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Sample records for acetaminophen drug particles

  1. Effect of the mechanical activation on size reduction of crystalline acetaminophen drug particles

    Directory of Open Access Journals (Sweden)

    Esmaeil Biazar1

    2009-12-01

    Full Text Available Esmaeil Biazar1, Ali Beitollahi2, S Mehdi Rezayat3, Tahmineh Forati4, Azadeh Asefnejad4, Mehdi Rahimi4, Reza Zeinali4, Mahmoud Ardeshir4, Farhad Hatamjafari1, Ali Sahebalzamani4, Majid Heidari41Chemistry Department, Islamic Azad University, Tonekabon Branch, Mazandaran, Iran; 2Material Department, Iran University of Science and Technology, Tehran, Iran; 3Department of Pharmacology, School of Medicine, Tehran University of Medical sciences, Tehran, Iran; 4Biomedicall Department, Islamic Azad University, Science and Research Branch, Tehran, IranAbstract: The decrease in particle size may offer new properties to drugs. In this study, we investigated the size reduction influence of the acetaminophen (C8H9O2N particles by mechanical activation using a dry ball mill. The activated samples with the average size of 1 µm were then investigated in different time periods with the infrared (IR, inductively coupled plasma (ICP, atomic force microscopy (AFM, and X-ray diffraction (XRD methods. The results of the IR and XRD images showed no change in the drug structure after the mechanical activation of all samples. With the peak height at full width at half maximum from XRD and the Scherrer equation, the size of the activated crystallite samples illustrated that the AFM images were in sound agreement with the Scherrer equation. According to the peaks of the AFM images, the average size of the particles in 30 hours of activation was 24 nm with a normal particle distribution. The ICP analysis demonstrated the presence of tungsten carbide particle impurities after activation from the powder sample impacting with the ball and jar. The greatest reduction in size was after milling for 30 hours.Keywords: acetaminophen, mechanical activation, structure investigation, nanoparticles, ball mill

  2. Acetaminophen

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    NyCair® (as a combination product containing Acetaminophen, Dextromethorphan, Doxylamine, Pseudoephedrine) ... Relief® (as a combination product containing Acetaminophen, Dextromethorphan, Doxylamine)

  3. Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

    OpenAIRE

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2012-02-01

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

  5. Electrochemical Synthesis and Kinetic Evaluation of Electrooxidation of Acetaminophen in the Presence of Antidepressant Drugs

    OpenAIRE

    Nematollahi, Davood; Feyzi Barnaji, Bahareh; Amani, Ameneh

    2015-01-01

    With the aim of obtaining information about drug-drug interaction (DDI) between acetaminophen and some of antidepressant drugs (fluoxetine, sertraline and nortriptyline), in the present work we studied the electrochemical oxidation of acetaminophen (paracetamol) in the presence of these drugs by means of cyclic voltammetry and Controlled-potential coulometry. The reaction between N-acetyl-p-benzoquinone-imine (NAPQI) produced from electrooxidation of acetaminophen and antidepressant drugs (se...

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

    Science.gov (United States)

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

    2013-07-01

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

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

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    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.

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

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    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.

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

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    Kuang-Ting Yeh

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

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

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    Yeh, Kuang-Ting; Wu, Wen-Tien; Subeq, Yi-Maun; Niu, Chi-Chien; Liao, Kuang-Wen; Chen, Ing-Ho; Wang, Jen-Hung; Lee, Ru-Ping

    2015-01-01

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

  11. 76 FR 2691 - Prescription Drug Products Containing Acetaminophen; Actions To Reduce Liver Injury From...

    Science.gov (United States)

    2011-01-14

    ... regional results in the first population-based study of ALF conducted in the United States, an estimated... is produced when acetaminophen is broken down by the body (Ref. 5). With low doses of acetaminophen... Syndrome, chronic alcoholism, acute excess alcohol use, and use of anticonvulsant or...

  12. Acetaminophen and codeine overdose

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    ... N-acetyl cysteine. This drug is called an antidote. It counteracts the effects of the acetaminophen. Without ... before treatment, brain injury may occur. If an antidote can be given, recovery from an acute overdose ...

