

  7. Limited Knowledge of Acetaminophen in Patients with Liver Disease

    PubMed Central

    Saab, Sammy; Konyn, Peter G.; Viramontes, Matthew R.; Jimenez, Melissa A.; Grotts, Jonathan F.; Hamidzadah, Wally; Dang, Veronica P.; Esmailzadeh, Negin L.; Choi, Gina; Durazo, Francisco A.; El-Kabany, Mohamed M.; Han, Steven-Huy B.; Tong, Myron J.

    2016-01-01

    Abstract Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease. Methods: We performed a cross-sectional study of patients with liver disease at the Pfleger Liver Institute at the University of California, Los Angeles between June 2015 and August 2016. Patients completed a demographic questionnaire and an acetaminophen knowledge survey. Additional information was obtained from the medical record. Results: Of 401 patients with liver disease, 30 (15.7%) were able to correctly identify that people without liver disease can safely take up to 4 g/day of acetaminophen. The majority of patients (79.9%–86.8%) did not know that Norco® (hydrocone/acetaminophen), Vicodin® (hydrocone/acetaminophen) and Percocet® (oxycodone/acetaminophen) contained acetaminophen. Only 45.3% of the patients knew that Tylenol® #3 contained acetaminophen. Conclusions: We conclude that patients with liver disease have critically low levels of knowledge of acetaminophen, putting them at risk both of acetaminophen overdose, as well as undermedication, and inadequate management of chronic pain. We recommend an increase in education efforts regarding acetaminophen dosage and its safety in the setting of liver disease. Increasing education for those at risk of low acetaminophen knowledge is essential to minimizing acetaminophen overdose rates and optimizing pain management. PMID:28097095

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

    PubMed

    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 < 0.05) increased in 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. Parents: Acetaminophen in Pain Relief Medicines Can Cause Liver Damage

    MedlinePlus

    ... Parents: Acetaminophen in pain relief medicines can cause liver damage Share Tweet Linkedin Pin it More sharing ... whole word or may have the abbreviation "APAP." Liver damage: Giving your child more acetaminophen than directed ...

  10. Transplacental Passage of Acetaminophen in Term Pregnancy.

    PubMed

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

    2016-11-02

    Objective The objective of this study was to determine the maternal and fetal pharmacokinetic (PK) profiles of acetaminophen after administration of a therapeutic oral dose. Study Design After obtaining Institutional Review Board approval and their written informed consent, pregnant women were given a single oral dose (1,000 mg) of acetaminophen upon admission for scheduled cesarean delivery. Maternal venous blood and fetal cord blood were obtained at the time of delivery and acetaminophen levels were measured using gas chromatography-mass spectroscopy. PK parameters were calculated by noncompartmental analysis. Nonparametric correlation of maternal/fetal acetaminophen levels and PK curves were calculated. Results In this study, 34 subjects were enrolled (median, 32 years; range, 25-39 years). The median maternal weight was 82 kg (range, 62-100 kg). All but two subjects were delivered beyond 39 weeks' gestation. The median newborn birth weight was 3,590 g (interquartile range, 3,403-3,848 g). Noncompartmental analysis described similar PK parameters in the maternal (T1/2, 84 minutes; apparent clearance [Cl/F], 28.8 L/h; apparent volume of distribution [Vd/F], 57.5 L) and fetal compartments (T1/2, 82 minutes; Cl/F, 31.2 L/h; Vd/F, 61.2 L). Paired maternal/fetal acetaminophen levels were highly correlated (p < 0.0001). Conclusion Fetal acetaminophen PKs in the fetus parallels that in the mother suggesting that placental transfer is flow limited. Maternal acetaminophen levels can be used as a surrogate for fetal exposure.

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

    PubMed

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

    2013-06-01

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

  12. Nonsteroidal antiinflammatory drugs, acetaminophen, and hypertension.

    PubMed

    Sudano, Isabella; Flammer, Andreas J; Roas, Susanne; Enseleit, Frank; Noll, Georg; Ruschitzka, Frank

    2012-08-01

    Selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen belong to the most widely prescribed therapeutic agents worldwide. Their efficacy in pain relief notwithstanding, the use of NSAIDs is associated with an increased cardiovascular risk, which can be partly attributed to their blood pressure raising potential. Adequately powered placebo-controlled trials specifically evaluating the cardiovascular safety of NSAIDs vs. selective COX inhibitors are currently underway. This review summarizes the current knowledge on the cardiovascular effects of NSAIDs and acetaminophen, and their potential clinical consequences.

  13. Multi-walled Carbon Nanotubes/Graphite Nanosheets Modified Glassy Carbon Electrode for the Simultaneous Determination of Acetaminophen and Dopamine.

    PubMed

    Zhang, Susu; He, Ping; Zhang, Guangli; Lei, Wen; He, Huichao

    2015-01-01

    Graphite nanosheets prepared by thermal expansion and successive sonication were utilized for the construction of a multi-walled carbon nanotubes/graphite nanosheets based amperometric sensing platform to simultaneously determine acetaminophen and dopamine in the presence of ascorbic acid in physiological conditions. The synergistic effect of multi-walled carbon nanotubes and graphite nanosheets catalyzed the electrooxidation of acetaminophen and dopamine, leading to a remarkable potential difference up to 200 mV. The as-prepared modified electrode exhibited linear responses to acetaminophen and dopamine in the concentration ranges of 2.0 × 10(-6) - 2.4 × 10(-4) M (R = 0.999) and 2.0 × 10(-6) - 2.0 × 10(-4) M (R = 0.998), respectively. The detection limits were down to 2.3 × 10(-7) M for acetaminophen and 3.5 × 10(-7) M for dopamine (S/N = 3). Based on the simple preparation and prominent electrochemical properties, the obtained multi-walled carbon nanotubes/graphite nanosheets modified electrode would be a good candidate for the determination of acetaminophen and dopamine without the interference of ascorbic acid.

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

    PubMed

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

    2017-02-01

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

  15. Aspirin (acetylsalicylic acid) effects on behavioral thermoregulation with microwave radiation.

    PubMed

    Vitulli, W F; Laconsay, K L; Agnew, A C; Henderson, M E; Quinn, J M; Holland, B E; DePace, A N

    1993-08-01

    Aspirin is a widely used over-the-counter drug in our society which has wide therapeutic value, yet not all of the behavioral side effects have been studied. Different doses of aspirin solutions were administered (ip) prior to fixed-interval 2-min. schedules of microwave reinforcement in rats tested in a cold environment. Four Sprague-Dawley rats were conditioned to regulate their thermal environment with 5-sec. exposures of MW reinforcement. Friedman's nonparametric test showed significant differences among aspirin and saline-control doses. Post hoc sign tests showed that a moderate dose of aspirin increased operant behavior reinforced by MW radiation, yet lower and higher doses decreased and then increased the rate of responding which resulted in an inverted U-shaped trend. Possible multiple effects of aspirin in terms of its thermoregulatory as well as its pain-tolerance properties, and implications for hypothalamic "set point" are discussed.

  16. Acetaminophen-induced cellulitis-like fixed drug eruption.

    PubMed

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

    2011-03-01

    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 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.

  17. Acetaminophen and Meloxicam Inhibit Platelet Aggregation and Coagulation in Blood Samples from Humans

    DTIC Science & Technology

    2014-01-01

    participant was sampled once with a total of 100-ml blood volume. Exclusion criteria included pregnancy, on- going therapeutic anticoagulation , and use...of thromboxane A2 (TxA2) from prostaglandin H2, which is generated from arachidonic acid by cyclo-oxygenase (COX-1). The antiplatelet effects of...is acetaminophen? Some practical cautions with this widely used agent . Clin Pediatr (Phila) 1973; 12:692– 696. 3 Whyte IM, Buckley NA, Reith DM

  18. Acetaminophen overdose associated with double serum concentration peaks

    PubMed Central

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

    2015-01-01

    Acetaminophen is the most commonly used analgesic–antipyretic medication in the United States. Acetaminophen overdose, a frequent cause of drug toxicity, has been recognized as the leading cause of fatal and non-fatal hepatic necrosis. N-Acetylcysteine is the recommended antidote for acetaminophen poisoning. Despite evidence on the efficacy of N-acetylcysteine for prevention of hepatic injury, controversy persists about the optimal duration of the therapy. Here, we describe the case of a 65-year-old male with acetaminophen overdose and opioid co-ingestion who developed a second peak in acetaminophen serum levels after completing the recommended 21-hour intravenous N-acetylcysteine protocol and when the standard criteria for monitoring drug levels was achieved. Prolongation of N-acetylcysteine infusion beyond the standard protocol, despite a significant gap in treatment, was critical for successful avoidance of hepatotoxicity. Delay in acetaminophen absorption may be associated with a second peak in serum concentration following an initial declining trend, especially in cases of concomitant ingestion of opioids. In patients with acetaminophen toxicity who co-ingest other medications that may potentially delay gastric emptying or in those with risk factors for delayed absorption of acetaminophen, we recommend close monitoring of aminotransferase enzyme levels, as well as trending acetaminophen concentrations until undetectable before discontinuing the antidote therapy. PMID:26653695

  19. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen-treated mice.

    PubMed

    Pumford, N R; Hinson, J A; Potter, D W; Rowland, K L; Benson, R W; Roberts, D W

    1989-01-01

    Using a recently developed enzyme-linked immunosorbent assay specific for 3-(cystein-S-yl)acetaminophen adducts we have quantitated the formation of these specific adducts in liver and serum protein of B6C3F1 male mice dosed with acetaminophen. Administration of acetaminophen at doses of 50, 100, 200, 300, 400 and 500 mg/kg to mice resulted in evidence of hepatotoxicity (increase in serum levels of alanine aminotransferase and aspartate aminotransferase) at 4 hr in the 300, 400 and 500 mg/kg treatment groups only. The formation of 3-(cystein-S-yl)acetaminophen adducts in liver protein was not observed in the groups receiving 50, 100 and 200 mg/kg doses, but was observed in the groups receiving doses above 300 mg/kg of acetaminophen. Greater levels of adduct formation were observed at the higher doses. 3-(Cystein-S-yl)acetaminophen protein adducts were also observed in serum of mice receiving hepatotoxic doses of acetaminophen. After a 400 mg/kg dose of acetaminophen, 3-(cystein-S-yl)acetaminophen adducts in the liver protein reached peak levels 2 hr after dosing. By 12 hr the levels decreased to approximately 10% of the peak level. In contrast, 3-(cystein-S-yl)acetaminophen adducts in serum protein were delayed, reaching a sustained peak 6 to 12 hr after dosing. The dose-response correlation between the appearance of serum aminotransferases and 3-(cystein-S-yl)acetaminophen adducts in serum protein and the temporal correlation between the decrease in 3-(cystein-S-yl)acetaminophen adducts in liver protein and the appearance of adducts in serum protein are consistent with a hepatic origin of the adducts detected in serum protein.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Sensitive detection of acetaminophen based on Fe₃O₄ nanoparticles-coated poly(diallyldimethylammonium chloride)-functionalized graphene nanocomposite film.

    PubMed

    Lu, Daban; Zhang, Yan; Wang, Letao; Lin, Shaoxiong; Wang, Chunming; Chen, Xiaofeng

    2012-01-15

    An electrochemical sensor based on Fe(3)O(4) nanoparticles (NPs)-coated poly(diallyldimethylammonium chloride) (PDDA)-functionalized graphene (Fe(3)O(4)-PDDA-G) nanocomposite was fabricated for sensitive detection of acetaminophen. The nanocomposite was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The electrochemical behaviors of acetaminophen on Fe(3)O(4)-PDDA-G composite film modified glassy carbon electrode (GCE) were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The experimental results indicated that the incorporation of Fe(3)O(4) NPs with PDDA-G greatly enhanced the electrochemical response of acetaminophen. This fabricated sensor displayed excellent analytical performance for acetaminophen detection over a range from 0.1 to 100 μ mol L(-1) with a detection limit of 3.7×10(-8) mol L(-1) (S/N=3). The redox peaks of acetaminophen, dopamine (DA) and ascorbic acid (AA) can be well separated on the Fe(3)O(4)-PDDA-G/GCE. Moreover, the proposed electrochemical sensor also exhibited good reproducibility and stability, and has been used to detect acetaminophen in tablets with satisfactory results.

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

    PubMed

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

    2012-02-01

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

  2. Decrease of plasma and urinary oxidative metabolites of acetaminophen after consumption of watercress by human volunteers.

    PubMed

    Chen, L; Mohr, S N; Yang, C S

    1996-12-01

    To investigate the effect of the consumption of watercress (Nasturtium officinale R. Br.), a cruciferous vegetable, on acetaminophen metabolism, the pharmacokinetics of acetaminophen and its metabolites were studied in a crossover trial of human volunteers. A single oral dose of acetaminophen (1 gm) was given 10 hours after ingestion of watercress homogenates (50 gm). In comparison with acetaminophen only, the ingestion of watercress resulted in a significant reduction in the area under the plasma cysteine acetaminophen (Cys-acetaminophen) concentration-time curve and in the peak plasma Cys-acetaminophen concentration by 28% +/- 3% and by 21% +/- 4% (mean +/- SE; n = 7; p < 0.005), respectively. Correspondingly, the Cys-acetaminophen formation rate constant and Cys-acetaminophen formation fraction were decreased by 55% +/- 9% and 52% +/- 7% (p < 0.01), respectively. Consistent with the results obtained from the plasma, the total urinary excretion of Cys-acetaminophen in 24 hours was also reduced. A decrease of mercapturate acetaminophen, a Cys-acetaminophen metabolite, was also shown in the plasma and urine samples. However, the plasma pharmacokinetic processes and the urinary excretions of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate were not altered significantly by the watercress treatment. These results suggest that the consumption of watercress causes a decrease in the levels of oxidative metabolites of acetaminophen, probably due to inhibition of oxidative metabolism of this drug.

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

    SciTech Connect

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

    1986-03-30

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

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

    SciTech Connect

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

    2005-01-15

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

  5. Possible effects of repeated exposure to ibuprofen and acetaminophen on the intestinal immune response in young infants.

    PubMed

    Langhendries, J-P; Allegaert, K; Van Den Anker, J N; Veyckemans, F; Smets, F

    2016-02-01

    There has been an exponential increase in the frequency of immune deviations in young children. Consequently, research investigating environmental causes for this increase has become a Public Health priority. We have summarized the experimental observations and epidemiological data that could link repeated acetaminophen and ibuprofen exposure in early infancy to this increase. Recent observations on the maturational immunity of the intestinal sub-mucosal lamina propria underscore indeed the importance of prostaglandins (PGE2s). PGE2 appearing at this sub-mucosal level is a product of arachidonic acid metabolism mediated by type-2 cyclooxygenase (COX-2) situated on the membrane of many immune cells. Moreover, it seems that acetaminophen - like ibuprofen - also carries a non-selective inhibitory action on peripheral COXs, besides its central action. This inhibitory action of acetaminophen on COX2 only relates to physiological, low arachidonic acid concentrations. This explains the difference in anti-inflammatory effects. The impact of repeated inhibition of mucosal PGE2 synthesis due to COX-inhibitor exposure on maturational immunity has been demonstrated in animal experiments. Repeatedly exposed young animals do not develop tolerance to food antigens and exhibit autoimmune deviations. Several recent epidemiological studies have also reported on the magnitude of acetaminophen and ibuprofen exposure in children and the increase in immune deviations, it is important to better understand the potential negative impact of repeated inhibitions of prostaglandin synthesis by COX2s during infancy. Since acetaminophen and ibuprofen are commonly administered analgesics and antipyretics, a well-designed prospective strategy for pharmacovigilance and -epidemiology of COX-inhibitor exposure in infancy is urgently needed.

  6. Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

    SciTech Connect

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

    2010-05-15

    Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1{sup -/-} mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1{sup -/-} mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1beta, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1{sup -/-} mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1{sup -/-} mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

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

    SciTech Connect

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

    2013-01-15

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

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

    PubMed Central

    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 (P<0.05). Meanwhile, the level of glutathione was found to be restored in extract treated animals compared to the groups treated with acetaminophen alone (P<0.05). Therapy of extract also showed its protective effect on histopathological alterations and supported the biochemical finding. Conclusion The present work confirmed the hepatoprotective effect of C. ternatea flower against model hepatotoxicant acetaminophen.

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

    PubMed

    Miettinen, Teemu P; Björklund, Mikael

    2014-12-01

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

  10. Acetaminophen induced Steven Johnson syndrome-toxic epidermal necrolysis overlap.

    PubMed

    Khawaja, Ali; Shahab, Ahmed; Hussain, Syed Ather

    2012-05-01

    Steven Johnson Syndrome and Toxic Epidermal Necrolysis are rare but severe form of hypersensitivity inflammatory reactions to multiple offending agents including drugs. Acetaminophen is extensively used due to its analgesic and anti-pyretic properties. It is rendered to be relatively safe, with hepatotoxicity considered to be the major adverse effect. However, very few cases of Steven Johnson Syndrome and Toxic Epidermal Necrolysis have been reported with acetaminophen usage in the past. We present the case of a 40 years old lady who developed an overlap of the two condition after taking several doses of acetaminophen for fever. She presented with widespread maculopapular rash, stinging in the eyes, oral mucosal ulcerations and high grade fever. She was successfully treated with corticosteroid therapy along with the supportive treatment. This case addresses the fact, that severe hypersensitivity reactions can occur with acetaminophen which can be potentially life threatening.

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

    MedlinePlus

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

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

    SciTech Connect

    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.

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

    PubMed

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

    2014-05-01

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

  14. Effect of acetaminophen on sulfamethazine acetylation in male volunteers.

    PubMed

    Tahir, I M; Iqbal, T; Saleem, S; Mehboob, H; Akhter, N; Riaz, M

    2016-03-01

    The effect of acetaminophen on sulfamethazine N-acetylation by human N-acetyltrasferase-2 (NAT2) was studied in 19 (n=19) healthy male volunteers in two different phases. In the first phase of the study the volunteers were given an oral dose of sulfamethazine 500 mg alone and blood and urine samples were collected. After the 10-day washout period the same selected volunteers were again administered sulfamethazine 500 mg along with 1000 mg acetaminophen. The acetylation of sulfamethazine by human NAT2 in both phases with and without acetaminophen was determined by HPLC to establish their respective phenotypes. In conclusion obtained statistics of present study revealed that acetaminophen significantly (P<0.0001) decreased sulfamethazine acetylation in plasma of both slow and fast acetylator male volunteers. A highly significant (P<0.0001) decrease in plasma-free and total sulfamethazine concentration was also observed when acetaminophen was co-administered. Urine acetylation status in both phases of the study was found not to be in complete concordance with that of plasma. Acetaminophen significantly (P<0.0001) increased the acetyl, free and total sulfamethazine concentration in urine of both slow and fast acetylators. Urine acetylation analysis has not been found to be a suitable approach for phenotypic studies.

  15. Acetaminophen for Chronic Pain: A Systematic Review on Efficacy.

    PubMed

    Ennis, Zandra Nymand; Dideriksen, Dorthe; Vaegter, Henrik Bjarke; Handberg, Gitte; Pottegård, Anton

    2016-03-01

    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 strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1551 hits were obtained. After cross-reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than 2 weeks with placebo were included. The review was conducted according to the PRISMA guidelines. All studies were conducted in patients with hip- or knee osteoarthritis and six of seven studies had observation periods of less than 3 months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little 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.

  16. The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin.

    PubMed

    Kwan, D; Bartle, W R; Walker, S E

    1999-01-01

    The oral anticoagulant warfarin is clinically administered as a racemic mixture of two enantiomers, (R) and (S). Many relevant drug interactions with warfarin have been attributed to the specific metabolic inhibition of the elimination of the more pharmacologically active (S)-enantiomer. To investigate reports that acetaminophen can potentiate the anticoagulant effect of warfarin, 20 healthy male volunteers were each given single oral 20 mg doses of racemic warfarin on three separate occasions: (1) alone, (2) after 1 day of acetaminophen (4 g/d), and (3) after 2 weeks of acetaminophen (4 g/d). The urinary excretion pattern of acetaminophen and its metabolites was not significantly altered over its course of administration. The (R)- and (S)-enantiomers of warfarin exhibited significantly different pharmacokinetic properties. However, acetaminophen did not alter the disposition of either (R)- or (S)-warfarin. All subjects exhibited a pharmacodynamic response to racemic warfarin. The response was not significantly altered in the presence of acute or chronic acetaminophen dosing, as assessed by prothrombin time and factor VII concentrations.

  17. Ferroptosis is Involved in Acetaminophen Induced Cell Death.

    PubMed

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

    2015-09-01

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

  18. Acetaminophen Induces Apoptosis in Rat Cortical Neurons

    PubMed Central

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

    2010-01-01

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

  19. [Correlation between the output and composition of essential oil and the level of salicylic acid in mint plants at different ontogenetic stages].

    PubMed

    Shelepova, O V; Kondrat'eva, V V; Voronkova, T V; Olekhnovich, L S

    2013-01-01

    Dynamic changes in the content of acetylsalicylic acid and the output and qualitative composition of essential oil have been studied in mint plants (Mentha spicata L. and cultivar Medichka) during their ontogenesis with allowance for changes in weather conditions. Ontogenetic changes in the level of acetylsalicylic acid in leaf tissues are found to be similar in both cv. Medichka and M. spicata. In the case of cv. Medichka, this change is connected with the dynamics of the production and the qualitative composition of essential oil; in the case of M. spicata, this connection is less expressed. The role of acetylsalicylic acid and essential oil in plant adaptation to the environment is discussed.

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

    PubMed

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

    2014-05-01

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

  1. Screening procedure for detection of non-steroidal anti-inflammatory drugs and their metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons by gas chromatography-mass spectrometry after extractive methylation.

    PubMed

    Maurer, H H; Tauvel, F X; Kraemer, T

    2001-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic and anti-rheumatic drugs, and they are often misused. A gas chromatographic-mass spectrometric (GC-MS) screening procedure was developed for their detection in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons after extractive methylation. The compounds were separated by capillary GC and identified by computerized MS in the full-scan mode. Using mass chromatography with the ions m/z 119, 135, 139, 152, 165, 229, 244, 266, 272, and 326, the possible presence of NSAIDs and their metabolites could be indicated. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with the reference spectra recorded during this study. This method allowed the detection of therapeutic concentrations of acemetacin, acetaminophen (paracetamol), acetylsalicylic acid, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indometacin, kebuzone, ketoprofen, lonazolac, meclofenamic acid, mefenamic acid, mofebutazone, naproxen, niflumic acid, phenylbutazone, suxibuzone, tiaprofenic acid, tolfenamic acid, and tolmetin in urine samples. The overall recoveries of the different NSAIDs ranged between 50 and 80% with coefficients of variation of less than 15% (n = 5), and the limits of detection of the different NSAIDs were between 10 and 50 ng/mL (S/N = 3) in the full-scan mode. Extractive methylation has proved to be a versatile method for STA of various acidic drugs, poisons, and their metabolites in urine. It has also successfully been used for plasma analysis.

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

    PubMed

    Krenzelok, Edward P; Royal, Mike A

    2012-06-01

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

  3. Acetaminophen protects brain endothelial cells against oxidative stress.

    PubMed

    Tripathy, Debjani; Grammas, Paula

    2009-05-01

    Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. Drugs that affect oxidant and inflammatory stress in the brain are of interest because both processes are thought to contribute to the pathogenesis of neurodegenerative disease. The objective of this study is to determine whether acetaminophen affects the response of brain endothelial cells to oxidative stress. Cultured brain endothelial cells are pre-treated with acetaminophen and then exposed to the superoxide-generating compound menadione (25 microM). Cell survival, inflammatory protein expression, and anti-oxidant enzyme activity are measured. Menadione causes a significant (p<0.001) increase in endothelial cell death as well as an increase in RNA and protein levels of tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES. Menadione also evokes a significant (p<0.001) increase in the activity of the anti-oxidant enzyme superoxide dismutase (SOD). Pre-treatment of endothelial cell cultures with acetaminophen (25-100 microM) increases endothelial cell survival and inhibits menadione-induced expression of inflammatory proteins and SOD activity. In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2. Suppressing Bcl2 with siRNA blocks the pro-survival effect of acetaminophen. These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on the cerebrovasculature and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as Alzheimer's disease that are characterized by oxidant and inflammatory stress.

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

    PubMed Central

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

    2015-01-01

    Background Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P < 0.05). The comet assay revealed increased detaching tail length and DNA concentration during the hepatic toxicity in the acetaminophen group. The malondialdehyde content was inhibited by Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Conclusions Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats. PMID:26543508

  5. Biochemical changes associated with the potentiation of acetaminophen hepatotoxicity by brief anesthesia with diethyl ether.

    PubMed

    To, E C; Wells, P G

    1986-12-01

    Acetaminophen hepatotoxicity in male CD-1 mice was enhanced markedly by brief anesthesia with diethyl ether (ether), and particularly so if acetaminophen was given several hours after ether. The present study was conducted to examine the possible biochemical mechanisms behind this delayed toxicologic synergism. In vitro biochemical studies indicated that ether anesthesia produced a delayed reduction in the activities of glucuronyl transferase and glutathione (GSH) S-transferase, and in the hepatic content of GSH. The hepatic content but not activity of the cytochromes P-450 was initially reduced by ether but recovered by the time of maximal toxicologic enhancement. In vivo studies showed that ether produced a small decrease in the plasma concentrations of glucuronide and sulfate conjugates of acetaminophen, with a concomitant, minor increase in the half-life of acetaminophen, and a major increase in the bioactivation of acetaminophen, as determined by an early, 2-fold increase in the plasma GSH and cysteine conjugates of acetaminophen, and a 3-fold increase in the covalent binding of acetaminophen to hepatocellular protein. Decreases produced by ether in the in vivo production of acetaminophen glucuronide correlated with increasing plasma concentrations of unmetabolised acetaminophen, decreasing hepatic GSH content and increasing covalent binding of acetaminophen to hepatocellular protein when these measurements were performed in the same animals. The biochemical mechanisms underlying the potentiation of acetaminophen hepatoxicity as measured by plasma glutamic pyruvic transaminase concentrations appeared to be due to delayed, complex effects of ether upon multiple enzymatic pathways of acetaminophen elimination and detoxification.