  13. Warfarin and acetaminophen interaction.

    Science.gov (United States)

    Gebauer, Markus G; Nyfort-Hansen, Karin; Henschke, Philip J; Gallus, Alexander S

    2003-01-01

    A 74-year-old man who was receiving warfarin for atrial fibrillation experienced an abrupt increase in his international normalized ratio (INR) after taking acetaminophen. To investigate this effect, the patient's anticoagulation therapy was stabilized, and he was given acetaminophen 1 g 4 times/day for 3 days. His INR rose from 2.3 before receiving acetaminophen to 6.4 on the day after acetaminophen was discontinued. Warfarin was stopped for 2 days, and the patient's INR returned to 2.0. Warfarin was restarted at the same dosage, and his INR remained within 2.0-3.0 for 6 months. Factor VII activity decreased from 29.4% before acetaminophen therapy to 15.5% when his INR was 6.4, and factor X activity fell from 27.0% to 20.2%. His warfarin plasma concentration was 1.54 microg/ml before acetaminophen compared with 1.34 microg/ml when his INR was 6.4. No significant changes in drug intake, clinical status, diet, or lifestyle were noted. Changes in INR of this magnitude with the addition of another drug during stable anticoagulation therapy suggest a drug interaction. The lack of an increase in warfarin plasma concentration associated with the increased INR suggests a possible pharmacodynamic mechanism for this interaction. Acetaminophen or a metabolite may enhance the effect of oral coumarin anticoagulants by augmenting vitamin K antagonism. Thus, the anticoagulant effect of warfarin may be significantly elevated after only a few days of acetaminophen therapy. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 g/day.

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

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

    2015-01-01

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

  15. Pediatric acetaminophen poisoning

    OpenAIRE

    Roldán, Tatiana; Hospital Universitario San Ignacio; López, Ángelo; Hospital Universitario San Ignacio

    2012-01-01

    Paracetamol (acetaminophen) is an important drug used in children because of its analgesic and antipyretic effects. It has a safety profile but high-dose administration can produce significant toxicity at risk of developing acute liver failure. The outcome depends on the timely recognition and starting specific therapeutic management.Paracetamol (acetaminophen) is one of the most used drugs in children, due to the efficient analgesic and antipyretic effects. It has good safety profile, but in...

  16. Pharmacokinetic Herb-Drug Interaction between Essential Oil of Aniseed (Pimpinella anisum L., Apiaceae) and Acetaminophen and Caffeine: A Potential Risk for Clinical Practice.

    Science.gov (United States)

    Samojlik, Isidora; Petković, Stojan; Stilinović, Nebojša; Vukmirović, Saša; Mijatović, Vesna; Božin, Biljana

    2016-02-01

    Aniseed (Pimpinella anisum L., Apiaceae) and its essential oil (EO) have been widely used. Because there are some data about the impact of aniseed EO on drug effects, this survey aimed to assess the potential of pharmacokinetic herb-drug interaction between aniseed EO and acetaminophen and caffeine in mice. The chemical analysis (gas chromatography-mass spectrometry) of aniseed EO has confirmed trans-anethole (87.96%) as the main component. The pharmacokinetic studies of intraperitoneally (i.p.) and orally applied acetaminophen (200 mg/kg) and caffeine (20 mg/kg) were performed in mice after 5 days of oral treatment with human equivalent dose of aniseed EO (0.3 mg/kg/day). The analysis of pharmacokinetic data showed that in the group treated by aniseed EO, the significant decrease in the peak plasma concentration of acetaminophen after oral application (p = 0.024) was revealed when compared with control group and the reduction of systemic exposure to the drug after oral application (74 ± 32% vs. 85 ± 35% in the control) was noted. The bioavailability of orally applied caffeine was also significantly decreased (p = 0.022) after the EO treatment in comparison with the control (57 ± 24% vs. 101 ± 29%). Therefore, the compromised therapeutic efficacy of acetaminophen and caffeine during the usage of aniseed EO preparations should be considered.

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

    Directory of Open Access Journals (Sweden)

    Esmaeil Biazar

    2010-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Laura James

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS: We analyzed pooled data from 12...... population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression...... and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. RESULTS: Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval...

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2010-04-07

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

  2. Investigation into the Effect of Ethylcellulose Viscosity Variation on the Drug Release of Metoprolol Tartrate and Acetaminophen Extended Release Multiparticulates-Part I.

    Science.gov (United States)

    Mehta, R; Teckoe, J; Schoener, C; Workentine, S; Ferrizzi, D; Rajabi-Siahboomi, A

    2016-12-01

    Ethylcellulose is one of the most commonly used polymers to develop reservoir type extended release multiparticulate dosage forms. For multiparticulate extended release dosage forms, the drug release is typically governed by the properties of the barrier membrane coating. The ICH Pharmaceutical Development Guideline (ICH Q8) requires an understanding of the influence of critical material attributes and critical process parameters on the drug release of a pharmaceutical product. Using this understanding, it is possible to develop robust formulations with consistent drug release characteristics. Critical material attributes for ethylcellulose were evaluated, and polymer molecular weight variation (viscosity) was considered to be the most critical attribute that can impact drug release. To investigate the effect of viscosity variation within the manufacturer's specifications of ethylcellulose, extended release multiparticulate formulations of two model drugs, metoprolol tartrate and acetaminophen, were developed using ETHOCEL™ as the rate controlling polymer. Quality by Design (QbD) samples of ETHOCEL Std. 10, 20, and 100 Premium grades representing the low, medium, and high molecular weight (viscosity) material were organically coated onto drug layered multiparticulates to a 15% weight gain (WG). The drug release was found to be similar (f 2 > 50) for both metoprolol tartrate and acetaminophen multiparticulates at different coating weight gains of ethylcellulose, highlighting consistent and robust drug release performance. The use of ETHOCEL QbD samples also serves as a means to develop multiparticulate dosage formulations according to regulatory guidelines.

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

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

    2016-01-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. PMID:26739624

  4. Non-destructive prediction of the drug content of an acetaminophen suppository by near-infrared spectroscopy and X-ray computed tomography.

    Science.gov (United States)

    Otsuka, Kuniko; Uchino, Tomohiro; Otsuka, Makoto

    2015-01-01

    The purpose of this study is to develop non-destructive methods to determine the drug content of suppositories using near-infrared (NIR) spectrometry and X-ray computed tomography (XCT). The suppository samples (acetaminophen content: 0, 100, 200, 300, 400 and 500 mg/suppository) consisted of acetaminophen powder and hard fat. NIR spectra of 18 standard suppository samples were recorded, and the data were divided into two wave number ranges, 4000-10 000 cm(-1) (LR), and 4280-6650 cm(-1) (SR). The best calibration model was determined to minimize the standard error of cross-validation (SECV) by the leave-one-out method in the partial least squares regression (PLS). Sliced XCT images of the suppositories were measured, and apparent density (AD) was evaluated using the image of the sample. The NIR models gave the best correlation coefficient constant (R) values, since the results for LR and SR gave straight lines with R of 0.9274 and 0.9707, respectively. The AD of the suppositories by XCT increased with increasing drug content, and the relationship between the AD and drug content had a straight line with R of 0.9958. Both NIR and X-ray CT performed accurate measurements of suppository samples through plastic packaging.

  5. Defensive nature of Sargassum polycystum (Brown alga)against acetaminophen-induced toxic hepatitis in rats: Role of drug metabolizing microsomal enzyme system, tumor necrosis factor-α and fate of liver cell structural integrity

    Institute of Scientific and Technical Information of China (English)

    H Balaji raghavendran; A Sathivel; T Devaki

    2006-01-01

    AIM: To assess the defensive nature of Sargassum polycystum (S. Polycystum) (Brown alga) against acetaminophen (AAP)-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor (TNF-α)and fine structural features of the liver during toxic hepatitis in rats.METHODS: Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group Ⅰ consisted of normal control rats fed with standard diet.Group Ⅱ rats were administered with acetaminophen (800 mg/kg body weight, intraperitoneally). Group Ⅲ rats were pre-treated with S. Polycystum extract alone.Group Ⅳ rats were orally pre-treated with S. Polycystum extract (200 mg/kg body weight for 21 d) prior to acetaminophen induction (800 mg/kg body weight,intraperitoneally). Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and b5.Serum TNF-α was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy.RESULTS: Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and b5 when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-α when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably prevented in the rats pretreated with S. Polycystum. The rats pretreated with S. Polycystum showed considerable inhibition in the elevation of TNF-α compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats,whereas the rats treated with S. Polycystum showed considerable protection against acetaminophen-induced alterations in

  6. [Paracetamol (acetaminophen) use in neonatology: a (re)appreciation of an old drug].