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

    PubMed

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

    2011-01-01

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

  7. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update

    PubMed Central

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

    2016-01-01

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

  8. Sulforaphane protects against acetaminophen-induced hepatotoxicity.

    PubMed

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

    2015-06-01

    Oxidative stress is closely associated with acetaminophen (APAP)-induced toxicity. Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. This study investigated whether sulforaphane (SFN), as a HO-1 inducer, plays a protective role against APAP hepatotoxicity in vitro and in vivo. Pretreatment of primary hepatocyte with SFN induced nuclear factor E2-factor related factor (Nrf2) target gene expression, especially HO-1 mRNA and protein expression, and suppressed APAP-induced glutathione (GSH) depletion and lipid peroxidation, which eventually leads to hepatocyte cell death. A comparable effect was observed in mice treated with APAP. Mice were treated with 300 mg/kg APAP 30 min after SFN (5 mg/kg) administration and were then sacrificed after 6 h. APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic reactive oxygen species (ROS) levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation. These results suggest that SFN plays a protective role against APAP-mediated hepatotoxicity through antioxidant effects mediated by HO-1 induction. SFN has preventive action in oxidative stress-mediated liver injury.

  9. Erdosteine against acetaminophen induced renal toxicity.

    PubMed

    Isik, Bunyamin; Bayrak, Reyhan; Akcay, Ali; Sogut, Sadik

    2006-07-01

    Acetaminophen (APAP) induced toxicities have been a major problem in clinical practice. The aim of the present study was to demonstrate a possible protective role of erdosteine, a mucolytic agent having antioxidant properties via its active metabolites, on APAP induced renal damage in rats. Female Wistar Albino rats were divided into groups including control, erdosteine (150 mg/kg, oral), APAP (1 g/kg, oral) APAP+erdosteine (150 mg/kg, oral) and APAP+erdosteine (300 mg/kg, oral). APAP treatment caused lipid peroxidation as well as high NO level in renal tissue. Also, APAP treated rats had decreased activities of CAT and GSH-Px, but not SOD. In addition, tubular epithelial degeneration, vacuolization and cell desquamation were clearly observed in the APAP treated rats. The cellular debris in the proximal tubules and cortical interstitial congestions were prominent in the kidneys of APAP treated rats. BUN and creatinine levels were increased after APAP administration. All these pathological changes were reversed after erdosteine treatments. Erdosteine treated APAP groups showed milder tubular degeneration, epithelial vacuolization in the proximal tubules, lesser cellular desquamation and better morphology when compared with APAP groups. In conclusion, erdosteine may be a choice of preventive treatment against APAP induced nephrotoxicity.

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

    PubMed

    Herndon, Christopher M; Dankenbring, Dawn M

    2014-06-01

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

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

    PubMed Central

    Sheehan, W.J.; Mauger, D.T.; Paul, I.M.; Moy, J.N.; Boehmer, S.J.; Szefler, S.J.; Fitzpatrick, A.M.; Jackson, D.J.; Bacharier, L.B.; Cabana, M.D.; Covar, R.; Holguin, F.; Lemanske, R.F.; Martinez, F.D.; Pongracic, J.A.; Beigelman, A.; Baxi, S.N.; Benson, M.; Blake, K.; Chmiel, J.F.; Daines, C.L.; Daines, M.O.; Gaffin, J.M.; Gentile, D.A.; Gower, W.A.; Israel, E.; Kumar, H.V.; Lang, J.E.; Lazarus, S.C.; Lima, J.J.; Ly, N.; Marbin, J.; Morgan, W.J.; Myers, R.E.; Olin, J.T.; Peters, S.P.; Raissy, H.H.; Robison, R.G.; Ross, K.; Sorkness, C.A.; Thyne, S.M.; Wechsler, M.E.; Phipatanakul, W.

    2016-01-01

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

  12. Application of a thin film of poly(solochrome black T) as a redox mediator for the electro-catalytic simultaneous determination of dopamine and acetaminophen in the pharmaceutical and biological samples.

    PubMed

    Daneshinejad, Hassan; Chamjangali, Mansour Arab; Goudarzi, Nasser; Roudbari, Aliakbar

    2016-01-01

    Glassy carbon electrode was successfully modified with a thin film of poly(solochrome black T) and applied for the sensitive and selective voltammetric simultaneous determination of dopamine and acetaminophen. The preparation and basic electrochemical behavior of poly(solochrome black T) film on the glassy carbon electrode were investigated in details. The modified electrode with polymeric thin film exhibits excellent electro-catalytic activity toward the oxidation of dopamine and acetaminophen. The anodic peaks of the both species were well defined with lowered oxidation potential and enhanced oxidation peak currents. The modified electrode was used as a voltammetric sensor for sensitive simultaneous determination of dopamine and acetaminophen free from ascorbic acid and uric acid interferences. Under the optimum conditions, the detection limits were 0.092 and 0.142 μmol L(-1) for DA and AP, respectively. The proposed sensor has been successfully used in analysis of pharmaceutical and biological samples.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-02-01

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

  15. Metabonomic analysis of Bombyx mori (Heterocera: Bombysidae) treated with acetaminophen.

    PubMed

    Yin, W M; Xu, X; He, Y; Wei, G B; Sima, Y H; Shi-Qing, Xu

    2014-01-01

    The feasibility of using Bombyx mori as model animal is attracting more attention. Whether the effect of drugs on the metabolite profiling was consistent with those in mammals was an aspect to evaluate the feasibility of B. mori as model animal. In this study, we used acetaminophen to treat Dazao fifth-instar B. mori, and its metabolites in hemolymph were detected by gas chromatography-mass spectrometry. The corresponding data were processed and analyzed by total model analysis, principal component analysis, partial least squares-discriminant analysis, orthogonal partial least squares-discriminant analysis, and finally, the difference metabolites between acetaminophen group and control group were selected and identified by our reference material database and the National Institute of Standard and Technology database. The results showed that acetaminophen administration induced elevation of metabolites related to energy source, the intermediate of cholesterol synthesis, and the metabolites related to melanization and also induced the decrease of metabolites in pathway of Krebs cycle, the cholesterol, and sitosterol, which suggested that acetaminophen administration inhibited energy metabolism and promoted the expenditure and imbalance of hormone and melanization.

  16. Efficacy of Intravenous Infusion of Acetaminophen for Intrapartum Analgesia

    PubMed Central

    Zutshi, Vijay; Rani, Kumari Usha; Patel, Madhumita

    2016-01-01

    Introduction The intensity of pain experienced by women in labour, has been found to affect the progress of labour, foetal well-being and maternal psychology. Adverse effects associated with commonly used opioids for providing intrapartum analgesia have created a need for an alternative non-opioid drug. Aim To evaluate the efficacy of an intravenous infusion of 1000 mg of acetaminophen as an intrapartum analgesic. Materials and Methods The present prospective single-centre, single blind, placebo-controlled randomized interventional study was conducted in Department of Obstetrics and Gynaecology in Vardhaman Mahavir Medical College & Safdarjung Hospital over a period of six months from September 2014 to March 2015. After receiving the ethical clearance and written informed consent. The first 200 consecutive parturients fulfilling the inclusion criteria were recruited into the study. Women were then randomised to receive either intravenous 1000 mg (100ml) of acetaminophen (Group A, n=100) or 100 ml normal saline (Group B, n=100). Primary outcome assessed was effectiveness of acetaminophen to provide an adequate amount of analgesia, as measured by a change in Visual Analogue Scale (VAS) pain intensity score at various times after drug administration. Secondary outcomes measured were duration of labour, need for additional rescue analgesia and presence of adverse maternal or foetal effect. Results There was pain reduction at 1 and 2 hours in both groups (p<0.001). However, it was more significant in the acetaminophen group, especially at 1 hour. Duration of labour was shortened in both the groups, without any maternal and foetal adverse effects. Conclusion Intravenous acetaminophen is an efficacious non-opioid drug for relieving labour pain without any significant maternal and foetal adverse effects. PMID:27656511

  17. Aspirin curtails the acetaminophen-induced rise in brain norepinephrine levels.

    PubMed

    Maharaj, Himant; Maharaj, Deepa S; Saravanan, Karruppagounder S; Mohanakumar, Kochupurackal P; Daya, Santy

    2004-06-01

    We previously showed that acetaminophen administration to rats increases forebrain serotonin levels as a result of the inhibition of liver tryptophan-2,3-dioxygenase (TDO). In this study we determined whether aspirin alone and in combination with acetaminophen could further influence brain serotonin as well as norepinephrine levels and if so whether the status of the liver TDO activity would be altered. The results show that acetaminophen alone increases brain serotonin as well as norepinephrine levels with a concomitant inhibition of liver TDO activity. In contrast, aspirin did not alter the levels of these monoamines but increased serotonin turnover in the brain while acetaminophen decreased the turnover. When combined with acetaminophen, aspirin overrides the reduced serotonin turnover induced by acetaminophen. This report demonstrates the potential of these agents to alter neurotransmitter levels in the brain.

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

    PubMed

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

    2015-11-26

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

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

    PubMed Central

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

    2015-01-01

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

  20. Diets with corn oil and/or low protein increase acute acetaminophen hepatotoxicity compared to diets with beef tallow in a rat model.

    PubMed

    Hwang, Jinah

    2009-01-01

    It has been reported that dietary polyunsaturated fats (PUFA) increase liver injury in response to ethanol feeding. We tested the hypothesis that diets rich in linoleic acid (18:2n-6) would affect acute liver injury after acetaminophen injection and that protein restriction might exacerbate the liver injury. We examined effects of feeding diets with either 15% (wt/wt) corn oil or 14% beef tallow and 1% corn oil for six weeks with either 6 or 20 g/100 g protein on acute hepatotoxicity. After the feeding period, liver injury was induced by injecting either with 600 mg/kg body weight acetaminophen suspended in gum arabic-based vehicle, or with vehicle alone during fasting status. Samples of liver and plasma were taken for analyses of hepatic glutathione (GSH) levels and liver-specific enzymes [(Glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase (GOT)], respectively. Whereas GSH level was significantly lower in only group fed 15% corn oil with 6 g/100 g protein among acetaminophen-treated groups, activities of GPT and GOT were significantly elevated in all groups except the one fed beef tallow with 20 g/100 g protein, suggesting low protein might exacerbate drug-induced hepatotoxicity. The feeding regimens changed the ratio of 18:2n-6 to oleic acid (18:1n-9) in total liver lipids approximately five-fold, and produced modest changes in arachidonic acid (20:4n-6). We conclude that diets with high 18:2n-6 promote acetaminophen-induced liver injury compared to diets with more saturated fatty acids (SFA). In addition, protein restriction appeared to exacerbate the liver injury.

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

    PubMed

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

    2015-08-01

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

  2. Aspirin and acetaminophen: should they be available over the counter?

    PubMed

    Brune, Kay; Hinz, Burkhard; Otterness, Ivan

    2009-02-01

    Traditional nonsteroidal anti-inflammatory drugs block cyclooxygenase (COX). They are the most widely used drugs for pain relief. They are indispensable for their effects but are condemned for their adverse drug reactions. Two COX inhibitors, acetaminophen and aspirin, are the most widely used over-the-counter drugs. They have low (but useful) therapeutic activity, but they are endowed with specific risks that are not seen with most other COX inhibitors. Both are lethal if taken in overdose. Each is stigmatized by severe adverse effects. Aspirin results in prolonged inhibition of blood coagulation, and acetaminophen can result in liver toxicity at normal dose and liver failure at higher dose. Both drugs cause many deaths every year. We recommend that the status of both drugs be changed to prescription only. Their continued availability over the counter poses an unacceptable risk to the general population.

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

    PubMed

    Mahmoud, Yomna I; Mahmoud, Asmaa A

    2016-06-01

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

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

    PubMed

    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.

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

    PubMed

    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.

  6. Acetaminophen effects on behavioral thermoregulation in albino rats.

    PubMed

    Vitulli, W F; Kaiser, G A; Maranto, D L; Blake, S E; Storey, T M; McPherson, K P; Luper, S L

    1999-02-01

    Acetaminophen (N-Acetyl-p-aminophenol) was administered intraperitoneally to 15 Sprague-Dawley rats partitioned into 3 studies (5 rats per study) using a within subjects, repeated-measures reversal design. Behavioral thermoregulation was assessed in a cold Skinner Box using 5-sec. exposures of microwave radiation [Specific Absorption Rate = 0.34 Watts/kg/(mW/cm2)] as reinforcing stimuli under a fixed-interval 2-min. schedule of positive reinforcement. Doses of 10, 20, 30, 40, and 50 mg/kg (in solutions of 1%, 2%, 3%, 4%, and 5%) acetaminophen showed stable rates of operant responding for heat compared with significant changes in rates for comparable doses of aspirin in a 1993 study by Vitulli, et al. Weight reductions and temperature increases varied significantly with before-session and after-session measures, respectively. 1994-95 biochemical data of Murphy, et al. from humans following aspirin or acetaminophen ingestion which affect thermoregulation and sleep patterns are discussed in conjunction with behavioral data from rats.

  7. Acute acetaminophen overdose is associated with dose-dependent hypokalaemia: a prospective study of 331 patients.

    PubMed

    Waring, W Stephen; Stephen, Alexandra F L; Malkowska, Aleks M; Robinson, Oliver D G

    2008-03-01

    Hypokalaemia is a recognized complication of acute acetaminophen overdose. It is unclear whether this might be a pharmacological effect of acetaminophen, or due to association with confounding factors. The present study sought to better characterize the relationship between acetaminophen concentrations and risk of hypokalaemia. A prospective study of patients received N-acetylcysteine treatment within 15 hr of acute acetaminophen ingestion. Serum potassium concentrations were determined before and after N-acetylcysteine. Serum acetaminophen concentrations were used to indicate overall drug exposure by comparison to the Rumack-Matthew nomogram. Hypokalaemia was pre-defined by serum concentrations <3.5 mmol/l, and groups compared by Mann-Whitney tests. There were 331 patients. Median (95% confidence interval) fall in serum potassium concentration after N-acetylcysteine was 0.05 mmol/l (-0.11-0.30 mmol/l) if acetaminophen concentrations were below the 'high-risk' treatment line, 0.30 mmol/l (0.17-0.40 mmol/l) if between the 'high-risk' and 'normal' treatment lines (P = 0.0358), and 0.40 mmol/l (0.20-0.50 mmol/l) if above the 'normal' treatment line (P = 0.0136). A receiver operating characteristic showed that high acetaminophen concentrations were predictive of hypokalaemia (P = 0.0001 versus zero discriminatory line), and 4 hr acetaminophen concentration >156 mmol/l gave 81% sensitivity and 48% specificity. The risk of hypokalaemia after acute acetaminophen overdose depends on the extent of acetaminophen exposure, irrespective of N-acetylcysteine administration and independent of whether vomiting occurred. Acetaminophen appears to cause concentration-dependent hypokalaemia after overdose, and the pharmacological basis requires further consideration.

  8. Immunoblot analysis of protein containing 3-(cystein-S-yl)acetaminophen adducts in serum and subcellular liver fractions from acetaminophen-treated mice.

    PubMed

    Pumford, N R; Hinson, J A; Benson, R W; Roberts, D W

    1990-07-01

    The hepatotoxicity of acetaminophen is believed to be mediated by the metabolic activation of acetaminophen to N-acetyl-p-benzoquinone imine which covalently binds to cysteinyl residues on proteins as 3-(cystein-S-yl)acetaminophen adducts. The formation of these adducts in hepatic protein correlates with the hepatotoxicity. In this study, the formation of 3-(cystein-S-yl)acetaminophen adducts in specific cellular proteins was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and detected using affinity-purified antisera specific for 3-(cystein-S-yl)acetaminophen adducts on immunoblots. These techniques were used to investigate the liver 10,000g supernatant and serum from B6C3F1 mice that received hepatotoxic doses of acetaminophen. More than 15 proteins containing 3-(cystein-S-yl)acetaminophen adducts were detected in the liver 10,000g supernatant. The most prominent protein containing 3-(cystein-S-yl)acetaminophen adducts in the hepatic 10,000g supernatant had a relative molecular mass of 55 kDa. Serum proteins containing 3-(cystein-S-yl)acetaminophen adducts had molecular masses similar to those found in the liver 10,000g supernatant (55, 87, and approximately 102 kDa). These data, combined with our previous findings describing the temporal relationship between the appearance of 3-(cystein-S-yl)acetaminophen adducts in protein in the serum and the decrease in the levels of 3-(cystein-S-yl)acetaminophen adducts in protein in the liver, suggested that liver adducts were released into the serum following lysis of hepatocytes. The temporal relationship between the formation of specific adducts and hepatotoxicity in mice following a hepatotoxic dose of acetaminophen was examined using immunoblots of mitochondria, microsomes, cytosol, and plasma membranes. Hepatotoxicity indicated by serum alanine aminotransferase levels was increased at 2 and 4 hr after dosing. The cytosolic fraction contained numerous proteins with 3-(cystein-S-yl)acetaminophen

  9. Sulphation of acetaminophen by the human cytosolic sulfotransferases: a systematic analysis.

    PubMed

    Yamamoto, Akihiro; Liu, Ming-Yih; Kurogi, Katsuhisa; Sakakibara, Yoichi; Saeki, Yuichi; Suiko, Masahito; Liu, Ming-Cheh

    2015-12-01

    Sulphation is known to be critically involved in the metabolism of acetaminophen in vivo. This study aimed to systematically identify the major human cytosolic sulfotransferase (SULT) enzyme(s) responsible for the sulphation of acetaminophen. A systematic analysis showed that three of the twelve human SULTs, SULT1A1, SULT1A3 and SULT1C4, displayed the strongest sulphating activity towards acetaminophen. The pH dependence of the sulphation of acetaminophen by each of these three SULTs was examined. Kinetic parameters of these three SULTs in catalysing acetaminophen sulphation were determined. Moreover, sulphation of acetaminophen was shown to occur in HepG2 human hepatoma cells and Caco-2 human intestinal epithelial cells under the metabolic setting. Of the four human organ samples tested, liver and intestine cytosols displayed considerably higher acetaminophen-sulphating activity than those of lung and kidney. Collectively, these results provided useful information concerning the biochemical basis underlying the metabolism of acetaminophen in vivo previously reported.

  10. Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice

    PubMed Central

    Kawakami, Kayoko; Moritani, Chie; Uraji, Misugi; Fujita, Akiko; Kawakami, Koji; Hatanaka, Tadashi; Suzaki, Etsuko; Tsuboi, Seiji

    2017-01-01

    Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We found that rice peptides increased intracellular glutathione levels in human hepatoblastoma HepG2 cells. Acetaminophen is a commonly used analgesic. However, an overdose of acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of rice peptides on acetaminophen-induced hepatotoxicity in mice. ICR mice were orally administered rice peptides (0, 100 or 500 mg/kg) for seven days, followed by the induction of hepatotoxicity via intraperitoneal injection of acetaminophen (700 mg/kg). Pretreatment with rice peptides significantly prevented increases in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels and protected against hepatic glutathione depletion. The expression of γ-glutamylcysteine synthetase, a key regulatory enzyme in the synthesis of glutathione, was decreased by treatment with acetaminophen, albeit rice peptides treatment recovered its expression compared to that achieved treatment with acetaminophen. In addition, histopathological evaluation of the livers also revealed that rice peptides prevented acetaminophen-induced centrilobular necrosis. These results suggest that rice peptides increased intracellular glutathione levels and could protect against acetaminophen-induced hepatotoxicity in mice.

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

    PubMed

    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 < .05). Immunoblotting and activity assays showed old saline-treated rats had twofold lower cytochrome P450 2E1 activity and threefold higher NAD(P)H quinone oxireductase 1 protein expression and activity than young saline-treated rats (p < .05), although Nrf2, glutathione cysteine ligase-modulatory subunit, glutathione cysteine ligase-catalytic subunit, and cytochrome P450 2E1 protein expressions were unchanged. Primary hepatocytes isolated from young rats treated with 10 mM acetaminophen had lower survival than those from old rats (52.4% ± 5.8%, young; 83.6% ± 1.7%, old, p < .05). The pharmacokinetic changes described may decrease susceptibility to acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age.

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

    PubMed

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

    2011-05-01

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

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

    SciTech Connect

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

    2012-03-15

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

  14. Acetaminophen self-administered in the drinking water increases the pain threshold of rats (Rattus norvegicus).

    PubMed

    Mickley, G Andrew; Hoxha, Zana; Biada, Jaclyn M; Kenmuir, Cynthia L; Bacik, Stephanie E

    2006-09-01

    Previous studies have suggested that the addition of flavored acetaminophen suspension (for example, Children's Tylenol) in the drinking water of rats may not be effective in producing postoperative analgesia because of low levels of consumption. However, these investigations neither measured analgesia nor compared the consumption by rats that had undergone surgery with that by unmanipulated rats. The present study reports that although unmanipulated rats naive to the taste of flavored acetaminophen do indeed drink significantly less of this liquid than tap water, they drank sufficient amounts of the acetaminophen-containing solution to significantly raise pain thresholds, as measured by the hot-plate test. Moreover, rats that had undergone surgery drank significantly more acetaminophen solution than did those that had no surgery. These data suggest that oral self-administration of flavored acetaminophen by rats may be an appropriate means to reduce pain.

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

    PubMed

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

    2016-01-01

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

  16. Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure.

    PubMed

    Court, Michael H; Peter, Inga; Hazarika, Suwagmani; Vasiadi, Magdalini; Greenblatt, David J; Lee, William M

    2014-01-01

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

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

    PubMed

    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.

  18. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen protein adducts in subcellular liver fractions following a hepatotoxic dose of acetaminophen.

    PubMed

    Pumford, N R; Roberts, D W; Benson, R W; Hinson, J A

    1990-08-01

    The hepatotoxicity of acetaminophen correlates with the formation of 3-(cystein-S-yl)acetaminophen protein adducts. Using a sensitive and specific immunochemical assay, we quantitated the formation of these protein adducts in liver fractions and serum after administration of a hepatotoxic dose of acetaminophen (400 mg/kg) to B6C3F1 mice. Adducts in the cytosolic fraction increased to 3.6 nmol/mg protein at 2 hr and then decreased to 1.1 nmol/mg protein by 8 hr. Concomitant with the decrease in adducts in the cytosol, 3-(cystein-S-yl)acetaminophen protein adducts appeared in serum and their levels paralleled increases in serum alanine aminotransferase. Microsomal protein adducts peaked at 1 hr (0.7 nmol/mg protein) and subsequently decreased to 0.2 nmol/mg at 8 hr. The 4000 g pellet (nuclei, plasma membranes, and cell debris) had the highest level of adducts (3.5 nmol/mg protein), which remained constant from 1 to 8 hr. Evaluation of fractions purified from a 960 g pellet indicated that the highest concentration of 3-(cystein-S-yl)acetaminophen protein adducts was located in plasma membranes and mitochondria; peak levels were 10.3 and 5.1 nmol/mg respectively. 3-(Cystein-S-yl)acetaminophen protein adducts were detected in nuclei only after enzymatic hydrolysis of the proteins. The localization of high levels of 3-(cystein-S-yl)acetaminophen protein adducts in plasma membranes and mitochondria may play a critical role in acetaminophen toxicity.

  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

    PubMed Central

    Sabiu, S.; O'Neill, F. H.

    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

  20. Influence of acetaminophen on performance during time trial cycling.

    PubMed

    Mauger, Alexis R; Jones, Andrew M; Williams, Craig A

    2010-01-01

    To establish whether acetaminophen improves performance of self-paced exercise through the reduction of perceived pain, 13 trained male cyclists performed a self-paced 10-mile (16.1 km) cycle time trial (TT) following the ingestion of either acetaminophen (ACT) or a placebo (PLA), administered in randomized double-blind design. TT were completed in a significantly faster time (t(12) = 2.55, P < 0.05) under the ACT condition (26 min 15 s +/- 1 min 36 s vs. 26 min 45 s +/- 2 min 2 s). Power output (PO) was higher during the middle section of the TT in the ACT condition, resulting in a higher mean PO (P < 0.05) (265 +/- 12 vs. 255 +/- 15 W). Blood lactate concentration (B[La]) and heart rate (HR) were higher in the ACT condition (B[La] = 6.1 +/- 2.9 mmol/l; HR = 87 +/- 7%max) than in the PLA condition (B[La] = 5.1 +/- 2.6 mmol/l; HR = 84 +/- 9%max) (P < 0.05). No significant difference in rating of perceived exertion (ACT = 15.5 +/- 0.2; PLA = 15.7 +/- 0.2) or perceived pain (ACT = 5.6 +/- 0.2; PLA = 5.5 +/- 0.2) (P > 0.05) was observed. Using acetaminophen, participants cycled at a higher mean PO, with an increased HR and B[La], but without changes in perceived pain or exertion. Consequently, completion time was significantly faster. These findings support the notion that exercise is regulated by pain perception, and increased pain tolerance can improve exercise capacity.

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

    PubMed Central

    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

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

    PubMed

    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.

  3. Use of acetaminophen in relation to the occurrence of cancer: a review of epidemiologic studies.

    PubMed

    Weiss, Noel S

    2016-12-01

    Acetaminophen has several pharmacologic properties that suggest it could be carcinogenic in human beings. A number of epidemiologic studies have been conducted to examine whether use of acetaminophen actually predisposes to the occurrence of one or more forms of cancer. There are inherent limitations to many of these studies, including the inaccurate identification of users and nonusers of acetaminophen, relatively short follow-up for cancer incidence, and the potential for confounding by indication. The present manuscript reviews the results of epidemiologic studies of acetaminophen use in relation to cancer incidence published through the end of 2015. The limitations of the underlying studies notwithstanding, some interim conclusions can be reached. For all but several forms of cancer, there is no suggestion that persons who have taken acetaminophen are at altered risk, even persons who have consumed a large quantity of the drug or those who have taken it for an extended duration. While in some studies the incidence of renal cell carcinoma has been observed to be increased among acetaminophen users, several other studies have failed to observe any such association; the reason for the discrepant findings is unclear. Some of the small number of studies that have presented data on the incidence of lymphoma, leukemia, and plasma cell disorders have found the risk to be modestly higher in users than nonusers of acetaminophen, but the results of other studies of these malignancies will be needed to gauge the possible role of publication bias as the basis for the positive results.

  4. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

    SciTech Connect

    Nagy, Gabor; Szarka, Andras; Lotz, Gabor; Doczi, Judit; Wunderlich, Livius; Kiss, Andras; Jemnitz, Katalin; Veres, Zsuzsa; Banhegyi, Gabor; Schaff, Zsuzsa; Suemegi, Balazs; Mandl, Jozsef

    2010-02-15

    It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

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

    PubMed

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

    2015-12-01

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

  6. Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring.

    PubMed

    Andrade, Chittaranjan

    2016-02-01

    Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%-65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention-deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring.

  7. Study on the reaction mechanism and the static injection chemiluminescence method for detection of acetaminophen.

    PubMed

    Wu, Yongjun; Zhang, Huili; Yu, Songcheng; Yu, Fei; Li, Yanqiang; Zhang, Hongquan; Qu, Lingbo; Harrington, Peter de B

    2013-01-01

    Acetaminophen, also called paracetamol, is found in Tylenol, Excedrin and other products as over-the-counter medicines. In this study, acetaminophen as a luminol signal enhancer was used in the chemiluminescence (CL) substrate solution of horseradish peroxidase (HRP) for the first time. The use of acetaminophen in the luminol-HRP-H2O2 system affected not only the intensity of the obtained signal, but also its kinetics. It was shown that acetaminophen was to be a potent enhancer of the luminol-HRP-H2O2 system. A putative enhancement mechanism for the luminol-H2O2-HRP-acetaminophen system is presented. The resonance of the nucleophilic amide group and the benzene ring of acetaminophen structure have a great effect on O-H bond dissociation energy of the phenol group and therefore on phenoxyl radical stabilization. These radicals act as mediators between HRP and luminol in an electron transfer reaction that generates luminol radicals and subsequently light emission, in which the intensity of CL is enhanced in the presence of acetaminophen. In addition, a simple method was developed to detect acetaminophen by static injection CL based on the enhanced CL system of luminol-H2O2-HRP by acetaminophen. Experimental conditions, such as pH and concentrations of substrates, have been examined and optimized. The proposed method exhibited good performance, the linear range was from 0.30 to 7.5 mM, the relative standard deviation was 1.86% (n = 10), limit of detection was 0.16 mM and recovery was 99 ± 4%.

  8. Direct Evidence of Acetaminophen Interference with Subcutaneous Glucose Sensing in Humans: A Pilot Study

    PubMed Central

    Basu, Ananda; Veettil, Sona; Dyer, Roy; Peyser, Thomas

    2016-01-01

    Abstract Background: Recent advances in accuracy and reliability of continuous glucose monitoring (CGM) devices have focused renewed interest on the use of such technology for therapeutic dosing of insulin without the need for independent confirmatory blood glucose meter measurements. An important issue that remains is the susceptibility of CGM devices to erroneous readings in the presence of common pharmacologic interferences. We report on a new method of assessing CGM sensor error to pharmacologic interferences using the example of oral administration of acetaminophen. Materials and Methods: We examined the responses of several different Food and Drug Administration–approved and commercially available CGM systems (Dexcom [San Diego, CA] Seven® Plus™, Medtronic Diabetes [Northridge, CA] Guardian®, and Dexcom G4® Platinum) to oral acetaminophen in 10 healthy volunteers without diabetes. Microdialysis catheters were placed in the abdominal subcutaneous tissue. Blood and microdialysate samples were collected periodically and analyzed for glucose and acetaminophen concentrations before and after oral ingestion of 1 g of acetaminophen. We compared the response of CGM sensors with the measured acetaminophen concentrations in the blood and interstitial fluid. Results: Although plasma glucose concentrations remained constant at approximately 90 mg/dL (approximately 5 mM) throughout the study, CGM glucose measurements varied between approximately 85 to 400 mg/dL (from approximately 5 to 22 mM) due to interference from the acetaminophen. The temporal profile of CGM interference followed acetaminophen concentrations measured in interstitial fluid (ISF). Conclusions: This is the first direct measurement of ISF concentrations of putative CGM interferences with simultaneous measurements of CGM performance in the presence of the interferences. The observed interference with glucose measurements in the tested CGM devices coincided temporally with appearance of

  9. Effect of Acetaminophen Ingestion on Thermoregulation of Normothermic, Non-febrile Humans.

    PubMed

    Foster, Josh; Mauger, Alexis; Thomasson, Katie; White, Stephanie; Taylor, Lee

    2016-01-01

    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 1) to determine plasma acetaminophen concentration following oral ingestion of 20 mg⋅kg lean body mass acetaminophen. Plasma samples (every 20 min up to 2-hours post ingestion) were analyzed via enzyme linked immunosorbent assay. Thirteen (eight recruited from Study 1) apparently healthy Caucasian males participated in Study 2, and were passively exposed to 20°C, 40% r.h. for 120 min on two occasions in a randomized, 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 10 min. In Study 1, the peak concentration of acetaminophen (14 ± 4 μg/ml) in plasma arose between 80 and 100 min following oral ingestion. In Study 2, 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 peak reduction in core temperature in the acetaminophen trial was reached at 120 min in six of the thirteen participants, and ranged from 0.1 to 0.39°C (average peak reduction from baseline = 0.19 ± 0.09°C). There was no significant difference in skin

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

    PubMed

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

    2013-07-01

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

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

    PubMed

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

    2015-01-29

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

  12. Surfactant and Gelation Properties of Acetylsalicylate Based Room Temperature Ionic Liquid in Aqueous Media.

    PubMed

    Sastry, Nandhibatla V; Singh, Dipak K

    2016-10-04

    An amphiphilic room temperature ionic liquid (RTIL) containing acetylsalicylate anion of type 1-dodecyl-1-methylpiperidinium acetylsalicylate, [C12mpip][AcSa], is synthesized from the precursor [C12mpip][Cl] by an ion exchange process. The sample is characterized, and its surface active and aggregation behavior in water has been studied and explained. The critical aggregation concentrations (CACs) are determined by a variety of methods, namely, electrical conductivity, surface tension, steady state florescence, and isothermal titration calorimetry (ITC) at different temperatures. As compared to its precursor, [C12mpip][AcSa] has low CAC values, indicating enhanced favorable interactions between the [alkylmpip](+) cation···bulky [AcSa](-) anion and also hydrogen bonding of both of the ions with water. The free energy of aggregation ΔG(0)a is always negative, and both enthalpy and entropy of aggregation drive the aggregation process. The micelle-like aggregates are ellipsoidal in shape. The aggregation numbers are determined from translational diffusion coefficients and florescence quenching measurements. Aggregates of [C12mpip][AcSa] are larger than those of its precursor IL with chloride anion. Therefore, it is evident that the close interactions between the ion pairs of [C12mpip](+)···[AcSa](-) facilitate packing of more molecules in an aggregate. The steady state and oscillatory rheology measurements in aqueous solutions consisting of mixtures of [C12mpip][AcSa] and sodium salicylate (SS), an hydrotope additive, were carried out. The analysis of zero shear viscosity and moduli properties as a function of concentration and temperature reveals that the addition of SS promotes the growth of small ellipsoid aggregates into large worm-like structures with a typical viscoelastic gel behavior. The moduli properties vs temperature profiles are complex and no hysteresis was produced in heating and cooling modes, suggesting the thermoirreversibile and complex nature

  13. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults.

    PubMed

    Gelotte, C K; Auiler, J F; Lynch, J M; Temple, A R; Slattery, J T

    2007-06-01

    The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single-dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher, strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose-dependent differences were detected in fCL of thiol metabolites formed via cytochrome P4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose-dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time-dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short-term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults.

  14. Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity.

    PubMed

    Roberts, D W; Bucci, T J; Benson, R W; Warbritton, A R; McRae, T A; Pumford, N R; Hinson, J A

    1991-02-01

    Acetaminophen overdose causes severe hepatotoxicity in humans and laboratory animals, presumably by metabolism to N-acetyl-p-benzoquinone imine: and binding to cysteine groups as 3-(cystein-S-yl)acetaminophen-protein adduct. Antiserum specific for the adduct was used immunohistochemically to demonstrate the formation, distribution, and concentration of this specific adduct in livers of treated mice and was correlated with cell injury as a function of dose and time. Within the liver lobule, immunohistochemically demonstrable adduct occurred in a temporally progressive, central-to-peripheral pattern. There was concordance between immunohistochemical staining and quantification of the adduct in hepatic 10,000g supernate, using a quantitative particle concentration fluorescence immunoassay. Findings include: 1) immunochemically detectable adduct before the appearance of centrilobular necrosis, 2) distinctive lobular zones of adduct localization with subsequent depletion during the progression of toxicity, 3) drug-protein binding in hepatocytes at subhepatotoxic doses and before depletion of total hepatic glutathione, 4) immunohistochemical evidence of drug binding in the nucleus, and 5) adduct in metabolically active and dividing hepatocytes and in macrophagelike cells in the regenerating liver.

  15. Detection of Salicylic Acid in Willow Bark: An Addition to a Classic Series of Experiments in the Introductory Organic Chemistry Laboratory

    ERIC Educational Resources Information Center

    Clay, Matthew D.; McLeod, Eric J.

    2012-01-01

    Salicylic acid and its derivative, acetylsalicylic acid, are often encountered in introductory organic chemistry experiments, and mention is often made that salicylic acid was originally isolated from the bark of the willow tree. This biological connection, however, is typically not further pursued, leaving students with an impression that biology…

  16. A zeolite modified carbon paste electrode as useful sensor for voltammetric determination of acetaminophen.

    PubMed

    Ahmadpour-Mobarakeh, Leila; Nezamzadeh-Ejhieh, Alireza

    2015-04-01

    The voltammetric behavior of a carbon paste electrode modified with Co(II)-exchanged zeolite A (Co(II)-A/ZMCPE) for determination of acetaminophen was studied. The proposed electrode showed a diffusion controlled reaction with the electron transfer rate constant (Ks) of 0.44s(-1) and charge transfer coefficient of 0.73 in the absence of acetaminophen. A linear voltammetric response was obtained in the range of 0.1 to 190μmolL(-1) of acetaminophen [r(2)=0.9979, r=0.9989 (n=10)] with a detection limit of 0.04μmolL(-1). The method was successfully applied to the analysis of acetaminophen in some drugs.

  17. Drugs in the Chemistry Laboratory: The Conversion of Acetaminophen into Phenacetin.

    ERIC Educational Resources Information Center

    Volker, Eugene J.; And Others

    1979-01-01

    Describes an experiment in which acetaminophen is converted into phenacetin, that has been used at Shepherd College in an introductory chemistry course for nurses and in the organic chemistry laboratory. (BT)

  18. The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats.

    PubMed

    Randles, Daniel; Heine, Steven J; Santos, Nathan

    2013-06-01

    The meaning-maintenance model posits that any violation of expectations leads to an affective experience that motivates compensatory affirmation. We explore whether the neural mechanism that responds to meaning threats can be inhibited by acetaminophen, in the same way that acetaminophen inhibits physical pain or the distress caused by social rejection. In two studies, participants received either acetaminophen or a placebo and were provided with either an unsettling experience or a control experience. In Study 1, participants wrote about either their death or a control topic. In Study 2, participants watched either a surrealist film clip or a control film clip. In both studies, participants in the meaning-threat condition who had taken a placebo showed typical compensatory affirmations by becoming more punitive toward lawbreakers, whereas those who had taken acetaminophen, and those in the control conditions, did not.

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

    PubMed

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

    2015-12-15

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

  20. LC-MS/MS method development for quantitative analysis of acetaminophen uptake by the aquatic fungus Mucor hiemalis.

    PubMed

    Esterhuizen-Londt, Maranda; Schwartz, Katrin; Balsano, Evelyn; Kühn, Sandra; Pflugmacher, Stephan

    2016-06-01

    Acetaminophen is a pharmaceutical, frequently found in surface water as a contaminant. Bioremediation, in particular, mycoremediation of acetaminophen is a method to remove this compound from waters. Owing to the lack of quantitative analytical method for acetaminophen in aquatic organisms, the present study aimed to develop a method for the determination of acetaminophen using LC-MS/MS in the aquatic fungus Mucor hiemalis. The method was then applied to evaluate the uptake of acetaminophen by M. hiemalis, cultured in pellet morphology. The method was robust, sensitive and reproducible with a lower limit of quantification of 5 pg acetaminophen on column. It was found that M. hiemalis internalize the pharmaceutical, and bioaccumulate it with time. Therefore, M. hiemalis was deemed a suitable candidate for further studies to elucidate its pharmaceutical tolerance and the longevity in mycoremediation applications.

  1. Acetaminophen intake and risk of asthma, hay fever and eczema in early adolescence.

    PubMed

    Vlaski, Emilija; Stavric, Katerina; Isjanovska, Rozalinda; Seckova, Lidija; Kimovska, Milica

    2007-09-01

    A positive association between acetaminophen intake and allergic diseases has recently been reported in developed countries with impaired oxidant/antioxidant balance and promotion of atopy as proposed underlying mechanisms. The aim of the study was to explore the relationship between acetaminophen intake and asthma, hay fever, and eczema in The Republic of Macedonia as a country with acetaminophen intake not physician-controlled, high passive smoke exposure and dietary antioxidant intake, and moderately low prevalence of allergic diseases. Self-reported data obtained through the standardized International Study of Asthma and Allergies in Childhood Phase Three written questionnaires of 3026 adolescents aged 13/14 years from randomly selected schools in Skopje, the capital of Macedonia, were used. The frequency of current acetaminophen intake--both unadjusted and adjusted for confounding factors--was correlated to current and ever-diagnosed asthma, hay fever and eczema by odds ratios (OR, 95% CI) in binary logistic regression. Use of acetaminophen at least once monthly increased the risk of current wheeze (adjusted OR 2.04, 1.31-3.20 p = 0.002), asthma 'ever' (adjusted OR 2.77, 1.06-7.26 p=0.039), current allergic rhinoconjunctivitis (adjusted OR 2.95, 1.79-4.88 p=0.000) and hay fever 'ever' (adjusted OR 2.25, 1.36-3.70 p=0.002). A significant association between frequent acetaminophen intake and atopic eczema and also between infrequent acetaminophen intake and investigated allergic diseases was not established. The findings suggest an increased risk of asthma and hay fever, but not atopic eczema associated with frequent acetaminophen use in a developing country.

  2. Liuweiwuling tablets protect against acetaminophen hepatotoxicity: What is the protective mechanism?

    PubMed Central

    Du, Kuo; Jaeschke, Hartmut

    2016-01-01

    Study of the effects of natural products, including traditional Chinese Medicines, on acetaminophen hepatotoxicity has gained considerable popularity in recent years, and some of them showed positive results and even promising therapeutic potentials. A recent report suggested that Liuweiwuling tablets protect against acetaminophen hepatotoxicity and promote liver regeneration in a rodent model through alleviating the inflammatory response. However, several concerns exist regarding the limitations of the experimental design and interpretation of the data presented in this manuscript. PMID:27004010

  3. Acetaminophen absorption kinetics in altered gastric emptying: establishing a relevant pharmacokinetic surrogate using published data.

    PubMed

    Srinivas, Nuggehally R

    2015-06-01

    Acetaminophen has been used as a tool for clinical and nonclinical experimental designs that evaluate gastric emptying because acetaminophen is not absorbed in stomach but efficiently absorbed from the small intestine. Published pharmacokinetic data of acetaminophen in subjects with normal gastric emptying vs. impaired gastric emptying (i.e., morphine treatment) were evaluated to select a key surrogate. Using Caverage (average concentration), computed from the exposure within the first hour, individual rank distribution was plotted across different studies. Caverage was highly correlated with Cmax (maximum concentration) in subjects with normal gastric emptying (R(2) = .7532) but not in those where gastric emptying was impaired (R(2) = .0213). The 50th percentile value of the distribution pattern of 1/Caverage in acetaminophen+morphine-treated group (coincided with the first shift in the slope) was considered as the cutoff point to figure out the impaired gastric emptying. The individual rank distribution plots for 1/Caverage across different studies supported similar trends in subjects with normal gastric emptying but showed a distinct distribution pattern in the cohort of impaired gastric emptying. Caverage, calculated within the first hour of dosing of acetaminophen (average concentration at 0-1 hour, C0-1havg), can be used as a key surrogate to distinguish the effects of gastric emptying on the absorption of acetaminophen. A 4 μg/mL C0-1havg of acetaminophen (dose: 1.5 g) may be used as cutoff point in future clinical investigations of acetaminophen to clarify the role of gastric emptying.

  4. Acetaminophen use and risk of myocardial infarction and stroke in a hypertensive cohort.

    PubMed

    Fulton, Rachael L; Walters, Matthew R; Morton, Ross; Touyz, Rhian M; Dominiczak, Anna F; Morrison, David S; Padmanabhan, Sandosh; Meredith, Peter A; McInnes, Gordon T; Dawson, Jesse

    2015-05-01

    Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and that acetaminophen causes a modest blood pressure rise. There are no randomized trials or studies using verified prescription data of this relationship. We aimed to assess the relationship between verified acetaminophen prescription data and risk of myocardial infarction or stroke in patients with hypertension. We performed a retrospective data analysis using information contained within the UK Clinical Research Practice Datalink. Multivariable Cox proportional hazard models were used to estimate hazard ratios for myocardial infarction (primary end point), stroke, and any cardiovascular event (secondary end points) associated with acetaminophen use during a 10-year period. Acetaminophen exposure was a time-dependent variable. A propensity-matched design was also used to reduce potential for confounding. We included 24,496 hypertensive individuals aged ≥ 65 years. Of these, 10,878 were acetaminophen-exposed and 13,618 were not. There was no relationship between risk of myocardial infarction, stroke, or any cardiovascular event and acetaminophen exposure on adjusted analysis (hazard ratio, 0.98; 95% confidence interval, 0.76-1.27; hazard ratio, 1.09; 95% confidence interval, 0.86-1.38; and hazard ratio, 1.17; 95% confidence interval, 0.99-1.37; respectively). Results in the propensity-matched sample (n=4000 per group) and when men and women were analyzed separately were similar. High-frequency users (defined as receiving a prescription for >75% of months) were also not at increased risk. After allowance for potentially confounding variables, the use of acetaminophen was not associated with an increased risk of myocardial infarction or stroke in a large cohort of hypertensive patients.

  5. Diabetic KK-A(y) mice are highly susceptible to oxidative hepatocellular damage induced by acetaminophen.

    PubMed

    Kon, Kazuyoshi; Ikejima, Kenichi; Okumura, Kyoko; Arai, Kumiko; Aoyama, Tomonori; Watanabe, Sumio

    2010-08-01

    Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-A(y) mice, an animal model of metabolic syndrome. Twelve-week-old male KK-A(y) and C57Bl/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun NH(2)-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichloro-dihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-A(y) mice than in C57Bl/6 mice and significantly increased serum alanine aminotransferase levels in KK-A(y) mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-A(y) mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-A(y) mice. Exposure to 20 microM tert-butyl hydroperoxide did not kill hepatocytes isolated from C57Bl/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-A(y) mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-A(y) mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury.

  6. Blockade of Notch signaling promotes acetaminophen-induced liver injury.

    PubMed

    Jiang, Longfeng; Ke, Michael; Yue, Shi; Xiao, Wen; Yan, Youde; Deng, Xiaozhao; Ying, Qi-Long; Li, Jun; Ke, Bibo

    2017-03-13

    Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS. Some animals were injected with γ-secretase inhibitor DAPT or DMSO vehicle. For the in vitro study, bone marrow-derived macrophages (BMMs) were transfected with Notch1 siRNA, TLR4 siRNA, and non-specific (NS) siRNA and stimulated with LPS. Indeed, paracetamol/acetaminophen-induced liver damage was worse after Notch blockade with DAPT in wild-type mice, which was accompanied by significantly increased ALT levels, diminished hairy and enhancer of split-1 (Hes1), and phosphorylated Stat3 and Akt but enhanced high mobility group box 1 (HMGB1), TLR4, NF-κB, and NLRP3 activation after APAP challenge. Mice receiving DAPT increased macrophage and neutrophil accumulation and hepatocellular apoptosis. However, TLR4 KO mice that received DAPT reduced APAP-induced liver damage and NF-κB, NLRP3, and cleaved caspase-1 activation. BMMs transfected with Notch1 siRNA reduced Hes1 and phosphorylated Stat3 and Akt but augmented HMGB1, TLR4, NF-κB, and NLRP3. Furthermore, TLR4 siRNA knockdown resulted in decreased NF-κB and NLRP3 and cleaved caspase-1 and IL-1β levels following LPS stimulation. These results demonstrate that Notch signaling regulates innate NLRP3 inflammasome activation through regulation of HMGB1/TLR4/NF-κB activation in APAP-induced liver injury. Our novel findings underscore the critical role of the Notch1-Hes1 signaling cascade in the regulation of innate immunity in APAP-triggered liver inflammation. This might imply a novel therapeutic

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

    PubMed

    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.

  8. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

    PubMed

    Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

    2000-01-01

    The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

  9. From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain.

    PubMed

    Mischkowski, Dominik; Crocker, Jennifer; Way, Baldwin M

    2016-09-01

    Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week.

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

    PubMed

    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.

  11. Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder

    PubMed Central

    Schultz, Stephen T; Gould, Georgianna G

    2016-01-01

    Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restrictive behavior, interests, and activities. Our previous case-control study showed that use of acetaminophen at age 12–18 months is associated with increased likelihood for ASD (OR 8.37, 95% CI 2.08–33.7). In this study, we again show that acetaminophen use is associated with ASD (p = 0.013). Because these children are older than in our first study, the association is reversed; fewer children with ASD vs. non-ASD children use acetaminophen as a “first choice” compared to “never use” (OR 0.165, 95% CI 0.045, 0.599). We found significantly more children with ASD vs. non- ASD children change to the use of ibuprofen when acetaminophen is not effective at reducing fever (p = 0.033) and theorize this change in use is due to endocannabinoid system dysfunction. We also found that children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever (p = 0.037) and theorize that this increase is due to anandamide activation of the endocannabinoid system in ASD children with low endocannabinoid tone from early acetaminophen use. In light of this we recommend that acetaminophen use be reviewed for safety in children. PMID:27695658

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

    PubMed

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

    2010-04-07

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

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

    PubMed Central

    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

  14. A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature.

    PubMed

    Ozkaya, Ozan; Genc, Gurkan; Bek, Kenan; Sullu, Yurdanur

    2010-01-01

    Acetaminophen (paracetamol) is a widely used drug and known as a safety antipyretic and analgesic drug in childhood. Acetaminophen-associated liver damage is more recognized than kidney damage. Nephrotoxicity and hepatotoxicity can be seen together after acetaminophen overdose, but renal damage without liver damage is a rarely seen entity in all age groups being reported more rarely in childhood. We present here a 16-year-old girl with renal failure without liver damage because of acetaminophen toxicity and a review of literature for pathophysiological mechanisms, clinical course, treatment, and outcome.

  15. Examination of gelling agents to produce acetaminophen jelly.

    PubMed

    Inoue, Yutaka; Iwazaki, Yuka; Onuki, Yoshinori; Funatani, Chiaki; Murata, Isamu; Kanamoto, Ikuo

    2015-01-01

    The current study used 3 types of carrageenan (denoted here as Car)-κ, ι, and λ-to prepare a jelly vehicle for acetaminophen (AAP), and then compared their usefulness as jelly vehicles. The rheological characteristics of each preparation were assessed and then drug elution from the preparation was assessed using dissolution testing. The behavior of each preparation when immersed in water was also examined using magnetic resonance imaging (MRI) in order to better understand the drug elution behaviour of each preparation. Viscoelasticity measurements revealed that 0.75 w/v%-ι-Car and 1.25 w/v%-λ-Car had viscoelasticity values equivalent to that of 0.5 w/v%-κ-Car. Dissolution testing of these 3 preparations indicated that 100% drug elution took 45 min with 0.5 w/v%-κ-Car while it took only 5 min with 0.75 w/v%-ι-Car and 1.25 w/v%-λ-Car. When deuterium oxide was added to κ-Car 0.5%, the MRI images darkened overall starting immediately after addition. The images revealed that the sample and deuterium oxide quickly mixed. In contrast, images revealed that deuterium oxide gradually penetrated κ-Car 1.0%. MRI images had uniform contrast, and deuterium oxide took 6 h or longer to penetrate the samples overall. These findings suggest that water is less apt to penetrate a jelly with an increased car concentration and a denser 3-dimensional network structure. Differences in the structure of car are said to result in better gelling, with κ having the best gelling characteristics, followed by ι and then λ. Thus, this paper discusses the role that vehicle gelling strength plays in the elution of acetaminophen.