    Science.gov (United States)

    Langhendries, J-P

    2015-10-01

    In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it has been demonstrated that paracetamol is also an anti-cyclooxygenase (COX) medication through its inhibitory action on the peroxidase arm of central and peripheral COX (Boutaud et al., 2002; Toussaint et al., 2010; Graham et al., 2013; Hinz et al., 2008; Hinz and Brune, 2011). As such, this drug interferes with the synthesis of prostaglandins. This inhibition of peroxidase is, however, limited to a low concentration of arachidonic acid (AA) (around 2μM, in vitro) when the plasmatic concentration of paracetamol is experimentally 10μM, actually within the same range as compared to the therapeutic concentrations in vivo. This may partly explain its low anti-inflammatory effect as compared to ibuprofen and indomethacin, which exert their inhibition on COX whatever the AA concentrations are. This new well-demonstrated action of paracetamol on peripheral COX-2 of intact cells could explain recent observations making this drug a potential alternative in treating patent ductus arteriosus. However, the higher dosages that have been claimed by some authors in this indication still remain to be validated. This inhibition that paracetamol shows on the physiological synthesis of prostaglandins E2 (PGE2) could also explain some long-term immune deviations because the physiological concentration of PGE2 is a well-known actor in the genesis of immune homeostasis in the submucosal area. Indeed, recent epidemiology studies have pointed out immune deviations in children repeatedly exposed to paracetamol earlier in life. Consequently, this is actually the new discovery of an old drug. From these new data on paracetamol, a more focused pharmacovigilance on the long-term effects of paracetamol repeatedly given in the early stage should be urgently initiated.

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

    Science.gov (United States)

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

    2013-06-01

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

  8. 感冒灵颗粒中对乙酰氨基酚含量测定方法的研究%Determination of acetaminophen in Ganmaoling particles

    Institute of Scientific and Technical Information of China (English)

    谭妙娟; 何炳洪; 冯焕村

    2013-01-01

    目的:建立简便快捷的高效液相色谱法测定感冒灵颗粒中对乙酰氨基酚含量.方法:采用Agilent1 100型高效液相色谱仪,Agilent Eclipse XDB C18柱(250 mm×4.6 mm,5μm),流动相为甲醇-水(1∶3),流速1.0 ml·min-1,检测波长为240 nm.结果:对乙酰氨基酚进样量在4.004~ 36.036 μg·ml-1范围内与峰面积线性关系良好(r =0.999 9),平均回收率为99.93%,RSD为0.29%(n=6).结论:高效液相色谱法测定感冒灵颗粒中对乙酰氨基酚含量操作简便,灵敏度高,重现性好,结果精确可靠.%Objective: To establish a simple and fast high performance liquid chromatography ( HPLC ) determination method to detect the acetaminophen content in Ganmaoling particles. Methods: Agilent 1100 liquid chromatograph and Agilent Eclipse XDB C18 column (250 mm×4. 6 mm, 5 μm) were used. Mobile phase was methanol-water(1:3) , flow rate was 1. 0 ml·min-1,detection wavelength was 240 nm. Results: The peak area of the acetaminophen injection volume in the range of 4. 004-36. 036 μg·ml-1 was with a good linear relationship (r =0. 999 9) , the average recovery rate was 99. 93% , RSD was 0. 29% (n =6). Conclusion; HPLC is simple, high sensitivity, good reproducibility, accurate to detect the acetaminophen content Ganmaoling particles. It can have reliable results.

  9. The Social Side Effects of Acetaminophen

    Science.gov (United States)

    Mischkowski, Dominik

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

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

    Science.gov (United States)

    Miettinen, Teemu P; Björklund, Mikael

    2014-12-01

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

  11. Microdose study of 14C-acetaminophen with accelerator mass spectrometry to examine pharmacokinetics of parent drug and metabolites in healthy subjects.