  16. Effects of doxylamine and acetaminophen on postoperative sleep.

    PubMed

    Smith, G M; Smith, P H

    1985-05-01

    The separate and combined effects of doxylamine succinate (25 mg) and acetaminophen (1 gm) on sleep were studied by interview procedures and information from medical records of 2,931 postoperative patients. The sample contained 1,617 patients with mild or moderate pain and 1,314 who were free of pain. Each received either doxylamine alone (S), acetaminophen alone (A), a combination of both drugs (C), or placebo (P). Drug treatment was double blind and randomized separately for the pain and pain-free subsamples. Twelve measures of sleep were determined. C was more beneficial than S or A, and S and A were each superior to P. For all 12 sleep measures, the effect of the combination (C - P) approximated or exceeded the sum of the two separate effects (S - P) + (A - P). The presence of either drug tended to enhance the sleep benefit of the other. The sedative and analgesic benefits to sleep were at least additive, and some outcome measures suggested synergism. In the total sample, the contributions of sedative and analgesic similar. Among patients with pain, contributions of the analgesic surpassed those of the sedative. For patients free of pain, the sedative was better, but even pain-free patients had enhanced sleep after the analgesic. The analgesic, but not the sedative, reduced pain; the analgesic induced the feeling of being well rested and not tired; the sedative induced a feeling of being drugged. Nondrug variables (e.g., pain, sex, age, and sleep expectations) influenced sleep outcome at least as much as drugs, but randomization and the large sample prevented those extraneous variables from biasing drug comparisons.

  17. Raman detected differential scanning calorimetry of polymorphic transformations in acetaminophen.

    PubMed

    Kauffman, John F; Batykefer, Linda M; Tuschel, David D

    2008-12-15

    Acetaminophen is known to crystallize in three polymorphic forms. Thermally induced transformations between the crystalline forms and the super-cooled liquid have been observed by differential scanning calorimetry (DSC), but the assignment of calorimetric transitions to specific polymorphic transformations remains challenging, because the transition temperatures for several transformations are close to one another, and the characteristics of the observed transitions depend on experimental variables that are often poorly controlled. This paper demonstrates the simultaneous application of DSC and Raman microscopy for the observation of thermally driven transitions between polymorphs of pharmaceutical materials. Raman detected differential scanning calorimetry (RD-DSC) has been used to monitor the DSC thermograms of super-cooled liquid acetaminophen and confirms the assignment of two exothermic transitions to specific polymorphic transformations. Principal component analysis of the Raman spectra have been used to determine the number of independent components that participate in the phase transformations, and multivariate regression has been used to determine transition temperatures from the spectral data. The influence of the laser excitation source on measured DSC thermograms has also been investigated, and it has been demonstrated that a baseline shift occurs in RD-DSC when a polymorphic transformation occurs between crystalline and amorphous forms. RD-DSC has been used to examine the influence of sample aging and sample pan configuration on the observed polymorphic transformations, and both of these variables were found to influence the thermal behavior of the sample. The results demonstrate the advantage of simultaneous Raman spectroscopy and differential scanning calorimetry for the unambiguous assignment of thermally driven polymorphic transformations.

  18. Acetaminophen Attenuates Lipid Peroxidation in Children Undergoing Cardiopulmonary Bypass

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-01-22

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

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

    PubMed

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

    2010-05-01

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

  1. Ultrasonic degradation of acetaminophen in water: effect of sonochemical parameters and water matrix.

    PubMed

    Villaroel, Erica; Silva-Agredo, Javier; Petrier, Christian; Taborda, Gonzalo; Torres-Palma, Ricardo A

    2014-09-01

    This paper deals about the sonochemical water treatment of acetaminophen (ACP, N-acetyl-p-aminophenol or paracetamol), one of the most popular pharmaceutical compounds found in natural and drinking waters. Effect of ultrasonic power (20-60 W), initial ACP concentration (33-1323 μmol L(-1)) and pH (3-12) were evaluated. High ultrasonic powers and, low and natural acidic pH values favored the efficiency of the treatment. Effect of initial substrate concentration showed that the Langmuir-type kinetic model fit well the ACP sonochemical degradation. The influence of organic compounds in the water matrix, at concentrations 10-fold higher than ACP, was also evaluated. The results indicated that only organic compounds having a higher value of the Henry's law constant than the substrate decrease the efficiency of the treatment. On the other hand, ACP degradation in mineral natural water showed to be strongly dependent of the initial substrate concentration. A positive matrix effect was observed at low ACP concentrations (1.65 μmol L(-1)), which was attributed to the presence of bicarbonate ion in solution. However, at relative high ACP concentrations a detrimental effect of matrix components was noticed. Finally, the results indicated that ultrasonic action is able to transform ACP in aliphatic organic compounds that could be subsequently eliminated in a biological system.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2013-12-01

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

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

    NASA Astrophysics Data System (ADS)

    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

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

    PubMed

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

    2014-01-01

    Acetaminophen (paracetamol) is a commonly used over-the-counter analgesic and antipyretic and has previously been shown to improve exercise performance through a reduction in perceived pain. This study sought to establish whether its antipyretic action may also improve exercise capacity in the heat by moderating the increase in core temperature. On separate days, 11 recreationally active participants completed two experimental time-to-exhaustion trials on a cycle ergometer in hot conditions (30°C, 50% relative humidity) after ingesting a placebo control or an oral dose of acetaminophen in a randomized, double-blind design. Following acetaminophen ingestion, participants cycled for a significantly longer period of time (acetaminophen, 23 ± 15 min versus placebo, 19 ± 13 min; P = 0.005; 95% confidence interval = 90-379 s), and this was accompanied by significantly lower core (-0.15°C), skin (-0.47°C) and body temperatures (0.19°C; P < 0.05). In the acetaminophen condition, participants also reported significantly lower ratings of thermal sensation (-0.39; P = 0.015), but no significant change in heart rate was observed (P > 0.05). This is the first study to demonstrate that an acute dose of acetaminophen can improve cycling capacity in hot conditions, and that this may be due to the observed reduction in core, skin and body temperature and the subjective perception of thermal comfort. These findings suggest that acetaminophen may reduce the thermoregulatory strain elicited from exercise, thus improving time to exhaustion.

  6. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.

    PubMed

    Imaeda, Avlin B; Watanabe, Azuma; Sohail, Muhammad A; Mahmood, Shamail; Mohamadnejad, Mehdi; Sutterwala, Fayyaz S; Flavell, Richard A; Mehal, Wajahat Z

    2009-02-01

    Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1beta and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1beta and IL-18 from pro-IL-1beta and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.

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

    PubMed

    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.

  8. Protective effect of pioglitazone, a PPARγ agonist against acetaminophen-induced hepatotoxicity in rats.

    PubMed

    Gupta, Gaurav; Krishna, Gopala; Chellappan, Dinesh Kumar; Gubbiyappa, Kumar Shiva; Candasamy, Mayuren; Dua, Kamal

    2014-08-01

    Acetaminophen has a reasonable safety profile when consumed in therapeutic doses. However, it could induce hepatotoxicity and even acute liver failure when taken at an overdose. Pioglitazone, PPARγ ligand, is clinically tested and used in treatment of diabetes. PPARγ is a key nuclear hormone receptor of lipid metabolisms and regulates several gene transcriptions associated with differentiation, growth arrest, and apoptosis. The aim of our study was to evaluate the hepatoprotective activity of pioglitazone on acetaminophen-induced hepatotoxicity and to understand the relationship between the PPARγ and acetaminophen-induced hepato injury. For the experiment, Sprague-Dawley rats (160-180 g) were used and divided into four groups. Groups I and II were normal and experimental controls, respectively. Groups III and IV received the pioglitazone 20 mg/kg for 10 days. Hepatotoxicity was induced in Groups II and III on the eighth day with acetaminophen (i.p. 350 mg/kg body weight). The hepatoprotective effect was evaluated by performing an assay of the total protein, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and α-fetoprotein as well as glutathione peroxidase, lipid peroxidation, catalase, superoxide dismutase, and glutathione transferase and liver histopathology. The assay results were presented as mean and standard error of mean for each group. The study group was compared with the control group by one-way ANOVA test. A p value of <0.05 was considered significant. Pioglitazone significantly reduced the elevated level of above serum marker enzymes and also inhibits the free radical formation by scavenging hydroxyl ions. It also restored the level of LPO and significantly elevated the levels of endogenous antioxidant enzymes in acetaminophen-challenged hepatotoxicity. Liver histopathological examination showed that pioglitazone administration antagonized acetaminophen -induced liver pathological damage. Various

  9. Glucuronidation in the chimpanzee (Pan troglodytes): studies with acetaminophen, oestradiol and morphine.

    PubMed

    Wong, H; Grace, J E; Wright, M R; Browning, M R; Grossman, S J; Bai, S A; Christ, D D

    2006-12-01

    The chimpanzee has recently been characterized as a surrogate for oxidative drug metabolism in humans and as a pharmacokinetic model for the selection of drug candidates. In the current study, the glucuronidation of acetaminophen, morphine and oestradiol was evaluated in the chimpanzee to extend the characterization of this important animal model. Following oral administration of acetaminophen (600 mg) to chimpanzees (n=2), pharmacokinetics were comparable with previously reported human values, namely mean oral clearance 0.91 vs. 0.62+/-0.05 l h-1 kg-1, apparent volume of distribution 2.29 vs. 1.65+/-0.25 l kg-1, and half-life 1.86 vs. 1.89+/-7h, for chimpanzee vs. human, respectively. Urinary excretions (percentage of dose) of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were also similar between chimpanzees and humans, namely 2.3 vs. 5.0, 63.1 vs. 54.7, and 25.0 vs. 32.3%, respectively. Acetaminophen, oestradiol and morphine glucuronide formation kinetics were investigated using chimpanzee (n=2) and pooled human liver microsomes (n=10). V(max) (app) and K(m)(app) (or S(50)(app)) for acetaminophen glucuronide, morphine 3- and 6-glucuronide, and oestradiol 3- and 17-glucuronide formation were comparable in both species. Eadie-Hofstee plots of oestradiol 3-glucuronide formation in chimpanzee microsomes were characteristic of autoactivation kinetics. Western immunoblot analysis of chimpanzee liver microsomes revealed a single immunoreactive band when probed with anti-human UGT1A1, anti-human UGT1A6, and anti-human UGT2B7. Taken collectively, these data demonstrate similar glucuronidation characteristics in chimpanzees and humans.

  10. Prediction of color changes in acetaminophen solution using the time-temperature superposition principle.

    PubMed

    Mochizuki, Koji; Takayama, Kozo

    2016-01-01

    A prediction method for color changes based on the time-temperature superposition principle (TTSP) was developed for acetaminophen solution. Color changes of acetaminophen solution are caused by the degradation of acetaminophen, such as hydrolysis and oxidation. In principle, the TTSP can be applied to only thermal aging. Therefore, the impact of oxidation on the color changes of acetaminophen solution was verified. The results of our experiment suggested that the oxidation products enhanced the color changes in acetaminophen solution. Next, the color changes of acetaminophen solution samples of the same head space volume after accelerated aging at various temperatures were investigated using the Commission Internationale de l'Eclairage (CIE) LAB color space (a*, b*, L* and ΔE*ab), following which the TTSP was adopted to kinetic analysis of the color changes. The apparent activation energies using the time-temperature shift factor of a*, b*, L* and ΔE*ab were calculated as 72.4, 69.2, 72.3 and 70.9 (kJ/mol), respectively, which are similar to the values for acetaminophen hydrolysis reported in the literature. The predicted values of a*, b*, L* and ΔE*ab at 40 °C were obtained by calculation using Arrhenius plots. A comparison between the experimental and predicted values for each color parameter revealed sufficiently high R(2) values (>0.98), suggesting the high reliability of the prediction. The kinetic analysis using TTSP was successfully applied to predicting the color changes under the controlled oxygen amount at any temperature and for any length of time.

  11. Comparison of Oral Acetaminophen Versus Ibuprofen in Premature Infants With Patent Ductus Arteriosus

    PubMed Central

    Bagheri, Mohammad Mehdi; Niknafs, Pedram; Sabsevari, Fatemeh; Torabi, Mohammad Hosein; Bahman Bijari, Bahareh; Noroozi, Elahe; Mossavi, Hamid

    2016-01-01

    Background Patent ductus arteriosus (PDA) is a common cause of morbidity. The aim of this study was to compare the efficacy of oral Acetaminophen and oral Ibuprofen for the closure of patent ductus arteriosus (PDA) in preterm infants. Objectives This study demonstrated that, there was no significant difference between treatment of PDA with either oral Acetaminophen or oral Ibuprofen in preterm neonates. Patients and Methods This clinical trial, randomized study, enrolled 120 infants, with a gestational age of < 37 weeks, who were admitted in neonatal intensive care unit of Afzalipour hospital, Kerman, Iran, in 2014. PDA was confirmed echocardiographically. The trial was registered in Iranian registry of clinical trials (Reg. No. 25542). Sixty-seven infants received oral Acetaminophen (15mg/kg every six hours for three days) and 62 infants received Ibuprofen (an initial dose of 20 mg/kg, followed by 10 mg/kg at 24 and 48 hours). To evaluate the efficacy of the treatment, a second echocardiography was done after completing the treatment. Results After the first course of the treatment, PDA closed in 55 (82.1 %) patients who received oral Acetaminophen vs. 47 (75.8 %) of those given oral Ibuprofen (P = 0.38). After the second course of treatment, PDA closed in 50 % of oral Acetaminophen group and 73.3% of oral Ibuprofen group (P = 0.21). Conclusions This study demonstrated that, there was no significant difference between treatment of PDA with either oral Acetaminophen or oral Ibuprofen in preterm neonates. Oral Ibuprofen can effectively close PDA but is unfortunately associated with some adverse effects limiting its utility thus we studied an alternative drug with similar efficacy and less adverse effects. This study has recommends Acetaminophen with minimal complications for the treatment of PDA in preterm neonates instead of Ibuprofen. PMID:27713809

  12. Metabolite kinetics: formation of acetaminophen from deuterated and nondeuterated phenacetin and acetanilide on acetaminophen sulfation kinetics in the perfused rat liver preparation

    SciTech Connect

    Pang, K.S.; Waller, L.; Horning, M.G.; Chan, K.K.

    1982-07-01

    The role of hepatic intrinsic clearance for metabolite formation from various precursors on subsequent metabolite elimination was was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors: (/sup 14/C) phenacetin-d5 and (/sup 3/H) phenacetin-do, (/sup 14/C) acetanilide and (/sup 3/H) phenacetin were delivered by constant flow (10 ml/min/liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The data showed that the higher the hepatocellular activity (intrinsic clearance) for acetaminophen formation, the greater the extent of subsequent acetaminophen sulfation. The findings were explained on the basis of blood transit time and metabolite duration time. Because of blood having only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite sulfation and the less will be the degree of subsequent sulfation. Conversely, when the drug forms the primary metabolite rapidly, a longer time will remain for the metabolite to be sulfated in liver to result in a greater degree of metabolite sulfation. Finally, the effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed.

  13. Effect of Methylsulfonylmethane Pretreatment on Aceta-minophen Induced Hepatotoxicity in Rats

    PubMed Central

    Bohlooli, Shahab; Mohammadi, Sadollah; Amirshahrokhi, Keyvan; Mirzanejad-asl, Hafez; Yosefi, Mohammad; Mohammadi-Nei, Amir; Chinifroush, Mir Mehdi

    2013-01-01

    Objective(s): Methylsulfonylmethane (MSM) is a sulfur-containing compound found in a wide range of human foods including fruits, vegetables, grains and beverages. In this study the effect of MSM pretreatment on acetaminophen induced liver damage was investigated. Materials and Methods: Male Sprague Dawley rats were pretreated with 100 mg/kg MSM for one week. On day seven rats were received acetaminophen (850 mg/kg, intraperitoneal). Twenty-four hours later, blood samples were taken to determine serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Tissue samples of liver were also taken for the determination of the levels of malondialdehyde (MDA); total glutathione (GSH), superoxide dismutase (SOD), and myeloperoxidase (MPO) activity together with histopathological observations. Results: High dose of acetaminophen administration caused a significant decrease in the GSH level of the liver tissue, which was accompanied with a decrease in SOD activity and increases in tissue MDA level and MPO activity. Serum ALT, AST levels were also found elevated in the acetaminophen-treated group. Pretreatment with MSM for one week was significantly attenuated all of these biochemical indices. Conclusion: Our findings suggest that MSM pretreatment could alleviate hepatic injury induced by acetaminophen intoxication, may be through its sulfur donating and antioxidant effects. PMID:24106592

  14. Comparative study of the adsorption of acetaminophen on activated carbons in simulated gastric fluid.

    PubMed

    Rey-Mafull, Carlos A; Tacoronte, Juan E; Garcia, Raquel; Tobella, Jorge; Llópiz, Julio C; Iglesias, Alberto; Hotza, Dachamir

    2014-01-01

    Samples of commercial activated carbons (AC) obtained from different sources: Norit E Supra USP, Norit B Test EUR, and ML (Baracoa, Cuba) were investigated. The adsorption of acetaminophen, Co = 2500 mg/L, occured in simulated gastric fluid (SGF) at pH 1.2 in contact with activated carbon for 4 h at 310 K in water bath with stirring. Residual acetaminophen was monitored by UV visible. The results were converted to scale adsorption isotherms using alternative models: Langmuir TI and TII, Freundlich, Dubinin-Radushkevich (DR) and Temkin. Linearized forms of the characteristic parameters were obtained in each case. The models that best fit the experimental data were Langmuir TI and Temkin with R(2) ≥0.98. The regression best fits followed the sequence: Langmuir TI = Temkin > DR > LangmuirTII > Freundlich. The microporosity determined by adsorption of CO2 at 273 K with a single term DR regression presented R(2) > 0.98. The adsorption of acetaminophen may occur in specific sites and also in the basal region. It was determined that the adsorption process of acetaminophen on AC in SGF is spontaneous (ΔG <0) and exothermic (-ΔHads.). Moreover, the area occupied by the acetaminophen molecule was calculated with a relative error from 7.8 to 50%.

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

    PubMed Central

    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

    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

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

    PubMed

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

    2015-12-07

    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.

  17. Enhancement of Antihyperalgesia by the Coadministration of N-palmitoylethanolamide and Acetaminophen in Diabetic Rats.

    PubMed

    Déciga-Campos, Myrna; Ortíz-Andrade, Rolffy

    2015-08-01

    Preclinical Research The objective of this study was to evaluate the pharmacological antihyperalgesic interaction between N-palmitoylethanolamide (PEA) and acetaminophen in diabetic rats using the formalin paw test. Streptozotocin (STZ)-induced diabetic rats received subcutaneous injections in the paw of PEA alone (1-100 μg/paw) or acetaminophen alone (3-300 μg/paw) 15 min before formalin (0.5%) injection. The results revealed concentration-dependent responses produced by PEA (EC50 = 7.19 ± 0.7 μg/paw) and acetaminophen (EC50 = 57.9 ± 1.9 μg/paw). Isobolographic analysis was used to evaluate the pharmacological interaction between the PEA + acetaminophen using the EC50 value and a fixed 1:1 ratio combination. The isobologram demonstrated that the combination investigated in this study produced a synergistic interaction; the experimental value (EC50 = 23.64 ± 1.9 μg/paw) was significantly smaller than those that resulted from theoretical calculations (EC50 = 32.56 μg/paw). These results provide evidence that PEA in combination with acetaminophen could be useful for pain therapy in neuropathic diabetic patients.

  18. Gene Expression in Rat Hearts Following Oral Administration of a Single Hepatotoxic Dose of Acetaminophen

    PubMed Central

    Kil, Hong Ryang; Park, Kwangsik; Noh, Chung Il

    2012-01-01

    Purpose Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage. Materials and Methods Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration. Results Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver. The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion. Conclusion The induced expression of genes implicated in oxidative stress and inflammatory processes in the myocardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology. PMID:22187249

  19. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    PubMed

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.

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

    PubMed Central

    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, 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. PMID:23864853

  1. Lophirones B and C Attenuate Acetaminophen-Induced Liver Damage in Mice: Studies on Hepatic, Oxidative Stress and Inflammatory Biomarkers.

    PubMed

    Ajiboye, Taofeek O

    2016-10-01

    Lophirones B and C are chalcone dimers with proven chemopreventive activity. This study evaluates the hepatoprotective effect lophirones B and C in acetaminophen-induced hepatic damage in mice using biomarkers of hepatocellular indices, oxidative stress, proinflammatory factors and lipid peroxidation. Oral administrations of lophirones B and C significantly (p < 0.05) attenuated acetaminophen-mediated alterations in serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin and total bilirubin. Similarly, acetaminophen-mediated decrease in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6- phosphate dehydrogenase were significantly attenuated in the liver of mice. Increased levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl and fragmented DNA were significantly lowered by lophirones B and C. Levels of tumour necrosis factor-α, interleukin-6 and 8 were significantly lowered in serum of acetaminophen treated mice by the chalcone dimers. Overall, results of this study show that lophirones B and C halted acetaminophen-mediated hepatotoxicity.

  2. Cannabinoid receptor-mediated antinociception with acetaminophen drug combinations in rats with neuropathic spinal cord injury pain

    PubMed Central

    Hama, Aldric T.; Sagen, Jacqueline

    2010-01-01

    Pre-clinical evidence demonstrates that neuropathic spinal cord injury (SCI) pain is maintained by a number of neurobiological mechanisms, suggesting that treatments directed at several pain-related targets may be more advantageous compared to a treatment focused on a single target. The current study evaluated the efficacy of the non-opiate analgesic acetaminophen, which has several putative analgesic mechanisms, combined with analgesic drugs used to treat neuropathic pain in a rat model of below-level neuropathic SCI pain. Following an acute compression of the mid-thoracic spinal cord, rats exhibited robust hind paw hypersensitivity to innocuous mechanical stimulation. Fifty percent antinociceptive doses of gabapentin, morphine, tramadol or memantine were combined with an ineffective dose of acetaminophen; acetaminophen alone was not antinociceptive. The combination of acetaminophen with either tramadol or memantine resulted in an additive antinociceptive effect. Acetaminophen combined with either morphine or gabapentin, however, resulted in supra-additive (synergistic) efficacy. One of the analgesic mechanisms of acetaminophen is inhibiting the uptake of endocannabinoids from the extracellular space. Pre-treatment with AM251, a cannabinoid receptor subtype-1 (CB1) antagonist, significantly diminished the antinociceptive effect of the acetaminophen+gabapentin combination. Pre-treatment with AM630, a cannabinoid receptor subtype-2 (CB2) antagonist, did not have an effect on this combination. By contrast, both AM251 and AM630 reduced the efficacy of the acetaminophen+morphine combination. None of the active drugs alone were affected by either CB receptor antagonist. The results imply that modulation of the endocannabinoid system in addition to other mechanisms mediate the synergistic antinociceptive effects of acetaminophen combinations. Despite the presence of a cannabinoid mechanism, synergism was not present in all acetaminophen combinations. The combination of

  3. Protective effects of acetaminophen on ibuprofen-induced gastric mucosal damage in rats with associated suppression of matrix metalloproteinase.

    PubMed

    Fukushima, Eriko; Monoi, Noriyuki; Mikoshiba, Shigeo; Hirayama, Yutaka; Serizawa, Tetsushi; Adachi, Kiyo; Koide, Misao; Ohdera, Motoyasu; Murakoshi, Michiaki; Kato, Hisanori

    2014-04-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage as a side effect. Acetaminophen, widely used as an analgesic and antipyretic drug, has gastroprotective effects against gastric lesions induced by absolute ethanol and certain NSAIDs. However, the mechanisms that underlie the gastroprotective effects of acetaminophen have not yet been clarified. In the present study, we examined the role and protective mechanism of acetaminophen on ibuprofen-induced gastric damage in rats. Ibuprofen and acetaminophen were administered orally, and the gastric mucosa was macroscopically examined 4 hours later. Acetaminophen decreased ibuprofen-induced gastric damage in a dose-dependent manner. To investigate the mechanisms involved, transcriptome analyses of the ibuprofen-damaged gastric mucosa were performed in the presence and absence of acetaminophen. Ingenuity pathway analysis (IPA) software revealed that acetaminophen suppressed the pathways related to cellular assembly and inflammation, whereas they were highly activated by ibuprofen. On the basis of gene classifications from the IPA Knowledge Base, we identified the following five genes that were related to gastric damage and showed significant changes in gene expression: interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), matrix metalloproteinase-10 (MMP-10), MMP-13, and FBJ osteosarcoma oncogene (FOS). Expression of these salient genes was confirmed using real-time polymerase chain reaction. The expression of MMP-13 was the most reactive to the treatments, showing strong induction by ibuprofen and suppression by acetaminophen. Moreover, MMP-13 inhibitors decreased ibuprofen-induced gastric damage. In conclusion, these results suggest that acetaminophen decreases ibuprofen-induced gastric mucosal damage and that the suppression of MMP-13 may play an important role in the gastroprotective effects of acetaminophen.

  4. Diallyl disulfide attenuates acetaminophen-induced renal injury in rats

    PubMed Central

    Shin, Jin-Young; Han, Ji-Hee; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Jung, Tae-Yang; Kim, Hyun-A; Kim, Sung-Hwan; Shin, In-Sik

    2016-01-01

    This study investigated the protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute renal injury in male rats. We also investigated the effects of DADS on kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), which are novel biomarkers of nephrotoxicity in renal tissues, in response to AAP treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) AAP (1,000 mg/kg), (3) AAP&DADS, and (4) DADS (50 mg/kg/day). AAP treatment caused acute kidney injury evidenced by increased serum blood urea nitrogen (BUN) levels and histopathological alterations. Additionally, Western blot and immunohistochemistry analysis showed increased expression of KIM-1 and NGAL proteins in renal tissues of AAP-treated rats. In contrast, DADS pretreatment significantly attenuated the AAP-induced nephrotoxic effects, including serum BUN level and expression of KIM-1 and NGAL proteins. Histopathological studies confirmed the renoprotective effect of DADS. The results suggest that DADS prevents AAP-induced acute nephrotoxicity, and that KIM-1 and NGAL may be useful biomarkers for the detection and monitoring of acute kidney injury associated with AAP exposure. PMID:28053613

  5. Effects of kale ingestion on pharmacokinetics of acetaminophen in rats.

    PubMed

    Yamasaki, Izumi; Uotsu, Nobuo; Yamaguchi, Kohji; Takayanagi, Risa; Yamada, Yasuhiko

    2011-12-01

    Kale is a cruciferous vegetable (Brassicaceae) that contains a large amount of health-promoting phytochemicals. The chronic ingestion of cabbage of the same family is known to accelerate conjugating acetaminophen (AA) and decrease the plasma AA level. Therefore, we examined to clarify the effects of kale on the pharmacokinetics of AA, its glucuronide (AA-G) and sulfate (AA-S). AA was orally administered to rats pre-treated with kale or cabbage (2000 mg/kg/day) for one week. Blood samples were collected from the jugular vein, and the concentrations of AA, AA-G and AA-S were determined. In results, kale ingestion induced an increase in the area under the concentration-time curve (AUC) and a decrease in the clearance of AA, whereas cabbage had almost no influence. In addition, there were significant differences in the AUC of AA-G between the control and kale groups. mRNA expression levels of UDP-glucuronosyltransferases, the enzymes involved in glucuronidation, in the kale group were significantly higher than those in the control group. In conclusion, kale ingestion increased the plasma concentrations of both AA and AA-G. The results suggest that kale ingestion accelerates the glucuronidation of AA, but an increase of plasma AA levels has a different cause than the cause of glucuronidation.