    Science.gov (United States)

    Tozuka, Z; Kusuhara, H; Nozawa, K; Hamabe, Y; Ikushima, I; Ikeda, T; Sugiyama, Y

    2010-12-01

    A study of the pharmacokinetics of (14)C-labeled acetaminophen (AAP) was performed in healthy Japanese subjects receiving an oral microdose of the drug. After separation by high-performance liquid chromatography (HPLC), the levels of AAP and its metabolites in the pooled plasma specimens were quantified using accelerator mass spectrometry (AMS). The total body clearance (CL(tot))/bioavailability (F) of AAP was within the variation in the reported values at therapeutic doses, indicating the linearity of AAP pharmacokinetics. AAP-glucuronide (Glu) and AAP-4-O-sulfate satisfied the criteria of safety testing of drug metabolites. AMS could detect AAP-Cys, the active metabolite of AAP conjugated with cysteine, in the urine. Probenecid prolonged the systemic elimination of total radioactivity and caused a marked decrease in AAP-Glu levels in plasma. Probenecid likely inhibited the glucuronidation of AAP and the renal elimination of AAP-4-O-sulfate. Microdosing of (14)C-labeled drug followed by AMS is a powerful tool that can be used in the early phase of drug development for pharmacokinetic analysis of drugs and their metabolites and for detecting the formation of active metabolites in humans.

  12. Acetaminophen overdose associated with double serum concentration peaks

    Directory of Open Access Journals (Sweden)

    Cristian Papazoglu

    2015-12-01

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

  13. Drug transport in HEMA conjunctival inserts containing precipitated drug particles.

    Science.gov (United States)

    Gupta, Chhavi; Chauhan, Anuj

    2010-07-01

    This paper focuses on exploring the mechanism of cyclosporine A transport in hydroxyethyl methacrylate (HEMA) rods to develop conjunctival inserts for extended ocular delivery. Cylindrical conjunctival HEMA inserts were prepared by thermal polymerization in presence of drug at high loadings to create rods containing particles of drug dispersed in the matrix. The drug release rates were measured to explore the effect of length, drug loading, crosslinking, and mixing in the release medium. Also microstructure of the inserts was characterized by SEM imaging. The inserts release the drug for a period of about a month at therapeutic rates. The rates of drug release are zero order and independent of drug loading and crosslinking for certain period of time. These effects were shown to arise due to a mass-transfer boundary layer in the fluid and a mathematical model was developed by coupling mass transfer in the insert with that in the boundary layer in the surrounding fluid. The model with diffusivity in the insert and boundary layer thickness as parameters fits the experimental data and explains all trends in release kinetics. The fitted diffusivity is about twice that obtained by direct measurements, which agreed well with the value obtained by using the Brinkman's equation but only after accounting for drug binding to the polymer.

  14. Acetaminophen for Chronic Pain

    DEFF Research Database (Denmark)

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

    2016-01-01

    strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1,551 hits were obtained. Following cross-reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than two weeks with placebo were included. The review...

  15. Acetaminophen use during pregnancy

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  16. EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: II. PARTICLE MOTION

    Science.gov (United States)

    ABSTRACTComputer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics...

  17. Determinating of Acetaminophen in some Commonly Used Antipyretic Analgesics Drugs%常用解热镇痛药中对乙酰氨基酚含量测定

    Institute of Scientific and Technical Information of China (English)

    孙晶; 薛壮

    2014-01-01

    本实验的目的是检测几种常用解热镇痛药中对乙酰氨基酚成分的含量。主要是利用高效液相色谱法及其相关手段,对5种解热镇痛药中对乙酰氨基酚成分的含量进行分析和测定。经实验证实,对乙酰氨基酚含量测定线性范围在6.25~200μg·mL-1,相关系数 r=0.9997。高效液相色谱法的分离效果灵敏度高、重复性好,可用于多种解热镇痛药中对乙酰氨基酚含量的测定。%Aim of this study was to analysis content of acetaminophen in some commonly used antipyretic analgesics drugs. Preparative high performance liquid chromatography (HPLC) technique was used in comparative analysis of acetaminophen in 5 commonly used antipyretic analgesics drugs. Linear relationship between the absorbance and concentration of acetaminophen was obtained in the range of 6.25~200μg·mL-1, with correlative coefficients of linear as 0.9997 (r=0.9997), and linear regression equation as y=56476.96x-451.31. It showed that HPLC is an ideal method in acetaminophen content determination analysis.