  6. Diallyl disulfide attenuates acetaminophen-induced renal injury in rats.

    PubMed

    Shin, Jin-Young; Han, Ji-Hee; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Jung, Tae-Yang; Kim, Hyun-A; Kim, Sung-Hwan; Shin, In-Sik; Kim, Jong-Choon

    2016-12-01

    This study investigated the protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute renal injury in male rats. We also investigated the effects of DADS on kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), which are novel biomarkers of nephrotoxicity in renal tissues, in response to AAP treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) AAP (1,000 mg/kg), (3) AAP&DADS, and (4) DADS (50 mg/kg/day). AAP treatment caused acute kidney injury evidenced by increased serum blood urea nitrogen (BUN) levels and histopathological alterations. Additionally, Western blot and immunohistochemistry analysis showed increased expression of KIM-1 and NGAL proteins in renal tissues of AAP-treated rats. In contrast, DADS pretreatment significantly attenuated the AAP-induced nephrotoxic effects, including serum BUN level and expression of KIM-1 and NGAL proteins. Histopathological studies confirmed the renoprotective effect of DADS. The results suggest that DADS prevents AAP-induced acute nephrotoxicity, and that KIM-1 and NGAL may be useful biomarkers for the detection and monitoring of acute kidney injury associated with AAP exposure.

  7. Characterization of acetaminophen-induced cytotoxicity in target tissues

    PubMed Central

    Guo, Chao; Xie, Guojie; Su, Min; Wu, Xinmou; Lu, Xiuli; Wu, Ka; Wei, Chaohe

    2016-01-01

    Acetaminophen (APAP), commonly used in clinical prescription, has time- and dose-dependent side effects. Thus, further animal study warrants to be investigated to assess possible adverse effect of APAP application. Here, we conducted pre-clinical research to elucidate the molecular mechanism regarding APAP-mediated toxicological action. Our data showed that serous/urinary and hepatic/renal APAP concentrations were significantly increased when compared with normal control, which the liver tissue showed the highest level. As an acute liver damage model induced by APAP, absolute liver weight, serum enzyme (ALT), urine protein content were notably elevated. Representatively, APAP-damaged liver resulted in increased pro-apoptotic Bax and compensatory Ki-67 positive cells, while the number of anti-apoptotic Bcl2 positive cells was reduced. In addition, the immunoactivity markers for NF-κB, TRL4, TNF-α in the kidney were increased, respectively. Furthermore, intracellular TRL4 and TNF-α mRNAs in the liver and kidney showed significant up-regulation. In summary, our current findings demonstrate that APAP-mediated the specific cytotoxicity is linked to the molecular mechanisms of facilitating apoptosis and inflammatory stress in the liver and kidney. PMID:27830028

  8. Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice

    PubMed Central

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

    2016-01-01

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

  9. Protective effects of diallyl sulfide on acetaminophen-induced toxicities.

    PubMed

    Hu, J J; Yoo, J S; Lin, M; Wang, E J; Yang, C S

    1996-10-01

    Diallyl sulfide (DAS), a major flavour component of garlic, is known to modulate drug metabolism and may protect animals from chemically induced toxicity and carcinogenesis. In this study the effects of DAS on the oxidative metabolism and hepatotoxicity induced by acetaminophen (APAP) in rats were investigated. In the hepatotoxicity evaluation of Fischer 344 rats there was a dose-dependent increase in the odds of mortality rate by APAP (P = 0.009); DAS treatment significantly protected rats from APAP-related mortality (P = 0.026). Liver toxicity determined by lactate dehydrogenase activity was significantly increased by APAP treatment (0.75 g/kg). Pretreatment with DAS protected animals from APAP-induced liver toxicity in a time- and dose-dependent fashion. Treatment of DAS (50 mg/kg) 3 hr after APAP dosing significantly (P < 0.05) protected rats from APAP-induced liver toxicity. The metabolism of APAP (50 microM) in vitro was significantly inhibited by DAS (0.3-1 mM) in liver microsomes isolated from F344 rats. As the effect of DAS on APAP-induced hepatotoxicity in vivo was observed only when DAS was administered before or shortly after (< 3 hr) APAP dosing, data suggested that the protective effect of DAS is mainly at the metabolic activation step of APAP. However, the possibility that DAS may also have effects on other drug metabolism systems, such as glutathione (GSH) and glutathione S-transferases, cannot be ruled out.

  10. Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats.

    PubMed

    Kuvandik, Guven; Duru, Mehmet; Nacar, Ahmet; Yonden, Zafer; Helvaci, Rami; Koc, Ahmet; Kozlu, Tolunay; Kaya, Hasan; Sogüt, Sadik

    2008-07-01

    We investigated the effects of erdosteine on acetaminophen (APAP)-induced hepatotoxicity in rats. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), AST (aspartate aminotransferase), and ALT (alanine transaminase) activities, and malonyldialdehyde (MDA) and nitric oxide levels as oxidant/antioxidant biochemical parameters were investigated with light microscopic evaluation in adult female Wistar Albino rats. APAP administration produced a decrease in hepatic SOD, CAT, and GSH-Px activities, and coadministration of erdosteine (150 and 300 mg/kg) resulted in increases in the activities. MDA and NO levels increased in the APAP group, and erdosteine treatments prevented these increases. Significant elevations in serum AST and ALT levels were observed in the APAP group, and when erdosteine and APAP were coadministered, their serum levels were close to those in the control group. Light microscopic evaluation of livers showed that there were remarkable centrilobular (zone III) hepatic necrosis and mild to moderate sinusoidal congestion in the APAP group, whereas in the erdosteine group, cellular necrosis was minimal and the hepatocytes maintained a better morphology when compared to the APAP group. Erdosteine prevented APAP-induced liver injury and toxic side effects probably through the antioxidant and radical scavenging effects of erdosteine.

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

    PubMed Central

    Hanafy, Abeer; Aldawsari, Hibah M.; Badr, Jihan M.; Ibrahim, Amany K.; Abdel-Hady, Seham El-Sayed

    2016-01-01

    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. PMID:27118980

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

    PubMed

    Hanafy, Abeer; Aldawsari, Hibah M; Badr, Jihan M; Ibrahim, Amany K; Abdel-Hady, Seham El-Sayed

    2016-01-01

    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.

  13. A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain.

    PubMed

    Altman, R D

    2004-01-01

    Analgesic therapy that combines individual agents with different mechanisms of action has potential advantages for the management of mild-to-moderate pain in the outpatient setting. Theoretically, this approach can lead to greater efficacy and fewer adverse events. While the precise mechanism of action for the analgesic effect of acetaminophen remains uncertain, accumulating evidence suggests that its activity resides primarily in the central nervous system. In contrast, the site of action for the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is predominantly peripheral, within injured or inflamed tissue. Several controlled clinical studies among patients with musculoskeletal conditions, dental pain, or postoperative pain have shown that combinations of acetaminophen and NSAIDs provide additive pain-relieving activity, thereby leading to dose-sparing effects and improved safety. Further studies are warranted to determine the clinical utility and safety of acetaminophen/NSAID combinations as analgesic therapy for common conditions associated with mild-to-moderate pain.

  14. Carbon based electrodes modified with horseradish peroxidase immobilized in conducting polymers for acetaminophen analysis.

    PubMed

    Tertis, Mihaela; Florea, Anca; Sandulescu, Robert; Cristea, Cecilia

    2013-04-11

    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. Antioxidant and hepatoprotective effects of punicalagin and punicalin on acetaminophen-induced liver damage in rats.

    PubMed

    Lin, C C; Hsu, Y F; Lin, T C; Hsu, H Y

    2001-05-01

    Punicalagin and punicalin were isolated from the leaves of Terminalia catappa L., a Combretaceous plant distributed throughout tropical and subtropical beaches, which is used for the treatment of dermatitis and hepatitis. Our previous studies showed that both of these compounds exert antioxidative activity. In this study, the antihepatotoxic activity of punicalagin and punicalin on acetaminophen-induced toxicity in the rat liver was evaluated. After evaluating the changes of several biochemical functions in serum, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased by acetaminophen administration and reduced by punicalagin and punicalin. Histological changes around the hepatic central vein and oxidative damage induced by acetaminophen were also recovered by both compounds. The data show that both punicalagin and punicalin exert antihepatotoxic activity, but treatment with larger doses enhanced liver damage. These results suggest that even if punicalagin and punicalin have antioxidant activity at small doses, treatment with larger doses will possibly induce some cell toxicities.

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

    PubMed Central

    Tertis, Mihaela; Florea, Anca; Sandulescu, Robert; Cristea, Cecilia

    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 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. PMID:23580052

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

    PubMed Central

    Kasmi, Irena; Sallabanda, Sashenka; Kasmi, Gentian

    2015-01-01

    BACKGROUND: Acetaminophen is a drug widely used in children because of its safety and efficacy. Although the risk of its toxicity is lower in children such reactions occur in pediatric patients from intentional overdoses and less frequently attributable to unintended inappropriate dosing. The aim of reporting this case is to attract the attention to the risk of the acetaminophen toxicity when administered in high doses. CASE PRESENTATION: We report here a 5 year old girl who developed fulminate liver failure with renal impairment and acute pancreatitis, as a result of acetaminophen toxicity caused from unintentional repeated supratherapeutic ingestion, with a total administered dose of 4800 mg in three consecutive days, 1600 mg/day, approximately 90 mg/kg/day. The blood level of acetaminophen after 10 hours of the last administered dose was 32 mg/l. The patient presented with high fever, jaundice, lethargic, agitating with abdominal pain accompanied by encephalopathy. The liver function test revealed with high level of alanine aminotransferase 5794 UI/l and aspartate aminotransferase 6000 UI/l. Early initiation of oral N-acetylcysteine (NAC) after biochemical evidence of liver toxicity was beneficial with rapid improvement of liver enzymes, hepatic function and encephalopathy. During the course of the illness the child developed acute pancreatitis with hyperamylasemia 255 UI/L and hyperlypasemia 514 UI/L. Patient totally recovered within 29 days. CONCLUSION: Healthcare providers should considered probable acetaminophen toxicity in any child who has received the drug and presented with liver failure. When there is a high index of suspicion of acetaminophen toxicity NAC should be initiated and continued until there are no signs of hepatic dysfunction. PMID:27275268

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

    PubMed

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

    2013-11-01

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

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

    PubMed

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

    2014-09-01

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

  20. Crystallization of acetaminophen form II by plastic-ball-assisted ultrasonic irradiation

    NASA Astrophysics Data System (ADS)

    Mori, Yoichiro; Maruyama, Mihoko; Takahashi, Yoshinori; Yoshikawa, Hiroshi Y.; Okada, Shino; Adachi, Hiroaki; Sugiyama, Shigeru; Takano, Kazufumi; Murakami, Satoshi; Matsumura, Hiroyoshi; Inoue, Tsuyoshi; Yoshimura, Masashi; Mori, Yusuke

    2017-02-01

    We report a novel method for crystallizing the metastable polymorph form II of acetaminophen by using a plastic ball during ultrasonic irradiation. The presence of a plastic ball during ultrasonic irradiation of aqueous acetaminophen solution effectively increased the probability and reduced the induction time of form II crystallization. This method facilitated both laboratory- and large-scale production of form II crystals. Our method has significant advantages for practical application of form II because it can reduce the time to production and enable large-scale production.

  1. Electrochemical sensors based on carbon nanomaterials for acetaminophen detection: A review.

    PubMed

    Cernat, Andreea; Tertiş, Mihaela; Săndulescu, Robert; Bedioui, Fethi; Cristea, Alexandru; Cristea, Cecilia

    2015-07-30

    This study describes the advancements made over the last five years in the development of electrochemical sensors and biosensors for acetaminophen detection. This study reviews the different configurations based on unmodified and chemically modified carbon nanotubes and graphene. The influence of various modifiers on the two types of materials is presented along with their role on the enhancement of the selectivity and sensitivity of (bio)sensors. The review is focused on a comparative description of the applications of carbon-based nanomaterials towards acetaminophen detection and presents the results in a critical manner.

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

    SciTech Connect

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

    2015-01-15

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

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

    PubMed Central

    Mehra, Lalita; Hasija, Yasha; Mittal, Gaurav

    2016-01-01

    Objective: Alpha-ketoglutarate (α-KG) is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP) induced toxicity in rats. Materials and Methods: Animals were divided into three groups of six animals each. Group I (Vehicle control): Normal Saline, Group II (APAP): A single intraperitoneal injection of 0.6 g/kg, Group III (APAP + α-KG): APAP as in Group II with α-KG treatment at a dose of 2 g/kg, orally for 5 days. Then the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) with oxidative stress markers including malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and histopathology were analyzed. Results: The results indicate that APAP caused significant elevations in ALT, AST, ALP, and MDA levels, while GSH, SOD, and CAT were significantly depleted while co-administration of α-KG showed a significant (P < 0.05) reduction in the severity of these damages. Histologically, the liver showed inflammation and necrosis after APAP treatment, which were significantly restored with co-administration of α-KG. Conclusion: These results indicate the possible therapeutic potential of α-KG in protecting liver damage by APAP in rats. PMID:28216953

  4. Protective Properties of 2-Acetylcyclopentanone in a Mouse Model of Acetaminophen Hepatotoxicity

    PubMed Central

    Zhang, Lihai; Gavin, Terrence; Geohagen, Brian C.; Liu, Qiang; Downey, Katherine J.

    2013-01-01

    Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile- or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with substantial changes in plasma liver enzyme activities, histopathological indices, and markers of hepatocyte oxidative stress. 2-ACP administered intraperitoneally 20 minutes before APAP completely prevented lethality over a 7-day observation period. This effect was dose-dependent (0.80–2.40 mmol/kg) and was correlated with normalization of measured parameters. Nearly complete protection was afforded when 2-ACP was administered 20 minutes post-APAP, but not 60 minutes after intoxication. Although intraperitoneal administration of N-acetylcysteine (NAC) was not effective over a broad dose range (2.40–7.20 mmol/kg), temporal studies indicated that intraperitoneal NAC was hepatoprotective when injected 60 minutes after APAP intoxication. Because of a loss of function in stomach acid, oral administration of 2-ACP was associated with modest APAP protection. In contrast, NAC administered orally provided dose-dependent (0.80–2.40 mmol/kg) protection against APAP hepatotoxicity. In chemico studies and quantum mechanical calculations indicated that 2-ACP acted as a surrogate nucleophilic target for the reactive electrophilic APAP metabolite N-acetyl-p-benzoquinone imine. Our findings suggest that 2-ACP or a derivative might be useful in treating acquired toxicities associated with electrophilic drugs and metabolites or environmental toxicants. PMID:23759509

  5. An effective antidote for paraquat poisonings: the treatment with lysine acetylsalicylate.

    PubMed

    Dinis-Oliveira, R J; Pontes, H; Bastos, M L; Remião, F; Duarte, J A; Carvalho, F

    2009-01-31

    Sodium salicylate (NaSAL) has been shown to have a multifactorial protection mechanism against paraquat (PQ)-induced toxicity, due to its ability to modulate inflammatory signalling systems, to prevent oxidative stress and to its capacity to chelate PQ. Considering that currently there is no pharmaceutical formulation available for parenteral administration of NaSAL, the aim of the present study was to evaluate the antidotal feasibility of a salicylate prodrug, lysine acetylsalicylate (LAS), accessible for parenteral administrations. PQ was administered to Wistar rats by gavage (125mg/kg of PQ ion) and the treatment was performed intraperitoneally with different doses (100, 200 and 400mg/kg of body weight) of LAS. Survival rate was followed during 30 days and living animals at this endpoint were sacrificed for lung, kidney, liver, jejune and heart histological analysis. It was shown, that the salicylate prodrug, LAS, available in a large number of hospitals, is also effective in the treatment of PQ intoxications. From all tested LAS doses, 200mg/kg assured animal's full survival. Comparatively to 60% of mortality observed in PQ only exposed animals, the lethality was higher (80%) in the group that received 400mg/kg of LAS 2h after PQ administration. The dose of 100mg/kg of LAS showed only a modest protection (60% of survival). Collagen deposition was observed by histological analysis in survived animals of all experimental groups, being less pronounced in animals receiving 200mg/kg of LAS, reinforcing the importance of this dose against tissue damage induced by PQ. The results allow us to suggest that LAS should be considered in the hospital treatment of PQ poisonings.

  6. Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation

    PubMed Central

    Posadas, Inmaculada; Santos, Pablo; Ceña, Valentín

    2012-01-01

    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-xL 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. PMID:23166834

  7. Acute acetaminophen toxicity in transgenic mice with elevated hepatic glutathione.

    PubMed

    Rzucidlo, S J; Bounous, D I; Jones, D P; Brackett, B G

    2000-06-01

    Previous studies demonstrated that elevation of hepatic glutathione (GSH) concentrations protect against acetaminophen (APAP) hepatotoxicity in mice. Employing transgenic mice overexpressing glutathione synthetase, this study was conducted to determine if sustained elevation of hepatic GSH concentrations could ameliorate or prevent APAP toxicity. International Cancer Research transgenic mouse males and matched (ie same strain, sex, and age) control nontransgenic mice were pretreated ip with GSH synthetase substrate gamma-glutamylcysteinyl ethyl ester (gamma-GCE) or with saline. After a 16-h fast, mice received a single dose of 500 mg APAP/kg bw in saline ip and were sacrificed 4 h later. Other mice similarly pretreated were killed without APAP challenge. The elevated GSH concentrations in transgenic mice livers did not lessen APAP hepatotoxicity. Instead higher degrees of hepatotoxicity and nephrotoxicity were observed in transgenic mice than in controls as indicated by higher serum alanine aminotransferase activity and more severe histopathological lesions in transgenic mice livers and kidneys. Pretreatment with gamma-GCE did not affect either initial or post-APAP treatment tissue GSH concentrations or observed degrees of toxicity. Detection of a higher level of serum APAP in transgenic mice and the histopathological lesions found in transgenic mice kidneys together with no observable nephrotoxicity in control mice indicated early kidney damage in transgenic mice. Our findings suggest that high levels of GSH-APAP conjugates resulting from increased GSH concentrations in the livers of transgenic mice caused rapid kidney damage. Compromised excretory ability may have caused retention of APAP, which, in effect, elicited higher hepatotoxicity than that observed in nontransgenic mice.

  8. Mechanism of protection by metallothionein against acetaminophen hepatotoxicity

    SciTech Connect

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

    2010-01-15

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

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

    PubMed

    Cuzzolin, Laura; Antonucci, Roberto; Fanos, Vassilios

    2013-02-01

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

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

    SciTech Connect

    Cover, Cathleen; Liu Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P.; Bajt, Mary Lynn; Jaeschke, Hartmut . E-mail: jaeschke@email.arizona.edu

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.

  11. Changes in Mouse Liver Protein Glutathionylation after Acetaminophen Exposure

    PubMed Central

    Yang, Xi; Greenhaw, James; Ali, Akhtar; Shi, Qiang; Roberts, Dean W.; Hinson, Jack A.; Muskhelishvili, Levan; Beger, Richard; Pence, Lisa M.; Ando, Yosuke; Sun, Jinchun; Davis, Kelly

    2012-01-01

    The role of protein glutathionylation in acetaminophen (APAP)-induced liver injury was investigated in this study. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase and aspartate aminotransferase levels and liver necrosis in a dose-dependent manner. The ratio of GSH to GSSG was decreased in a dose-dependent manner, suggesting that APAP produced a more oxidizing environment within the liver. Despite the increased oxidation state, the level of global protein glutathionylation was decreased at 1 h and continued to decline through 24 h. Immunohistochemical localization of glutathionylated proteins showed a complex dynamic change in the lobule zonation of glutathionylated proteins. At 1 h after APAP exposure, the level of glutathionylation decreased in the single layer of hepatocytes around the central veins but increased mildly in the remaining centrilobular hepatocytes. This increase correlated with the immunohistochemical localization of APAP covalently bound to protein. Thereafter, the level of glutathionylation decreased dramatically over time in the centrilobular regions with major decreases observed at 6 and 24 h. Despite the overall decreased glutathionylation, a layer of cells lying between the undamaged periportal region and the damaged centrilobular hepatocytes exhibited high levels of glutathionylation at 3 and 6 h in all samples and in some 24-h samples that had milder injury. These temporal and zonal pattern changes in protein glutathionylation after APAP exposure indicate that protein glutathionylation may play a role in protein homeostasis during APAP-induced hepatocellular injury. PMID:22045778

  12. Mouse Liver Protein Sulfhydryl Depletion after Acetaminophen Exposure

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2016-01-28

    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.

  14. Melatonin prevents acetaminophen-induced nephrotoxicity in rats.

    PubMed

    Ilbey, Yusuf Ozlem; Ozbek, Emin; Cekmen, Mustafa; Somay, Adnan; Ozcan, Levent; Otünctemur, Alper; Simsek, Abdulmuttalip; Mete, Fatih

    2009-01-01

    Nephrotoxicity is a major complication of acetaminophen (APAP), a widely used analgesic and antipyretic drug, and there is no specific treatment for APAP-induced renal damage. It has been reported that reactive oxygen metabolites or free radicals are important mediators of APAP toxicity. In this study, the protective role of melatonin (MLT) on APAP-induced nephrotoxicity was investigated in rats. For this purpose, nephrotoxicity was induced in male Wistar albino rats by intraperitoneal (i.p.) administration of a single dose of 1,000 mg/kg APAP. Some of these rats also received i.p. melatonin (10 mg/kg) 20 min after administration of APAP. The rats were sacrificed 24 h after administration of APAP. Urea and creatinine levels were measured in the blood, and levels of malondialdehyde (MDA) and glutathione (GSH), and glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity were determined in renal tissue. Serum urea and creatinine levels increased significantly as a result of APAP nephrotoxicity. A significant increase in MDA and decreases in GSH level and GSH-Px, CAT, and SOD activity indicated that APAP-induced renal damage was mediated through oxidative stress. Significant beneficial changes were noted in serum and tissue oxidative stress indicators in rats treated with MLT. These biochemical observations were supplemented by histopathological examination of kidney sections, which revealed that MLT also reduced the severity of APAP-induced histological alterations in the kidney. These results indicate that administration of APAP causes oxidative stress to renal tissue and that MLT protects against the oxidative damage associated with APAP.

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

    PubMed Central

    Huseinovic, Angelina; van Leeuwen, Jolanda S.; van Welsem, Tibor; Stulemeijer, Iris; van Leeuwen, Fred; Vermeulen, Nico P. E.; Kooter, Jan M.; Vos, J. Chris

    2017-01-01

    Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity. PMID:28291796

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    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.

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

    PubMed

    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

  19. Opposing effects of aspirin and acetaminophen use on risk of adult acute leukemia.

    PubMed

    Weiss, Joli R; Baker, Julie A; Baer, Maria R; Menezes, Ravi J; Nowell, Susan; Moysich, Kirsten B

    2006-02-01

    Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of hematologic cancer, although previous results have been inconsistent. The current study investigated the effects of aspirin or acetaminophen use on adult acute leukemia risk among 169 individuals with leukemia and 676 age and sex matched hospital controls with non-neoplastic conditions who completed a comprehensive epidemiologic questionnaire. Results indicate that regular aspirin use may be associated with a modest decrease in leukemia risk [adjusted odds ratio (aOR), 0.84; 95% confidence interval (CI), 0.59-1.21]. In contrast, ever using acetaminophen was associated with elevated leukemia risk (aOR, 1.53; 95% CI, 1.03-2.26). Results did not differ between men and women. Other studies have demonstrated that acetaminophen is associated with transient decreases in DNA repair, and lymphocytes may be particularly susceptible to DNA damage, suggesting a mechanism for the elevated acute leukemia risk observed among acetaminophen users.

  20. An Experiment in Physical Chemistry: Polymorphism and Phase Stability in Acetaminophen (Paracetamol)

    ERIC Educational Resources Information Center

    Myrick, Michael L.; Baranowski, Megan; Profeta, Luisa T. M.

    2010-01-01

    Differential scanning calorimetry analyses of two easily prepared polymorphs of acetaminophen (also known as paracetamol) are recorded. The density of the forms can be found in the literature. Rules for heats of transition, heats of fusion, and density, as well as methods for determining the solid-solid transition temperature between the forms,…

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

    PubMed

    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.

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

    ERIC Educational Resources Information Center

    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)

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

    ERIC Educational Resources Information Center

    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…

  4. 76 FR 2691 - Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-14

    ... To Reduce Liver Injury From Unintentional Overdose AGENCY: Food and Drug Administration, HHS. ACTION... safety to help prevent liver damage due to acetaminophen overdosing, a serious public health problem...-containing prescription drug products to address new safety information about the risk of liver damage....

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

    PubMed

    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.

  6. Protective effects of Baccharis dracunculifolia leaves extract against carbon tetrachloride- and acetaminophen-induced hepatotoxicity in experimental animals.

    PubMed

    Rezende, Túlio P; do A Corrêa, José Otávio; Aarestrup, Beatriz J V; Aarestrup, Fernando M; de Sousa, Orlando V; da Silva Filho, Ademar A

    2014-07-02

    In this work we investigated the in vivo protective effects of Baccharis dracunculifolia leaves extract (BdE) against carbon tetrachloride (CCl4)- and acetaminophen (APAP)-induced hepatotoxicity. Total phenolic content, total flavonoid content, antioxidant DPPH radical scavenging activity, and HPLC analysis were performed. Our results showed that pretreatment with BdE significantly reduced the damage caused by CCl4 and APAP on the serum markers of hepatic injury, AST, ALT, and ALP. Results were confirmed by histopathological analysis. Phytochemical analysis, performed by HPLC, showed that BdE was rich in p-coumaric acid derivatives, caffeoylquinic acids and flavonoids. BdE also showed DPPH antioxidant activity (EC50 of 15.75±0.43 μg/mL), and high total phenolic (142.90±0.77 mg GAE/g) and flavonoid (51.47±0.60 mg RE/g) contents. This study indicated that B. dracunculifolia leaves extract has relevant in vivo hepatoprotective properties.

  7. Simultaneous determination of acetaminophen, guaifenesin, pseudoephedrine, pholcodine, and paraben preservatives in cough mixture by high-performance liquid chromatography.

    PubMed

    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. Effectiveness of postoperative intravenous acetaminophen (Acelio) after gastrectomy: A propensity score-matched analysis.

    PubMed

    Ohkura, Yu; Haruta, Shusuke; Shindoh, Junichi; Tanaka, Tsuyoshi; Ueno, Masaki; Udagawa, Harushi

    2016-11-01

    The aim of this study was to investigate the efficacy of postoperative scheduled intravenous acetaminophen to reduce the opioid use and enhance recovery after gastrectomy.Opioid use is reportedly associated with delayed recovery of gastrointestinal (GI) peristalsis and postoperative nausea/vomiting (PONV) despite of acceptable efficacy for pain control.Of 147 and 96 consecutive patients who underwent gastrectomy for gastric cancer before and after introduction of postoperative scheduled intravenous acetaminophen, propensity score matched population was created and short-term clinical outcomes were compared.Significant defervescence was demonstrated in Acetaminophen group (A-group) compared with control group (C-group) during the perioperative period (P < 0.001), whereas no significant difference was observed in postoperative inflammatory parameters. The incidence of postoperative complications was similar between the groups. The number of patient-controlled analgesia (PCA) pushes was significantly reduced in the A-group (P = 0.007) and the frequency of use of other nonopioid analgesics was also significantly reduced in the A-group (P < 0.001). Both daily and cumulative opioid use was significantly reduced in the A-group (P < 0.001). The time to first flatus and defecation was decreased in the A-group (P < 0.001 and P = 0.038, respectively). The incidence of PONV was significantly reduced from 26.0% to 12.5% after introduction of intravenous acetaminophen (P = 0.017), and hospital stay tended to be decreased in the A-group (13.2 vs 14.7 days, P = 0.069)Postoperative scheduled intravenous acetaminophen decreased opioid use and may be associated with enhanced recovery after gastrectomy.

  9. A new screening method to detect water-soluble antioxidants: acetaminophen (Tylenol) and other phenols react as antioxidants and destroy peroxynitrite-based luminol-dependent chemiluminescence.

    PubMed

    Van Dyke, K; Sacks, M; Qazi, N

    1998-01-01

    This study is based on a simple chemical interaction of peroxynitrite (O = N-O-O-) and luminol, which produces blue light upon oxidation. Since peroxynitrite has a half-life of about 1 s, a drug known as linsidomine (SIN-1) is used as a peroxynitrite generator. Peroxynitrite can oxidize lipids, proteins and nucleic acids. Upon the stimulation of inflammation and/or infection, macrophages and neutrophils can be induced to produce large amounts of peroxynitrite, which can oxidize phenols and sulphhydryl-containing compounds. Therefore, phenols and sulphhydryls eliminate peroxynitrite. This is an example of the Yin-Yang hypothesis e.g. oxidation-reduction. Acetaminophen (Tylenol) can inhibit fever and some types of pain without being a particularly effective anti-inflammatory. Since it is a phenol, it could act as a nitration target for peroxynitrite. Then peroxynitrite, the possible cause of pain and elevated temperature, might be destroyed in the reaction. Acetaminophen is a phenolic compound which produces a clear inhibitory dose-response curve with peroxynitrite in its range of clinical effectiveness. Whether acetaminophen actually works as we suggest is to be proven. Three different types of reaction could decrease the amount of peroxynitrite: (a) interference with base-catalysed opening of the SIN-1 molecule; (b) destruction of one or both substances needed to form it--superoxide and/or nitric oxide; when the SIN-1 degrades to superoxide and nitric oxide, the former may be destroyed by superoxide dismutase (SOD); (c) peroxynitrite may react directly with phenols (mono-, di-, tri- and tetraphenols), possibly by nitration. Nordihydroguaiaretic acid and 2-hydroxyestradiol (catechol estrogen) are potent inhibitors of luminol light emission. Epineprine, isoproterenol, pyrogallol, catechol and ascorbic acid (a classic antioxidant) are all inhibitors of luminol chemiluminescence. Isoproterenol, norepinephrine/and epinephrine first inhibit light but overall stimulate

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

    SciTech Connect

    Gardner, Carol R.; Hankey, Pamela; Mishin, Vladimir; Francis, Mary; Yu, Shan; Laskin, Jeffrey D.; Laskin, Debra L.

    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

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

    PubMed Central

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

    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 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. PMID:24379968

  12. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring.

    PubMed

    Andrade, Chittaranjan

    2016-03-01

    Prenatal exposure to acetaminophen may result in compromised neurodevelopment through inflammatory and immunologic mechanisms, through predisposition to oxidative stress, and through endocrine, endogenous cannabinoid, and other mechanisms. Several small and large prospective studies have found an association between gestational acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD)-like behaviors, use of ADHD medication, and ADHD diagnoses in offspring during childhood; the only negative study was a small investigation that examined only one aspect of attention as an outcome. Creditably, most of the studies adjusted analyses for many (but not all) confounds associated with ADHD risk. Importantly, one pivotal study also adjusted for pain, infection, inflammation, and fever to reduce confounding by indication; this study found a dose-dependent risk. In the light of the finding of a single study that infection and fever during pregnancy by themselves do not raise the ADHD risk, it appears possible that the use of acetaminophen during pregnancy is itself responsible for the increased risk of ADHD. This suggests that acetaminophen may not be as safe in pregnancy as is widely believed. However, since fever during pregnancy may itself be associated with adverse gestational outcomes, given the present level of uncertainty about the ADHD risk with acetaminophen, it is suggested that, until more data are available, the use of acetaminophen in pregnancy should not be denied in situations in which the need for the drug is clear.

  13. Bazhen Decoction Protects against Acetaminophen Induced Acute Liver Injury by Inhibiting Oxidative Stress, Inflammation and Apoptosis in Mice

    PubMed Central

    Song, Erqun; Fu, Juanli; Xia, Xiaomin; Su, Chuanyang; Song, Yang

    2014-01-01

    Bazhen decoction is a widely used traditional Chinese medicinal decoction, but the scientific validation of its therapeutic potential is lacking. The objective of this study was to investigate corresponding anti-oxidative, anti-inflammatory and anti-apoptosis activities of Bazhen decoction, using acetaminophen-treated mice as a model system. A total of 48 mice were divided into four groups. Group I, negative control, treated with vehicle only. Group II, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days. Group III, received a single dose of 900 mg/kg acetaminophen. Group IV, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days and a single dose of 900 mg/kg acetaminophen 30 min before last Bazhen decoction administration. Bazhen decoction administration significantly decrease acetaminophen-induced serum ALT, AST, ALP, LDH, TNF-α, IL-1β, ROS, TBARS and protein carbonyl group levels, as well as GSH depletion and loss of MMP. Bazhen decoction restore SOD, CAT, GR and GPx activities and depress the expression of pro-inflammatory factors, such as iNOS, COX-2, TNF-α, NF-κB, IL-1β and IL-6, respectively. Moreover, Bazhen decoction down-regulate acetaminophen-induced Bax/Bcl-2 ratio, caspase 3, caspase 8 and caspase 9. These results suggest the anti-oxidative, anti-inflammatory and anti-apoptosis properties of Bazhen decoction towards acetaminophen-induced liver injury in mice. PMID:25222049

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

    PubMed

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

    2014-01-01

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

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

    SciTech Connect

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

    2013-06-15

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

  16. A Randomized Controlled Trial on Analgesic Effects of Intravenous Acetaminophen versus Dexamethasone after Pediatric Tonsillectomy

    PubMed Central

    Faiz, Seyed Hamid Reza; Rahimzadeh, Poupak; Alebouyeh, Mahmoud Reza; Sedaghat, Minow

    2013-01-01

    Background A few studies are available actually comparing the clinical efficacy of intravenous acetaminophen with other medications such as dexamethasone to inhibit postoperative adverse events in children. Objectives This randomized blinded controlled trial was designed to compare controlling status of postoperative events in children after tonsillectomy randomized to receive either intravenous acetaminophen or dexamethasone. Patients and Methods Eighty four children aged between 4 to 13 undergoing tonsillectomy were randomized using a computer-generated schedule to double-blind treatment with intravenous acetaminophen (15 mg/kg) or intravenous dexamethasone (0.1 mg/kg). Children were post-operatively assessed for swallowing pain, pain while opening mouth, ear pain, and postoperative sore throat in recovery room (within one hour after surgery), at the time of admission to the ward, as well as at 12 and 24 hours after surgery, assessed by the objective pain scoring system (OPS; minimum score: 0 = no pain, maximum score: 10 = extreme pain). Results There were no significant differences between the two groups with regard to the severity of postoperative pain due to swallowing or opening mouth measured at the different study time points from postoperative recovery to 24 hours after the surgery. There was no difference in ear pain severity at the time of postoperative recovery, at the admission time to ward and also at 12 hours after surgery; however mean score of ear pain severity was significantly higher in those who administered acetaminophen 24 hours after operation. Also, the mean score severity of sore throat was significantly higher in the acetaminophen compared with the dexamethasone group within 12 hours of surgery. Postoperative vomiting and bleeding were similarly observed between the two study groups. The severity of swallowing pain, pain while opening mouth, ear pain, as well as postoperative sore throat as gradually assuaged within 24 hours of

  17. Anti-cytochrome P450 IIE1 (anti IIE1) and dimethyl sulfoxide inhibit acetaminophen and dimethylnitrosamine oxidation similarly

    SciTech Connect

    Jaw, S.; Jeffery, E.H. ); Roberts, D.W. )

    1991-03-11

    To evaluate specificity of dimethyl sulfoxide (DMSO), the authors compared anti IIE1 and DMSO inhibition of P450 oxidations. Hepatic microsomes from control and acetone-induced female Swiss-Webster mice were preincubated with polyclonal anti IIE1 or IgG for 20 min at 4C before addition of an NADPH-generating system, DMSO or buffer, and substrate (Ethylmorphine, EM; dimethylnitrosamine, DMN; or acetaminophen, AP; 1 mM final concentration). After 20 min at 37C, the incubations were terminated by adding 20% trichloroacetic acid or methanol. Formaldehyde was determined by the Nash method when using EM or DMN as substrate. AP-glutathione conjugate was determined by HPLC when using AP as substrate. Anti IIE1 and DMSO did not inhibit EM demethylation in control or acetone microsomes. However, DMSO inhibited DMN demethylation by 26% and 64% in control and 30% and 75% in acetone microsomes. Anti IIE1 inhibited DMN demethylation by 44% and 24% in control and acetone microsomes, respectively. DMSO inhibited AP metabolism by 31% and 56% and anti IIE1 inhibited AP metabolism by 33%, in control microsomes. The inhibitions of DMN and AP metabolism by anti IIE1 and DMSO were only additive at submaximal inhibitor concentrations and confirm that DMSO specifically inhibits IIE1 activity.

  18. A new electrochemical sensor for the simultaneous determination of acetaminophen and codeine based on porous silicon/palladium nanostructure.

    PubMed

    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.

  19. Application of CdS quantum dots modified carbon paste electrode for monitoring the process of acetaminophen preparation.

    PubMed

    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.

  20. Electrocatalytical oxidation and sensitive determination of acetaminophen on glassy carbon electrode modified with graphene-chitosan composite.

    PubMed

    Zheng, Meixia; Gao, Feng; Wang, Qingxiang; Cai, Xili; Jiang, Shulian; Huang, Lizhang; Gao, Fei

    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 (ks), diffusion coefficient (D) and the surface adsorption amount (Γ(*)) of ACOP on GR-CS/GCE were determined to be 0.25s(-1), 3.61×10(-5) cm(2) s(-1) and 1.09×10(-9) mol cm(-2), respectively. Additionally, a 2e(-)/2H(+) 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(-6) to 1.0×10(-4) M with a low detection limit of 3.0×10(-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.

  1. Electrochemical preparation of nickel and copper oxides-decorated graphene composite for simultaneous determination of dopamine, acetaminophen and tryptophan.

    PubMed

    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.

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

    PubMed Central

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

    2013-01-01

    Acetaminophen (APAP) administration results in hepatotoxicity and hematotoxicity in cats. The response to three different treatments against APAP poisoning was evaluated. Free glutathione (GSH) (200mg/kg), niosomal GSH (14 mg/kg) and free amino acids (180 mg/kg of N-acetylcysteine and 280 mg/kg of methionine) were administered to cats that were intoxicated with APAP (a single dose of 150 mg/kg, p.o.). Serum concentration of alanine aminotransferase (ALT) along with serum, liver and erythrocyte concentration of GSH and methemoglobin percentage were measured before and 4, 24 and 72 hours after APAP administration. Free GSH (200 mg/kg) and niosomal GSH (14 mg/kg) were effective in reducing hepatotoxicity and hematotoxicity in cats intoxicated with a dose of 150 mg/kg APAP. We conclude that both types of treatments can protect the liver and haemoglobin against oxidative stress in APAP intoxicated cats. Furthermore, our results showed that treatment with niosomal GSH represents an effective therapeutic approach for APAP poisoning. PMID:26623313

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

    PubMed

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

    2012-06-01

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

  4. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults

    PubMed Central

    Toms, Laurence; McQuay, Henry J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way. Objectives To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected. Main results Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at

  5. [Effect of paracetamol (acetaminophen) on blood pressure in patients with coronary heart disease].

    PubMed

    Sudano, I; Roas, S; Flammer, A J; Noll, G; Ruschitzka, F

    2012-06-06

    Analgesic drugs, non-steroidal anti-inflammatory drugs and paracetamol (acetaminophen) in particular, belong to the most widely prescribed therapeutic agents. Beside their efficacy in pain relief, these drugs were recently linked to increased cardiovascular risk. Indeed, epidemiological and clinical studies showed that non-selective non-steroidal anti-inflammatory drugs, as well as selective cyclooxygenase-2 inhibitors both may increase blood pressure and cardiovascular events. However, the effect of paracetamol (acetaminophen) on blood pressure and cardiovascular health should not be neglected, too. Unfortunately, long-term randomized controlled trials appropriately powered to evaluate cardiovascular outcomes are lacking. This review summarizes the available data about the effect of paracetamol in particular, on blood pressure and other cardiovascular outcomes.

  6. Protective effects of Capparis sepiaria root extracts against acetaminophen-induced hepatotoxicity in Wistar rats.

    PubMed

    Madhavan, V; Pandey, Ajay Shankar; Murali, Anita; Yoganarasimhan, S N

    2012-01-09

    Capparis sepiaria L. known as Himsra is an important drug in Ayurveda. In this study extracts of the root of C. sepiaria were evaluated for their hepatoprotective potential on acetaminophen-induced hepatotoxicity in albino Wistar rats. The extent of hepatoprotection was evaluated by estimating the serum levels of hepatic transaminases (SGPT and SGOT), alkaline phosphatase (ALP), total protein (TP), and bilirubin (total and direct). Aqueous and ethanol extracts of C. sepiaria significantly reduced the increased liver weight as well as serum levels of SGPT, SGOT, ALP, and bilirubin, and normalized the reduced serum protein levels in the treated rats. These observations were supported by the results of histopathology studies as well. The extracts were also subjected to preliminary organic analysis and chromatographic studies including HPTLC finger print studies. The results indicate that the roots of C. sepiaria show significant hepatoprotective effect on acetaminophen-induced hepatotoxicity, thus substantiating its use as a potential hepatoprotective drug.

  7. Effect of sesame oil against acetaminophen-induced acute oxidative hepatic damage in rats.

    PubMed

    Chandrasekaran, Victor Raj Mohan; Wan, Chang-Hsin; Liu, Li-Lian; Hsu, Dur-Zong; Liu, Ming-Yie

    2008-08-01

    Acetaminophen (APAP) overdose causes acute liver injury or even death in both humans and experimental animals. We investigated the effect of sesame oil on APAP-induced acute liver injury. Male Wistar rats were given APAP (1,000 mg/kg; orally) to induce acute liver injury. Acetaminophen significantly increased aspartate transaminase, alanine transaminase, lipid peroxidation, and superoxide anion and hydroxyl radical generation levels; it also induced glutathione depletion. Sesame oil (8 mL/kg; orally) did not alter the gastric absorption of APAP, but it inhibited all the parameters altered by APAP and protected the rats against APAP-induced acute liver injury. We hypothesize that sesame oil maintained the intracellular glutathione levels, reduced reactive oxygen species levels, and inhibited lipid peroxidation in rats with APAP-induced acute liver injury.

  8. Liquid microjunction surface sampling of acetaminophen, terfenadine and their metabolites in thin tissue sections

    DOE PAGES

    Kertesz, Vilmos; Paranthaman, Nithya; Moench, Paul; ...

    2014-10-01

    The aim of this paper was to evaluate the analytical performance of a fully automated droplet-based surface-sampling system for determining the distribution of the drugs acetaminophen and terfenadine, and their metabolites, in rat thin tissue sections. The following are the results: The rank order of acetaminophen concentration observed in tissues was stomach > small intestine > liver, while the concentrations of its glucuronide and sulfate metabolites were greatest in the liver and small intestine. Terfenadine was most concentrated in the liver and kidney, while its major metabolite, fexofenadine, was found in the liver and small intestine. In conclusion, the spatialmore » distributions of both drugs and their respective metabolites observed in this work were consistent with previous studies using radiolabeled drugs.« less

  9. Liquid microjunction surface sampling of acetaminophen, terfenadine and their metabolites in thin tissue sections

    SciTech Connect

    Kertesz, Vilmos; Paranthaman, Nithya; Moench, Paul; Catoire, Alexandre; Flarakos, Jimmy; Van Berkel, Gary J.

    2014-10-01

    The aim of this paper was to evaluate the analytical performance of a fully automated droplet-based surface-sampling system for determining the distribution of the drugs acetaminophen and terfenadine, and their metabolites, in rat thin tissue sections. The following are the results: The rank order of acetaminophen concentration observed in tissues was stomach > small intestine > liver, while the concentrations of its glucuronide and sulfate metabolites were greatest in the liver and small intestine. Terfenadine was most concentrated in the liver and kidney, while its major metabolite, fexofenadine, was found in the liver and small intestine. In conclusion, the spatial distributions of both drugs and their respective metabolites observed in this work were consistent with previous studies using radiolabeled drugs.

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

    NASA Astrophysics Data System (ADS)

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

    2011-07-01

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

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

    PubMed

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

    2011-12-08

    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?

  12. Acrolein scavengers, cysteamine and N-benzylhydroxylamine, reduces the mouse liver damage after acetaminophen overdose

    PubMed Central

    KOYAMA, Ryo; MIZUTA, Ryushin

    2016-01-01

    Our previous study suggested that the highly toxic α,β-unsaturated aldehyde acrolein, a byproduct of oxidative stress, plays a major role in acetaminophen-induced liver injury. In this study, to determine the involvement of acrolein in the liver injury and to identify novel therapeutic options for the liver damage, we examined two putative acrolein scavengers, a thiol compound cysteamine and a hydroxylamine N-benzylhydroxylamine, in cell culture and in mice. Our results showed that cysteamine and N-benzylhydroxylamine effectively prevented the cell toxicity of acrolein in vitro and acetaminophen-induced liver injury in vivo, which suggested that acrolein is involved in the liver damage, and these two drugs can be potential therapeutic options for this condition. PMID:27594275

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

    PubMed Central

    Bekhit, Mary Hanna

    2015-01-01

    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. PMID:26527898

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

    PubMed

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

    2009-08-01

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

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

    PubMed Central

    Thiel, Karolin; Klingert, Wilfried; Klingert, Kathrin; Morgalla, Matthias H; Schuhmann, Martin U; Leckie, Pamela; Sharifi, Yalda; Davies, Nathan A; Jalan, Rajiv; Peter, Andreas; Grasshoff, Christian; Königsrainer, Alfred; Schenk, Martin; Thiel, Christian

    2017-01-01

    AIM To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose. METHODS Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy. RESULTS Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 mL/min at study end. Thrombocyte values (baseline 307 × 103/µL ± 34 × 103/µL) of intoxicated animals declined slowly to values of 145 × 103/µL ± 46 × 103/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 103/µL ± 3 × 103/µL preceding fatality within few hours which was significant (P > 0.01). CONCLUSION Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model. PMID:28321158

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

    PubMed Central

    Mahshidfar, Babak; Sameti, Azadeh; Abbasi, Saeed; Farsi, Davood; Mofidi, Mani; Hafezimoghadam, Peyman; Rahimzadeh, Popak; Rezai, Mahdi

    2016-01-01

    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 1st and 3rd days of admission and placebo during the 2nd and 4th 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 2nd and 4th days (4.33 and 3.66, respectively; mean: 4.0) in which the patients had received just morphine sulfate compared to the 1st and 3rd 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 1st and 3rd days (8.92 and 3.15 mg, respectively; 12.07 mg in total) compared to the 2nd and 4th 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. PMID:27630458

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

    PubMed Central

    Smith, Andrew K.; Ropella, Glen E. P.; Kennedy, Ryan C.; Kaplowitz, Neil; Ookhtens, Murad

    2016-01-01

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

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

    PubMed

    Smith, Andrew K; Petersen, Brenden K; Ropella, Glen E P; Kennedy, Ryan C; Kaplowitz, Neil; Ookhtens, Murad; Hunt, C Anthony

    2016-12-01

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

  19. Brown tree snake (Boiga irregularis) population density and carcass locations following exposure to acetaminophen.

    PubMed

    Smith, Joshua B; Turner, Kelsey L; Beasley, James C; DeVault, Travis L; Pitt, William C; Rhodes, Olin E

    2016-10-01

    Mass aerial delivery of dead mouse baits treated with acetaminophen has been evaluated as a means to reduce brown tree snake (Boiga irregularis) populations over large areas, increasing the likelihood of wide-scale eradication on Guam. Given the high density of snakes in some areas of their invasive range, eradication efforts could result in a resource pulse that may influence food web dynamics and the indirect transport of acetaminophen among trophic levels. We evaluated abundance, habitat type, and snake size (i.e., age) within two study sites on Guam, a secondary limestone forest (upland) and an abandoned coconut plantation (coastal), to determine how experimentally dosing snakes with acetaminophen is likely to influence carrion availability. We found snakes trapped in 3.24 ha plots occurred in greater abundance (population size = 72.5 snakes; SE = 8.8) and were significantly larger (978.6 mm, SE = 14.9) in the coastal than in the upland site (population size = 26.9, SE = 21.5; length = 903.0 mm, SE = 15.9). Despite these differences, carcasses of snakes that died after consuming acetaminophen-laced mice (80 mg) were recovered in consistent locations between sites, with 92 % located on the ground, 4 % in trees, and 4 % found in rock cavities at both sites. Given that most snakes were found on the ground rather than in the tree canopy, our results suggest that many poisoned snake carcasses will be accessible to a wide range of potential scavengers, possibly influencing food web dynamics and potentially contributing to indirect toxicant transfer within affected ecosystems.

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

    PubMed Central

    Akhavanakbari, Godrat; Entezariasl, Masood; Isazadehfar, Khatereh; Kahnamoyiagdam, Fariba

    2013-01-01

    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. PMID:23833739

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

    SciTech Connect

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

    2014-03-01

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

  2. Regular use of aspirin or acetaminophen and risk of non-Hodgkin lymphoma.

    PubMed

    Baker, Julie A; Weiss, Joli R; Czuczman, Myron S; Menezes, Ravi J; Ambrosone, Christine B; Moysich, Kirsten B

    2005-04-01

    Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of non-Hodgkin lymphoma (NHL), although previous results have been inconsistent. The current study investigated the effects of regular aspirin or acetaminophen use on non-Hodgkin lymphoma risk among 625 individuals with primary, incident NHL and 2512 age and sex matched hospital controls with non-neoplastic conditions who completed a comprehensive epidemiologic questionnaire. Results indicate that regular aspirin use may be associated with decreased NHL risk among men [adjusted odds ratio (aOR) 0.82, 95% confidence interval (CI), 0.65--1.04], but not among women (aOR 0.93, 95% CI, 0.71--1.23). In contrast, regular acetaminophen use was associated with elevated NHL risk among women (aOR 1.71, 95% CI, 1.18--2.50) but not among men (aOR 0.75, 95% CI, 0.48--1.17). Other studies have demonstrated that acetaminophen is associated with transient decreases in DNA repair, and lymphocytes may be particularly susceptible to DNA damage, suggesting a mechanism for the elevated NHL risk observed.

  3. Application of differential scanning calorimetry in evaluation of solid state interactions in tablets containing acetaminophen.

    PubMed

    Mazurek-Wadołkowska, Edyta; Winnicka, Katarzyna; Czajkowska-Kośnik, Anna; Czyzewska, Urszula; Miltyk, Wojciech

    2013-01-01

    Differential scanning calorimetry (DSC) is an analytical procedure used to determine the differences in the heat flow generated or absorbed by the sample. This method allows to assess purity and polymorphic form of drug compounds, to detect interactions between ingredients of solid dosage forms and to analyze stability of solid formulations. The aim of this study was the assessment of compatibility between acetaminophen (API) and different types of excipients often used in tablets compression: polyvinylpyrrolidone, crospovidone, pregelatinized starch, microcrystalline cellulose and magnesium stearate by differential scanning calorimetry. The study contains results of thermal analysis of excipients and individually performed mixtures of these substances with acetaminophen before and after compression and after 6 months storage of tablets at different temperature and relative humidity conditions (25 +/- 2 degrees C /40 +/- 5% RH, 25 +/- 2 degrees C /60 +/- 5% RH, 40 +/- 2 degrees C /75 +/- 5% RH) for a period of 6 months. To detect possible changes of API chemical structure, gas chromatography-mass spectrometry (GC-MS) was also applied. GC-MS with electron impact ionization (EI) was employed to determine the fragmentation pattern of API. It was shown that the developed formulations showed excellent compatibility among all excipients used except Kollidon CL. The interaction with Kollidon CL is probably a result of a physical reaction as confirmed by GC-MS analyses. Obtained results revealed that DSC can be successfully applied to evaluate possible incompatibilities between acetaminophen and Kollidon.

  4. Synthesis, characterization, and electrochemical response of iron oxide nanoparticles for sensing acetaminophen

    NASA Astrophysics Data System (ADS)

    Pal Singh, Beer; Kumar, Arun; Duarte, Armando P.; Rojas, Segundo J.; Crespo-Medina, Marielys; Areizaga-Martinez, Hector I.; Vega-Olivencia, Carmen A.; Tomar, M. S.

    2016-10-01

    Magnetite (Fe3O4) and hematite (α-Fe2O3) iron oxide nanoparticles were synthesized using the co-precipitation method via subsequent heat treatment using ferrous chloride (FeCl2.4H2O) as a source of iron. The synthesized powder was annealed at high temperature in an air atmosphere to promote the formation of the hematite (α-Fe2O3) phase. Both oxide phases of iron oxide were characterized using x-ray diffraction, thermogravimetric, and differential scanning calorimetric analysis, and Raman spectroscopy. The phases of as-synthesized nanoparticles were confirmed by XRD and Raman studies. The thermal behavior and weight loss of the initial powdered Fe3O4 to α-Fe2O3 was studied using TG-DSC analysis. In the present case, the Fe3O4 and α-Fe2O3 nanoparticles were used for the electrochemical sensing of acetaminophen (C6H9NO2). The sensing of acetaminophen was performed by Fe3O4 and α-Fe2O3 modified glassy carbon electrode, using a potential controlled cyclic voltammetric technique. The Fe3O4 and α-Fe2O3 nanoparticles exhibited electrocatalytic ability for sensing acetaminophen. Detailed results are included.

  5. Poly(ethyleneglycol) column for the determination of acetaminophen, phenylephrine and chlorpheniramine in pharmaceutical formulations.

    PubMed

    García, A; Rupérez, F J; Marín, A; de la Maza, A; Barbas, C

    2003-03-05

    New polar reversed-phase stationary phases in HPLC provide specific selectivities which can help to solve traditional chromatographic problems related to the development of chromatographic methods with widely different retention times for the sample components. One such case is the analysis of pharmaceutical formulations against the common cold. Acetaminophen, phenylephrine and chlorpheniramine, compounds with different polarities, are frequently associated in these drugs. An isocratic and rapid HPLC method for the simultaneous determination of the three compounds, acetaminophen, phenylephrine and chlorpheniramine, in capsules as pharmaceutical formulations, including the separation of impurities (4-aminophenol and 4-chloracetanilide) and excipients, has been developed and validated. The final chromatographic conditions employed a Supelco Discovery HS PEG column poly(ethyleneglycol) 15x0.46 cm, 5 microm. The mobile phase was 20 mM phosphate buffer, pH 7.0-acetonitrile (90:10, v/v) at a flow-rate of 1 ml/min. UV detection was performed at 215 nm for all the compounds except acetaminophen, which was measured at 310 nm. Validation parameters permit us to consider this method suitable.

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

    PubMed Central

    Yakubu, Ndatsu; Oboh, Ganiyu; Olalekan, Amuzat Aliyu

    2013-01-01

    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. PMID:23533782

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

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

    2015-12-01

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

  9. The Prescription Pattern of Acetaminophen and Non-Steroidal Anti-Inflammatory Drugs in Patients with Liver Cirrhosis.

    PubMed

    Hong, Young Mi; Yoon, Ki Tae; Heo, Jeong; Woo, Hyun Young; Lim, Won; An, Dae Seong; Han, Jun Hee; Cho, Mong

    2016-10-01

    Analgesics, known to be hepatotoxic drugs, are frequently prescribed to patients with liver cirrhosis who are prone to drug-induced liver injury. No guidelines are available regarding the prescription of analgesics in these patients. Therefore, we aimed to evaluate the prescription pattern of most frequently used analgesics in patients with cirrhosis. We assessed the prescription pattern of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with liver cirrhosis registered in Health Insurance Review Assessment Service database between January 1, 2012 and December 31, 2012. A total of 125,505 patients with liver cirrhosis were registered from January 1, 2012 to December 31, 2012. Of that group, 50,798 (40.5%) patients claimed reimbursement for at least one prescription for acetaminophen or NSAIDs during the one year follow-up period. Overall, NSAIDs (82.7%) were more prescribed than acetaminophen (64.5%). NSAIDs were more prescribed than acetaminophen even in decompensated cirrhosis compared with compensated cirrhosis (71.5% vs. 68.8%, P value < 0.001). There was a marked difference in prescription preference between acetaminophen and NSAIDs among physicians. Internists more frequently prescribed acetaminophen than NSAIDs compared to other physicians (50.9% vs. 76.2%, P < 0.001). Gastroenterologists more frequently prescribed acetaminophen over NSAIDs compared to other internists (80.9% vs. 51.2%, P < 0.001). Analgesics were prescribed in 40.5% of patients with cirrhosis. NSAIDs were more frequently prescribed although they should be avoided. The prescription pattern of analgesics were different significantly among physicians in patients with liver cirrhosis. The harmful effects of NSAIDs in patients with cirrhosis should be reminded to all physicians prescribing analgesics.

  10. The Prescription Pattern of Acetaminophen and Non-Steroidal Anti-Inflammatory Drugs in Patients with Liver Cirrhosis

    PubMed Central

    2016-01-01

    Analgesics, known to be hepatotoxic drugs, are frequently prescribed to patients with liver cirrhosis who are prone to drug-induced liver injury. No guidelines are available regarding the prescription of analgesics in these patients. Therefore, we aimed to evaluate the prescription pattern of most frequently used analgesics in patients with cirrhosis. We assessed the prescription pattern of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with liver cirrhosis registered in Health Insurance Review Assessment Service database between January 1, 2012 and December 31, 2012. A total of 125,505 patients with liver cirrhosis were registered from January 1, 2012 to December 31, 2012. Of that group, 50,798 (40.5%) patients claimed reimbursement for at least one prescription for acetaminophen or NSAIDs during the one year follow-up period. Overall, NSAIDs (82.7%) were more prescribed than acetaminophen (64.5%). NSAIDs were more prescribed than acetaminophen even in decompensated cirrhosis compared with compensated cirrhosis (71.5% vs. 68.8%, P value < 0.001). There was a marked difference in prescription preference between acetaminophen and NSAIDs among physicians. Internists more frequently prescribed acetaminophen than NSAIDs compared to other physicians (50.9% vs. 76.2%, P < 0.001). Gastroenterologists more frequently prescribed acetaminophen over NSAIDs compared to other internists (80.9% vs. 51.2%, P < 0.001). Analgesics were prescribed in 40.5% of patients with cirrhosis. NSAIDs were more frequently prescribed although they should be avoided. The prescription pattern of analgesics were different significantly among physicians in patients with liver cirrhosis. The harmful effects of NSAIDs in patients with cirrhosis should be reminded to all physicians prescribing analgesics. PMID:27550489

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

    PubMed

    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.

  12. Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders

    PubMed Central

    Blanchard, Helene C.; Taha, Ameer Y.; Rapoport, Stanley I; Yuan, Zhi-Xin

    2015-01-01

    Background Older human immunodeficiency virus (HIV)-1 transgenic rats are a model for HIV-1 associated neurocognitive disorders (HAND). They show behavioral changes, neuroinflammation, neuronal loss, and increased brain arachidonic acid (AA) enzymes. Aspirin (acetylsalicylate, ASA) inhibits AA oxidation by cyclooxygenase (COX)-1 and COX-2. Hypothesis Chronic low-dose ASA will downregulate brain AA metabolism in HIV-1 transgenic rats. Methods Nine month-old HIV-1 transgenic and wildtype rats were given 42 days of 10 mg/kg/day ASA or nothing in drinking water; eicosanoids were measured using ELISAs on microwaved brain extracts. Results Brain 15-epi-lipoxin A4 and 8-isoprostane concentrations were significantly higher in HIV-1 transgenic than wildtype rats; these differences were prevented by ASA. ASA reduced prostaglandin E2 and leukotriene B4 concentrations in HIV-1 Tg but not wildtype rats. Thromboxane B2, 15-HETE, lipoxin A4 and resolvin D1 concentrations were unaffected by genotype or treatment. Conclusion Chronic low-dose ASA reduces AA-metabolite markers of neuroinflammation and oxidative stress in a rat model for HAND. PMID:25638779

  13. 17β-Estradiol protects against acetaminophen-overdose-induced acute oxidative hepatic damage and increases the survival rate in mice.

    PubMed

    Chandrasekaran, Victor Raj Mohan; Periasamy, Srinivasan; Liu, Li-Lian; Liu, Ming-Yie

    2011-01-01

    Acetaminophen overdose causes acute liver injury or even death in both humans and experimental animals. We investigated the effect of 17β-estradiol against acetaminophen-induced acute liver injury and mortality in mice. Male mice were given acetaminophen (p-acetamidophenol; 300 mg/kg; orally) to induce acute liver injury. Acetaminophen significantly increased the levels of aspartate transaminase, alanine transaminase, myeloperoxidase, lipid peroxidation, and glutathione reductase, but it decreased superoxide dismutase, catalase, and glutathione. In addition, acetaminophen-induced mortality began 4h post-treatment, and all mice died within 9h. 17β-Estradiol (200 μg/kg; i.p.) protected against acetaminophen-induced oxidative hepatic damage by inhibiting neutrophil infiltration and stimulating the antioxidant defense system. However, 17β-estradiol did not affect acetaminophen-induced glutathione depletion or increased glutathione reductase activity. We conclude that 17β-estradiol specifically attenuates acute hepatic damage and decreases mortality in acetaminophen-overdosed male mice.

  14. Effects of the analgesic acetaminophen (Paracetamol) and its para-aminophenol metabolite on viability of mouse-cultured cortical neurons.

    PubMed

    Schultz, Stephen; DeSilva, Mauris; Gu, Ting Ting; Qiang, Mei; Whang, Kyumin

    2012-02-01

    Acetaminophen has been used as an analgesic for more than a hundred years, but its mechanism of action has remained elusive. Recently, it has been shown that acetaminophen produces analgesia by the activation of the brain endocannabinoid receptor CB1 through its para-aminophenol (p-aminophenol) metabolite. The objective of this study was to determine whether p-aminophenol could be toxic for in vitro developing mouse cortical neurons as a first step in establishing a link between acetaminophen use and neuronal apoptosis. We exposed developing mouse cortical neurons to various concentrations of drugs for 24 hr in vitro. Acetaminophen itself was not toxic to developing mouse cortical neurons at therapeutic concentrations of 10-250 μg/ml. However, concentrations of p-aminophenol from 1 to 100 μg/ml produced significant (p < 0.05) loss of mouse cortical neuron viability at 24 hr compared to the controls. The naturally occurring endocannabinoid anandamide also caused similar 24-hr loss of cell viability in developing mouse cortical neurons at concentrations from 1 to 100 μg/ml, which indicates the mechanism of cell death could be through the cannabinoid receptors. The results of our experiments have shown a detrimental effect of the acetaminophen metabolite p-aminophenol on in vitro developing cortical neuron viability which could act through CB1 receptors of the endocannabinoid system. These results could be especially important in recommending an analgesic for children or individuals with traumatic brain injury who have developing cortical neurons.

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

    PubMed

    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.

  16. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.

    PubMed

    Gamal, Wesam; Treskes, Philipp; Samuel, Kay; Sullivan, Gareth J; Siller, Richard; Srsen, Vlastimil; Morgan, Katie; Bryans, Anna; Kozlowska, Ada; Koulovasilopoulos, Andreas; Underwood, Ian; Smith, Stewart; Del-Pozo, Jorge; Moss, Sharon; Thompson, Alexandra Inés; Henderson, Neil C; Hayes, Peter C; Plevris, John N; Bagnaninchi, Pierre-Olivier; Nelson, Leonard J

    2017-01-30

    Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.

  17. Pharmacokinetics of hydrocodone/acetaminophen combination product in children ages 6-17 with moderate to moderately severe postoperative pain.

    PubMed

    Liu, Wei; Dutta, Sandeep; Kearns, Greg; Awni, Walid; Neville, Kathleen A

    2015-02-01

    Lortab® Elixir, a proprietary combination product containing hydrocodone and acetaminophen, is approved in the US for the treatment of moderate to moderately severe pain in children. Despite this approval, pediatric pharmacokinetic data using this product have not been previously published. Using a single-dose open-label study approach, we evaluated the pharmacokinetics, tolerability, and safety of this product in 17 healthy children 6-17 years of age. Results showed that the body weight-normalized oral clearance (L/h/kg) of hydrocodone and acetaminophen were 42% and 27% higher, respectively when compared to data from healthy adults. This suggests that a higher mg/kg dose would be required in children to achieve exposures similar to adults. We found adjustment of hydrocodone and acetaminophen dose by body surface area to be more optimal than body weight-based dose adjustments for achieving similar systemic exposure in children and adults. However, body weight-based hydrocodone and acetaminophen dosing regimens provided close approximation of adult exposures in pediatric patients with approximately 22% to 24% lower hydrocodone and acetaminophen dose/BW-normalized AUC in pediatric patients compared to adults. Finally, the adverse event profile in our pediatric cohort was consistent with that expected of opioid-naive subjects receiving opioid-combination therapy.

  18. Symptomatic treatment of chronically recurring tension headache: a placebo-controlled, multicenter investigation of Fioricet and acetaminophen with codeine.

    PubMed

    Friedman, A P; DiSerio, F J

    1987-01-01

    A double-blind, randomized, multicenter investigation was conducted to compare the efficacy and safety of Fioricet, acetaminophen with codeine, and placebo for the symptomatic treatment of tension headache. At the onset of a typical headache, the patients took two capsules of their assigned study medication and rated responses over the next four hours in three target symptoms areas: pain, emotional or psychic tension, and muscle contractions or stiffness in the head and neck. Physicians made global assessments of the same symptom responses and of adverse reactions for each patient. One hundred ninety-eight patients were evaluated. Both active analgesic preparations were more effective than placebo in relieving pain and muscle stiffness or contractions. Fioricet, but not acetaminophen with codeine, was significantly better than placebo in alleviating emotional or psychic tension; Fioricet was also significantly better than acetaminophen with codeine in relieving this symptom. Certain analyses suggested the possibility that Fioricet had a faster and more sustained analgesic effect than acetaminophen with codeine. By the end of the four-hour trial, significantly more patients achieved complete pain relief with Fioricet than with acetaminophen with codeine. The quality and quantity of adverse reactions did not differ significantly among the treatment groups. None was serious, and all abated without medical intervention.

  19. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver

    PubMed Central

    Gamal, Wesam; Treskes, Philipp; Samuel, Kay; Sullivan, Gareth J.; Siller, Richard; Srsen, Vlastimil; Morgan, Katie; Bryans, Anna; Kozlowska, Ada; Koulovasilopoulos, Andreas; Underwood, Ian; Smith, Stewart; del-Pozo, Jorge; Moss, Sharon; Thompson, Alexandra Inés; Henderson, Neil C.; Hayes, Peter C.; Plevris, John N.; Bagnaninchi, Pierre-Olivier; Nelson, Leonard J.

    2017-01-01

    Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization. PMID:28134251

  20. Simultaneous analysis of acetaminophen, p-aminophenol and aspirin metabolites by hydrophilic interaction and strong anion exchange capillary liquid chromatography coupled to amperometric detection.

    PubMed

    Zheng, Minmin; Wu, Yimin; Lu, Lanxiang; Ding, Kang; Tang, Fengxiang; Lin, Zian; Wu, Xiaoping

    2011-08-01

    A simple and sensitive method has been developed for the simultaneous determination of polar nonsteroidal pharmaceuticals and metabolites, including acetaminophen, p-aminophenol and several aspirin metabolites (salicylic acid, gentisic acid, salicyluric acid and 2,3-dihydroxybenzoic acid), by capillary liquid chromatography with amperometric detection. Using a capillary monolithic column with mixed mode stationary phases and a mobile phase composed of acetonitrile and Tris buffer, rapid separation of six polar analytes was achieved within 8 min, and a hydrophilic interaction and strong anion exchange separation mechanism were exhibited. Method detection limits of six analytes ranged from 10 to 50 ng/mL. In terms of precision, the intra- and interday relative standard deviation values in all analytes never exceeded 3.1% for migration time and 8.9% for peak areas, respectively. This method provided a simple, rapid and cost-effective approach for the analysis of polar pharmaceuticals. The applicability of the method in pharmacokinetics was verified by spiking human serum samples with the compounds and analyzing the recoveries.

  1. Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors.

    PubMed

    Liu, Jean; Reid, Allison R; Sawynok, Jana

    2013-03-01

    Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3μg. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200μg produced antinociception in the formalin test, and this was blocked by co-administration of the selective A(1)R antagonist DPCPX 4.5μg. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen.

  2. [Effect of magnesium, acetylsalicilic acid and emoxypine on aggregation of platelets].

    PubMed

    Loznikova, S Zh; Sukhodola, A A; Shcharbina, N Iu; Shcharbin, D G

    2014-01-01

    The thrombin-induced platelet aggregation was studied in the absence and presence of magnesium sulfate, acetylsalicylic acid and emoxypine. It was found that all the preparations studied were able separately to decrease platelet aggregation. In contrast, their joint action was not able to affect the aggregation of platelets. The data obtained can be used to choose the treatment strategy for patients with ischemic stroke.

  3. Low-Dose Acetylsalicylic Acid in Treating Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-28

    Adenocarcinoma of the Lung; Recurrent Non-small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  4. Simultaneous estimation of ramipril, acetylsalicylic acid and atorvastatin calcium by chemometrics assisted UV-spectrophotometric method in capsules.

    PubMed

    Sankar, A S Kamatchi; Vetrichelvan, Thangarasu; Venkappaya, Devashya

    2011-09-01

    In the present work, three different spectrophotometric methods for simultaneous estimation of ramipril, aspirin and atorvastatin calcium in raw materials and in formulations are described. Overlapped data was quantitatively resolved by using chemometric methods, viz. inverse least squares (ILS), principal component regression (PCR) and partial least squares (PLS). Calibrations were constructed using the absorption data matrix corresponding to the concentration data matrix. The linearity range was found to be 1-5, 10-50 and 2-10 μg mL-1 for ramipril, aspirin and atorvastatin calcium, respectively. The absorbance matrix was obtained by measuring the zero-order absorbance in the wavelength range between 210 and 320 nm. A training set design of the concentration data corresponding to the ramipril, aspirin and atorvastatin calcium mixtures was organized statistically to maximize the information content from the spectra and to minimize the error of multivariate calibrations. By applying the respective algorithms for PLS 1, PCR and ILS to the measured spectra of the calibration set, a suitable model was obtained. This model was selected on the basis of RMSECV and RMSEP values. The same was applied to the prediction set and capsule formulation. Mean recoveries of the commercial formulation set together with the figures of merit (calibration sensitivity, selectivity, limit of detection, limit of quantification and analytical sensitivity) were estimated. Validity of the proposed approaches was successfully assessed for analyses of drugs in the various prepared physical mixtures and formulations.

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

    PubMed

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

    2016-06-01

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

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

    SciTech Connect

    Rajaraman, Ganesh; Chen, Jie; Chang, Thomas K.H. . E-mail: tchang@interchange.ubc.ca

    2006-12-01

    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 {mu}g/ml and {>=} 750 {mu}g/ml after a 72 h and 24 h treatment period, respectively. G. biloba extract (25 or 50 {mu}g/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 [{sup 14}C]-leucine incorporation. At the level present in a modulating concentration (50 {mu}g/ml) of the extract, ginkgolide A (0.55 {mu}g/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.

  7. In-source formation of N-acetyl-p-benzoquinone imine (NAPQI), the putatively toxic acetaminophen (paracetamol) metabolite, after derivatization with pentafluorobenzyl bromide and GC-ECNICI-MS analysis.

    PubMed

    Tsikas, Dimitrios; Trettin, Arne; Zörner, Alexander A; Gutzki, Frank-Mathias

    2011-05-15

    Pentafluorobenzyl (PFB) bromide (PFB-Br) is a versatile derivatization reagent for numerous classes of compounds. Under electron-capture negative-ion chemical ionization (ECNICI) conditions PFB derivatives of acidic compounds readily and abundantly ionize to produce intense anions due to [M-PFB](-). In the present article we investigated the PFB-Br derivatization of unlabelled acetaminophen (N-acetyl-p-aminophenol, NAPAP-d(0); paracetamol; MW 151) and tetradeuterated acetaminophen (NAPAP-d(4); MW 155) in anhydrous acetonitrile and their GC-ECNICI-MS behavior using methane as the buffer gas. In addition to the expected anions [M-PFB](-) at m/z 150 from NAPAP-d(0) and m/z 154 from NAPAP-d(4), we observed highly reproducibly almost equally intense anions at m/z 149 and m/z 153, respectively. Selected ion monitoring of these ions is suitable for specific and sensitive quantification of acetaminophen in human plasma and urine. Detailed investigations suggest in-source formation of N-acetyl-p-benzoquinone imine (NAPQI; MW 149), the putatively toxic acetaminophen metabolite, from the PFB ether derivative of NAPAP. GC-ECNICI-MS of non-derivatized NAPAP did not produce NAPQI. The peak area ratio of m/z 149 to m/z 150 and of m/z 153 to m/z 154 decreased with increasing ion-source temperature in the range 100-250°C. Most likely, NAPQI formed in the ion-source captures secondary electrons to become negatively charged (i.e., [NAPQI](-)) and thus detectable. Formation of NAPQI was not observed under electron ionization (EI) conditions, i.e., by GC-EI-MS, from derivatized and non-derivatized NAPAP. NAPQI was not detectable in flow injection analysis LC-MS of native NAPAP in positive electrospray ionization (ESI) mode, whereas in negative ESI mode low extent NAPQI formation was observed (<5%). Our results suggest that oxidation of drug derivatives in the ion-sources of mass spectrometers may form intermediates that are produced from activated drugs in enzyme-catalyzed reactions.

  8. Neither nefopam nor acetaminophen can be used as postoperative analgesics in a rat model of ischemic stroke.

    PubMed

    Pétrault, Maud; Gautier, Sophie; Bérézowski, Vincent; Ouk, Thavarak; Bastide, Michèle; Pétrault, Olivier; Bordet, Régis

    2017-04-01

    Analgesics such as opioid agonists are usually not given during the postoperative phase of experimental stroke because they are susceptible to interfere with the evaluation of neuroprotective therapies. Here, we investigate the potential of acetaminophen and nefopam, two nonopioid analgesic drugs, to exert an analgesic effect without inducing neuroprotection in a murine model of ischemic stroke. We demonstrate that acetaminophen (200 mg/kg, PO) induces a significant decrease in the infarct volume, particularly in the cortex (VEHICLE: 200.1 mm(3) vs.

  9. Efficacy of oxycodone/acetaminophen and codeine/acetaminophen vs. conventional therapy in elderly women with persistent, moderate to severe osteoarthritis-related pain.

    PubMed

    Corsinovi, Laura; Martinelli, Elisa; Fonte, Gianfranco; Astengo, Marco; Sona, Alessandro; Gatti, Antonia; Massaia, Massimiliano; Bo, Mario; Zanocchi, Mauro; Michelis, Giuliana; Isaia, Gianluca; Molaschi, Mario

    2009-01-01

    We aimed to evaluate the efficacy and safety of oxycodone/acetaminophen (O/A) and codeine/acetaminophen (C/A) vs. conventional therapy (CT) without opioids in older women suffering from osteoarthritis (OA)-related pain, sub-optimally responsive to prior conventional treatments. We performed a 6 week, randomized, single blind, controlled study in three nursing homes. We enrolled 154 women with painful OA. They were assigned to treatment with O/A (n=52) and C/A (n=52) vs. CT (n=50). We evaluated at baseline and at week 6: average pain in the last week (mean pain, MeP), pain at rest (RP), pain in movement (MP) (numeric rating scale, NRS); depressive symptoms (Beck Depression Inventory-II, BDI-II); functional status (activities of daily living, ADL) and cognitive status (mini mental state evaluation, MMSE). We considered the adverse events (AEs) in the study period. At week 6, MeP, RP and MP were significantly reduced in all three groups (p<0.001); compared to CT, O/A and C/A were associated with greater reductions in MeP (p<0.001 and p=0.004, respectively), in RP (p=0.028 and p=0.032, respectively) in MP (p<0.001 and p=0.002, respectively) and with significant improvement in BDI-II score (p=0.05 and p=0.04, respectively) and ADL value (p=0.04 and p=0.05, respectively). AE rates did not differ between groups.

  10. Correlation between degradation pathway and toxicity of acetaminophen and its by-products by using the electro-Fenton process in aqueous media.

    PubMed

    Le, Thi Xuan Huong; Nguyen, Thi Van; Amadou Yacouba, Zoulkifli; Zoungrana, Laetitia; Avril, Florent; Nguyen, Duy Linh; Petit, Eddy; Mendret, Julie; Bonniol, Valerie; Bechelany, Mikhael; Lacour, Stella; Lesage, Geoffroy; Cretin, Marc

    2017-04-01

    The evolution of the degradation by-products of an acetaminophen (ACE) solution was monitored by HPLC-UV/MS and IC in parallel with its ecotoxicity (Vibrio fischeri 81.9%, Microtox(®) screening tests) during electro-Fenton (EF) oxidation performed on carbon felt. The aromatic compounds 2-hydroxy-4-(N-acetyl) aminophenol, 1,4-benzoquinone, benzaldehyde and benzoic acid were identified as toxic sub-products during the first stage of the electrochemical treatment, whereas aliphatic short-chain carboxylic acids (oxalic, maleic, oxamic, formic, acetic and fumaric acids) and inorganic ions (ammonium and nitrate) were well identified as non-toxic terminal sub-products. Electrogenerated hydroxyl radicals then converted the eco-toxic and bio-refractory property of initial ACE molecule (500 mL, 1 mM) and subsequent aromatic sub-products into non-toxic compounds after 2 h of EF treatment. The toxicity of every intermediate produced during the mineralization of ACE was quantified, and a relationship was established between the degradation pathway of ACE and the global toxicity evolution of the solution. After 8 h of treatment, a total organic carbon removal of 86.9% could be reached for 0.1 mM ACE at applied current of 500 mA with 0.2 mM of Fe(2+) used as catalyst.

  11. Protective effects of Parinari curatellifolia flavonoids against acetaminophen-induced hepatic necrosis in rats

    PubMed Central

    Olaleye, Mary Tolulope; Amobonye, Ayodeji Emmannuel; Komolafe, Kayode; Akinmoladun, Afolabi Clement

    2014-01-01

    In the present study, we investigated the hepatoprotective potential of Parinari curatellifolia Planch (Chrysobalanaceae) in experimental rats in order to ascertain the validity of folkloric claims of its effectiveness in the treatment of hepatic-related disorders. Flavonoid extract of P. curatellifolia seed, PCF (10-, 20- or 30 mg/kg body weight) or silymarin (25 mg/kg), dissolved in corn oil, was administered by gavage to experimental animals once daily for 14 consecutive days before liver damage was chemically induced through the administration of acetaminophen (2 g/kg p.o.) on the 14th day. Hepatoprotection was assessed by analyzing liver homogenate and serum for markers of hepatotoxicity – alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (GGT) and lactate dehydrogenase (LDH) activities as well as prothrombin time (PT). Evaluation of biochemical indices of oxidative stress – level of lipid peroxides (LPO), activities of superoxide dismutase (SOD) and catalase, along with histological assessment of hepatic tissue sections were also carried out. Results revealed that all doses of PCF significantly (P < 0.001) and dose dependently prevented acetaminophen-induced increase in serum activities of hepatic enzymes (ALT, AST, GGT, LDH) and PT. Furthermore, PCF (10- and 20 mg/kg) significantly (P < 0.001) reduced lipid peroxidation in liver tissue and restored the activities of the antioxidant enzymes SOD and catalase toward normal levels. Histopathology of the liver tissue showed that PCF mitigated the toxicant-induced hepatocellular necrosis, reduced inflammatory cell infiltration and enhanced hepatocyte regeneration. The results indicated that P. curatellifolia flavonoids demonstrated remarkable hepatoprotective activity in acute liver injury caused by acetaminophen. PMID:25313285

  12. CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes

    SciTech Connect

    Reisman, Scott A.; Buckley, David B.; Tanaka, Yuji; Klaassen, Curtis D.

    2009-04-01

    CDDO-Im is a synthetic triterpenoid recently shown to induce cytoprotective genes through the Nrf2-Keap1 pathway, an important mechanism for the induction of cytoprotective genes in response to oxidative stress. Upon oxidative or electrophilic insult, the transcription factor Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins, and binds to antioxidant response elements (AREs) in the upstream promoter regions of various cytoprotective genes. To further elucidate the hepatoprotective effects of CDDO-Im, wild-type and Nrf2-null mice were pretreated with CDDO-Im (1 mg/kg, i.p.) or vehicle (DMSO), and then administered acetaminophen (500 mg/kg, i.p.). Pretreatment of wild-type mice with CDDO-Im reduced liver injury caused by acetaminophen. In contrast, hepatoprotection by CDDO-Im was not observed in Nrf2-null mice. CDDO-Im increased Nrf2 protein expression and Nrf2-ARE binding in wild-type, but not Nrf2-null mice. Furthermore, CDDO-Im increased the mRNA expression of the Nrf2 target genes NAD(P)H: quinone oxidoreductase-1 (Nqo1); glutamate-cysteine ligase, catalytic subunit (Gclc); and heme-oxygenase-1 (Ho-1), in both a dose- and time-dependent manner. Conversely, CDDO-Im did not induce Nqo1, Gclc, and Ho-1 mRNA expression in Nrf2-null mice. Collectively, the present study shows that CDDO-Im pretreatment induces Nrf2-dependent cytoprotective genes and protects the liver from acetaminophen-induced hepatic injury.

  13. Aspirin, NSAID, and acetaminophen use and the risk of endometrial cancer.

    PubMed

    Viswanathan, Akila N; Feskanich, Diane; Schernhammer, Eva S; Hankinson, Susan E

    2008-04-01

    To date, no prospective studies have explored the relationship between the use of aspirin, other nonsteroidal anti-inflammatory medications (NSAID), and acetaminophen and endometrial adenocarcinoma. Of the 82,971 women enrolled in a prospective cohort study, 747 developed medical record-confirmed invasive endometrial cancer over a 24-year period. Use of aspirin was ascertained from 1980 to 2004, and for other NSAIDs and acetaminophen, from 1990 to 2004. Cox regression models calculated multivariate relative risks (MV RR), controlling for body mass index (BMI), postmenopausal hormone (PMH) use, and other endometrial cancer risk factors. Currency, duration, and quantity of aspirin were not associated with endometrial cancer risk overall [current use: MV RR, 1.03; 95% confidence interval (CI) 0.83-1.27; >10 years of use: MV RR, 1.01; 95% CI, 0.78-1.30; and cumulative average >7 tablets per week: (MV RR, 1.10; 95% CI, 0.84-1.44)]. However, stratified analyses showed that a lower risk of endometrial cancer among obese (BMI, >or=30 kg/m(2)) women was seen with current aspirin use (MV RR, 0.66; 95% CI, 0.46-0.95). The greatest risk reduction for current aspirin users was seen in postmenopausal obese women who had never used PMH (MV RR, 0.43; 95% CI, 0.26-0.73). The use of other NSAIDs or acetaminophen was not associated with endometrial cancer. Our data suggest that use of aspirin or other NSAIDs does not play an important role in endometrial cancer risk overall. However, risk was significantly lower for current aspirin users who were obese or who were postmenopausal and had never used PMHs; these subgroup findings require further confirmation.

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

    PubMed

    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. 

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

    PubMed Central

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

    2016-01-01

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

  16. Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced ToxicityS⃞

    PubMed Central

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

    2009-01-01

    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. PMID:19460945

  17. Preparation and pharmaceutical evaluation of acetaminophen nano-fiber tablets: Application of a solvent-based electrospinning method for tableting.

    PubMed

    Hamori, Mami; Nagano, Kana; Kakimoto, Sayaka; Naruhashi, Kazumasa; Kiriyama, Akiko; Nishimura, Asako; Shibata, Nobuhito

    2016-03-01

    In this study, we developed nano-fiber-based tablets with acetaminophen (AAP; LogPow=0.51) for controlled-release delivery systems and evaluated in vitro drug dissolution and in vivo pharmacokinetics in rats. Nano-fibers made from methacrylic acid copolymer S (MAC; EUDRAGIT S100) and containing AAP were prepared using a solvent-based electrospinning (ES) method. In vitro dissolution rate profiles of AAP showed tableting pressure-dependent decreases and pH-dependent increases. The results of tablet tracking by X-ray irradiation showed tablets based on MAC nano-fibers did not disintegrate in the upper intestinal lumen and had the properties of a long-term-acting tablet. In addition, the in vitro release profiles of AAP from nano-fiber tablets prepared by dissolving MAC with AAP (NFT), nano-fiber tablets prepared by adsorbing AAP to drug-free MAC nano-fibers (NFTadso), and tablets prepared by adsorbing half the amount of AAP to MAC nano-fibers containing the remaining amount of AAP (NFThalf) showed independent controlled-release aspects of AAP compared with physical mixture tablets (PMT). In vivo pharmacokinetic studies in rats after intraduodenal administration of 14 mg/rat AAP in NFT, NFTadso, and NFThalf demonstrated that all these tablets based on MAC nano-fibers showed sustained-release profiles compared with PMT, and showed ultra-sustained release properties for AAP. These new tablets based on MAC nano-fibers did not disintegrate in the intestine in the lower pH region, and the tablets could regulate the release of AAP in a pH-dependent manner. The ES method is a useful technique to prepare nano-fibers and showed promising results as an oral delivery system for sustained-release regulation.

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

    PubMed

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

    2009-08-01

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

  19. A composite material based on nanoparticles of yttrium (III) oxide for the selective and sensitive electrochemical determination of acetaminophen.

    PubMed

    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.

  20. Macrophage activation by factors released from acetaminophen-injured hepatocytes: Potential role of HMGB1

    SciTech Connect

    Dragomir, Ana-Cristina; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-06-15

    Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24 hr after treatment of mouse hepatocytes with 5 mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1{alpha} and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1{alpha} and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1{alpha} or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity. - Research Highlights: > These studies analyze macrophage activation by mediators released from acetaminophen-damaged hepatocytes. > Factors released from acetaminophen-injured hepatocytes induce

  1. Evaluation of medicated gel as a supplement to providing acetaminophen in the drinking water of C57BL/6 mice after surgery.

    PubMed

    Christy, Amanda C; Byrnes, Kimberly R; Settle, Timothy L

    2014-03-01

    After surgery, rodents frequently receive acetaminophen-treated drinking water for pain relief, but the effectiveness of this practice is often questioned. Gel products are now available to facilitate the delivery of oral medication to rodents after surgery. We sought to compare consumption of flavored medicated gel and medicated water after surgery and to determine whether providing supplemental acetaminophen in gel form ensures the ingestion of a therapeutic dose of an analgesic after surgery. Male C57BL/6 mice were allocated into 3 groups after surgery: those that received acetaminophen-treated water and untreated gel (MW group); those that received medicated gel and untreated water (MG group); and those that received acetaminophen in both forms (MWG group). Total water and gel consumption were monitored daily from the day before surgery until 2 d thereafter. Mice in the MG group consumed significantly less gel than water, and consequently, the total acetaminophen dose per mouse in the MG group (49 mg/kg) was significantly less than that of the MWG group (347 mg/kg). Although the dose consumed by mice in the MW group (158 mg/kg) approached the targeted acetaminophen dose of 200 mg/kg, only mice in the MWG group actually achieved the desired dose. The results of this study indicate that flavored acetaminophen-containing gel can be used in combination with medicated water to ensure that rodents ingest the targeted dose of medication.

  2. Comparison of the efficacy of low doses of methylprednisolone, acetaminophen, and dexketoprofen trometamol on the swelling developed after the removal of impacted third molar

    PubMed Central

    Ataoglu, Hanife; Yildirim, Gulsun; Kiresi, Demet

    2015-01-01

    Background The aim of the present study was to compare the efficacy of low doses of methylprednisolone, acetaminophen and dexketoprofen trometamol, which are among the drug groups used in our clinic, on postoperative swelling developing after removal of impacted third molar. Material and Methods The three group of patients received either 40 mg methylprednisolone or 300 mg acetaminophen or 12.5 mg dexketoprofen trometamol one hour before the procedure, according to the patient groups. The patients in the methylprednisolone group were injected with methylprednisolone at a dose of 20 mg 24 hour after the procedure and prescribed 300 mg acetaminophen as rescue analgesic. During the postoperative period, the doses that were given before the procedure were continued 3 times a day for 2 days in the acetaminophen and dexketoprofen trometamol groups. Maximal swelling was assessed preoperatively and at the postoperative 48 hours by ultrasound images. Results Swelling was 34% lower in the methylprednisolone than in the other groups; however, no statistically significant difference was found between the groups. The acetaminophen and dexketoprofen trometamol groups exhibited clinical results close to each other. Conclusions Combination of low doses of methylprednisolone and acetaminophen provide a safe and adequate clinical success on swelling. Key words: Methylprednisolone, acetaminophen, dexketoprofen trometamol, third molar extraction, swelling. PMID:26241458

  3. Ultrasensitive peroxynitrite-based luminescence with L-012 as a screening system for antioxidative/antinitrating substances, e.g. Tylenol (acetaminophen), 4-OH tempol, quercetin and carboxy-PTIO.

    PubMed

    Van Dyke, Knox; Ghareeb, Erica; Van Dyke, Mark; Van Thiel, David H

    2007-01-01

    Previously our group developed a water-soluble antioxidant screening system using the luminescence of the reaction of peroxynitrite and luminol. In the present study we replaced luminol with the luminol-like compound L-012. This increases the production of luminescence approximately 100-fold and therefore, with a higher signal:noise ratio, this new system can detect antioxidation and antinitration effects at lower doses of the inhibitor. We studied acetaminophen (Tylenol) and its metabolite 3-nitroacetaminophen, tyrosine and nitrotyrosine and all these substances were inhibitory in a dose-responsive manner and below micromolar amounts. In addition quercetin, a polyphenol, was highly active (below micromolar amounts) as an antioxidant and antinitrating compound. 4-OH tempol, the stable free radical, superoxide dismutase (SOD) mimetic, was inhibitory in a dose-responsive manner and below micromolar amounts. Carboxy-PTIO was inhibitory at 10 times micromolar amount but not below that dose, which may be related to colour quenching, since the drug is deeply blue, or possibly it is an inhibitor with a slow kinetic profile. Finally, the amino acid tyrosine has been found to be inhibitory in micromolar amounts, similar to acetaminophen. This indicates that tyrosine can act as an antioxidant and antinitration target alone or conjugated in protein, e.g. insulin.

  4. Paracetamol (acetaminophen) decreases hydrogen sulfide tissue concentration in brain but increases it in the heart, liver and kidney in mice.

    PubMed

    Wiliński, Bogdan; Wiliński, Jerzy; Somogyi, Eugeniusz; Góralska, Marta; Piotrowska, Joanna

    2011-01-01

    The biological action ofN-acetyl-p-aminophenol - paracetamol (acetaminophen) has been demonstrated to involve different mechanisms and is still not clear. Hydrogen sulfide (H2S) has been shown to play an important role in many physiological and pathological processes including nociception. The interaction between acetaminophen and endogenous H2S is unknown. Twenty four female CBA strain mice were administered intraperitoneal injections of N-acetyl-p-aminophenol solution: paracetemol in doses of 30 mg/kg b.w. per day (group D1, n = 8) or 100 mg/kg b.w. per day (group D2, n = 8).. The control group (n = 8) received physiological saline in portions of the same volume--0.2 ml. The measurements of tissue H2S concentration were performed with the Siegel spectrophotometric modified method. In the brain, the H2S tissue level decreased, but more significantly in the lower drug dose group. Conversely, there was a significant rise in the H2S tissue concentration in D1 and D2 groups in heart and kidney with the increase more pronounced in the group with the lower paracetamol dose. In the liver only the higher acetaminophen dose elicited a change in H2S concentration, increasing after administration of acetaminophen at 100 mg/kg. Our study demonstrates that paracetamol induces H2S tissue concentration changes in different mouse organs.

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

    PubMed

    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.value<0.001), but no statistically significant difference was found in mean pain scores between the two drug groups (acetaminophen and liquefied ibuprofen) (P.value=1). Acetaminophen and liquefied ibuprofen have similar potential in pain reduction during separation.

  6. Intravenous non-opioid analgesia for peri- and postoperative pain management: a scientific review of intravenous acetaminophen and ibuprofen

    PubMed Central

    Koh, Wonuk; Nguyen, Kimngan Pham

    2015-01-01

    Pain is a predictable consequence following operations, but the management of postoperative pain is another challenge for anesthesiologists and inappropriately controlled pain may lead to unwanted outcomes in the postoperative period. Opioids are indeed still at the mainstream of postoperative pain control, but solely using only opioids for postoperative pain management may be connected with risks of complications and adverse effects. As a consequence, the concept of multimodal analgesia has been proposed and is recommended whenever possible. Acetaminophen is one of the most commonly used analgesic and antipyretic drug for its good tolerance and high safety profiles. The introduction of intravenous form of acetaminophen has led to a wider flexibility of its use during peri- and postoperative periods, allowing the early initiation of multimodal analgesia. Many studies have revealed the efficacy, safety and opioid sparing effects of intravenous acetaminophen. Intravenous ibuprofen has also shown to be well tolerated and demonstrated to have significant opioid sparing effects during the postoperative period. However, the number of randomized controlled trials confirming the efficacy and safety is small and should be used in caution in certain group of patients. Intravenous acetaminophen and ibuprofen are important options for multimodal postoperative analgesia, improving pain and patient satisfaction. PMID:25664148

  7. Transitional cell cancer of the urinary tract and renal cell cancer in relation to acetaminophen use (United States).

    PubMed

    Rosenberg, L; Rao, R S; Palmer, J R; Strom, B L; Zauber, A; Warshauer, M E; Stolley, P D; Shapiro, S

    1998-01-01

    Experimental and epidemiologic evidence have suggested that phenacetin use increases the risk of transitional cell cancers of the urinary tract. The drug is no longer marketed but a commonly used metabolite, acetaminophen, has been linked recently to an increased risk of renal cancer. We assessed the relation of acetaminophen use to the risk of transitional cell cancer of the urinary tract and of renal cell cancer with data from a hospital-based study of cancers and medication use conducted from 1976-96 in the eastern United States. We compared 498 cases of transitional cell cancer and 383 cases of renal cell cancer with 8,149 noncancer controls and 6,499 cancer controls and controlled confounding factors with logistic regression. For transitional cell cancer, the relative risk (RR) estimate for regular acetaminophen use that had begun at least a year before admission was 1.1 (95 percent confidence interval [CI] = 0.6-1.9) based on noncancer controls, and 0.9 (CI = 0.5-1.6) based on cancer controls. RR estimates for use that lasted at least five years, and for nonregular use, were also close to 1.0. For renal cell cancer, the corresponding estimates were again close to 1.0. Our results suggest that acetaminophen, as used in present study population, does not influence the risk of transitional cell cancer of the urinary tract or of renal cell cancer.

  8. Quantitative analysis of the scientific literature on acetaminophen in medicine and biology: a 2003-2005 study.

    PubMed

    Robert, Claude; Saenz-Feijoo, Rosa; Gaudy, Jean-François; Arreto, Charles-Daniel

    2009-04-01

    This study quantifies the utilization of acetaminophen in life sciences and clinical medicine using bibliometric indicators. A total of 1626 documents involving acetaminophen published by 74 countries during 2003-2005 in the Thompson-Scientific Life sciences and Clinical Medicine collections were identified and analyzed. The USA leads in the number of publications followed by the UK, and industrialized countries, including France, Japan and Germany; the presence of countries such as China, India and Turkey among the top 15 countries deserves to be noticed. The European Union stands as a comparable contributor to the USA, both in terms of number of publications and in terms of profile of papers distributed among subcategories of Life Sciences and Clinical Medicine disciplines. All documents were published in 539 different journals. The most prolific journals were related to pharmacology and/or pharmaceutics. All aspects of acetaminophen (chemistry, pharmacokinetics, metabolism, etc.) were studied with primary interest for therapeutic use (42%) and adverse effects (28%) comprising a large part of publications focusing on acetaminophen hepatotoxicity. This quantitative overview provides as to the interest of the scientific community in this analgesic and completes the various review documents that regularly appear in the scientific literature.

  9. Development of a Rapid Derivative Spectrophotometric Method for Simultaneous Determination of Acetaminophen, Diphenhydramine and Pseudoephedrine in Tablets

    PubMed Central

    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 1D value of acetaminophen at 281.5 nm, 2D value of diphenhydramine hydrochloride at 226.0 nm and 4D 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. PMID:25901150

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

    ERIC Educational Resources Information Center

    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…

  11. Chitosan and blueberry treatment induces arginase activity and inhibits nitric oxide production during acetaminophen-induced hepatotoxicity

    PubMed Central

    Ozcelik, Eda; Uslu, Sema; Burukoglu, Dilek; Musmul, Ahmet

    2014-01-01

    Background: Liver diseases have become a major problem of the worldwide. More than 50% of all cases of liver failure can be attributed to drugs. Among these, acetaminophen is the most common cause. Objective: The aim of this study was to investigate the the hepatoprotective effects of blueberry and chitosan on tissue arginase activity, ornithine and nitric oxide levels during the acetaminophen-induced hepatotoxicity. Materials and Methods: Acetaminophen (250 mg/kg body weight per day), blueberry (60 mg/kg body weight per day) and, chitosan (200 mg/kg body weight per day) were administered to the rats by oral gavage during the experimental period. Results: Blueberry and chitosan significantly decreased liver arginase activity and ornithine levelsand and increased nitric oxide levels. Glutathione levels were remarkably increased by chitosan and blueberry treatments. Conclusion: The results of the present study indicate that blueberry and chitosan effectively protected against the acetaminophen-induced hepatotoxicity. The hepatoprotective effect afforded by blueberry and chitosan can be attributed to its antioxidant and anti-inflammatory activities. PMID:24991095

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

    PubMed Central

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

    2014-01-01

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

  13. Effect of pressure on molecular and ionic motions in ultraviscous acetaminophen-aspirin mixture.

    PubMed

    Andersson, Ove; Johari, G P; Shanker, R M

    2006-11-01

    Effect of pressure and temperature on molecular motions and dc conductivity in ultraviscous, 50 wt% acetaminophen-aspirin melt has been studied by dielectric relaxation spectroscopy. The spectra obtained over the pressure range, 5-300 MPa and temperature range, 295-320 K show a distribution of relaxation times greater than found in pure acetaminophen. The equilibrium dielectric permittivity and relaxation time, tau, of the melt increase with increase in pressure and decrease in temperature and the dc conductivity, sigma(dc), decreases. The pressure and temperature variation of the limiting high frequency permittivity shows significant contribution from infrared polarization. The volumes of activation for sigma(dc) and tau vary with both the pressure and temperature, indicating that there is also a structural effect that determine sigma(dc). This effect would add a non-linear term to the Debye-Stokes-Einstein equation for variation of sigma(dc) with tau. The ultraviscous liquid remains stable with time, and with change in temperature and pressure, suggesting that a more stable glassy state of a pharmaceutical may be obtained by mixing a second component.

  14. Impact of perinatal exposure to acetaminophen on hepatocellular metabolic function in offspring

    PubMed Central

    Wu, Ka; Guo, Chao; Lu, Xiuli; Wu, Xinmou; Pan, Hongmei; Su, Min

    2016-01-01

    Acetaminophen (APAP), an over the counter (OTC) medication, is widely used in antipyretic treatment. Although the risk of dose-dependent cytotoxicity has been known, the potential effect of perinatal exposure to acetaminophen on metabolic function in offspring remains uninvestigated. Therefore, we established a prenatally APAP-exposed pregnancy mouse model to assess the possible adverse effect on liver metabolic function in offspring. Biochemical assays were applied in analysis of basic metabolic parameters in postnatal mice. Further, immunoblotting assay was used to assess the expressions of insulin receptor β (IRβ), insulin receptor substrate 1 (IRS1), phospho-Akt and phospho-GSK-3β proteins in liver cells. In addition, hepatic glucose transporter 2 (GLUT2) immunoactivity was determined by using immunohistochemistry staining. Compared with untreated postnatal mice, APAP-exposed offspring induced impaired glucose metabolism, increased plasma insulin level, and reduced liver glycogen content. In addition, APAP exposure decreased the expressions of IRS1 and phospho-GSK-3β, phospho-AKT proteins and down-regulated the level of glucose-import regulator GLUT2 in the liver. Taken together, our preliminary findings indicate that perinatal APAP exposure-impaired hepatic glucose metabolism in offspring may be associated with disturbance of insulin-dependent AKT signaling in the liver. PMID:28078035

  15. Validation of a HPLC quantification of acetaminophen, phenylephrine and chlorpheniramine in pharmaceutical formulations: capsules and sachets.

    PubMed

    Marín, A; García, E; García, A; Barbas, C

    2002-07-20

    Acetaminophen, phenylephrine and chlorpheniramine are frequently associated in pharmaceutical formulations against the common cold. Their quantification presents several problems. A HPLC method for the simultaneous determination of these compounds in pharmaceutical formulations such as capsules and sachets, including the separation of impurities and excipients has been developed and validated. The selectivity of the method was also tested to be used if phenylpropanolamine hydrochloride were employed instead of phenylephrine. Final chromatographic conditions were a gradient elution, being solvent A: phosphate buffer 40 mM at pH 6.0 and solvent B: acetonitrile. At t=0, the mobile phase consisted of 92% A and 8% B and it changed with a linear gradient during 8 min to 75% A and 25% B. At min 8, it changed to 30% A and 70% B for 5 min and at t=15 min, it returns to the initial conditions (92% A and 8% B) during 1 min remaining at this composition until t=20 min. UV detection was performed at 215 nm for phenylephrine and chlorpheniramine, because at this wavelength sensitivity was higher than in other more characteristic wavelengths and it was necessary for the detection of minor compounds. For acetaminophen 280 nm was employed. Validation parameters permit to consider the method adequate.

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

    PubMed

    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.

  17. Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co-crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters.

    PubMed

    Mukaida, Makoto; Sato, Haruna; Sugano, Kiyohiko; Terada, Katsuhide

    2017-01-01

    The aim of this study was to determine the thermodynamic stability order of co-crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using