  18. Reducing Fever in Children: Safe Use of Acetaminophen

    Science.gov (United States)

    ... For Consumers Home For Consumers Consumer Updates Reducing Fever in Children: Safe Use of Acetaminophen Share Tweet ... re in the drug store, looking for a fever-reducing medicine for your children. They range in ...

  19. Determination of Acetaminophen in Anti-cold Drugs by Internal Standard Method of FT-IR%抗感冒药中对乙酰氨基酚含量的红外光谱法测定

    Institute of Scientific and Technical Information of China (English)

    何优选; 卢凯; 陈燕娜; 邱冰花; 梁奇峰

    2016-01-01

    建立了红外光谱内标法测定抗感冒药中对乙酰氨基酚的方法。选择铁氰化钾作为内标物,定量添加到对乙酰氨基酚中,在对乙酰氨基酚百分含量为0.16%~1.67%范围内,测得混合物红外光谱中对乙酰氨基酚测量峰(1564.1cm-1)和铁氰化钾内标峰(2117.6cm-1)的峰高比(y=hi/hs)与两者质量比(x=mi/ms)有良好的线性关系,其线性回归方程为y=0.8448x+0.0842,相关系数r=0.9983。据此测得抗感冒药样品中对乙酰氨基酚的含量,测定结果与药典法相近。%A novel method for the determination of acetaminophen in anti-cold drugs by internal standard method of Fourier transform infrared spectrophotometry (FT-IR) was establlished. Potassium ferricyanide was added into acetaminophen as internal reference and the mixtures were detected by FT-IR. The peak of acetaminophen at (1564±1)cm-1 was chosen as quantitative peak and the one of potassium ferricyanide at (2117±1) cm-1 was chosen as inside mark quantitative peak. The ratio of two peak’s absorbance (y=hi/hs ) had good linear relationship with their mass ratio (x=mi/ms) when the mass fraction of acetaminophen was 0.16%~1.67%. The linear regression equation wasy=0.8448x+0.0842, and the linear correlation coefficient was 0.9983. The contents of acetaminophen in the anti-cold drugs sample was detected and the determination results were similar to those of pharmacopoeia method.

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

    Science.gov (United States)

    Herndon, Christopher M; Dankenbring, Dawn M

    2014-06-01

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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    L. I. Dvoretski

    2016-01-01

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

  3. Multifunctional inverse opal particles for drug delivery and monitoring.

    Science.gov (United States)

    Zhang, Bin; Cheng, Yao; Wang, Huan; Ye, Baofen; Shang, Luoran; Zhao, Yuanjin; Gu, Zhongze

    2015-06-28

    Particle-based delivery systems have a demonstrated value for drug discovery and development. Here, we report a new type of particle-based delivery system that has controllable release and is self-monitoring. The particles were composed of poly(N-isopropylacrylamide) (pNIPAM) hydrogel with an inverse opal structure. The presence of macropores in the particles provides channels for active drug loading and release from the materials.

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  5. Acetaminophen protects against iron-induced cardiac damage in gerbils.

    Science.gov (United States)

    Walker, Ernest M; Epling, Christopher P; Parris, Cordel; Cansino, Silvestre; Ghosh, Protip; Desai, Devashish H; Morrison, Ryan G; Wright, Gary L; Wehner, Paulette; Mangiarua, Elsa I; Walker, Sandra M; Blough, Eric R

    2007-01-01

    There are few effective agents that safely remove excess iron from iron-overloaded individuals. Our goal was to evaluate the iron-removing effectiveness of acetaminophen given ip or orally in the gerbil iron-overload model. Male gerbils were divided into 5 groups: saline controls, iron-overloaded controls, iron-overloaded treated with ip acetaminophen, iron-overloaded treated with oral acetaminophen, and iron-overloaded treated with ipdeferoxamine. Iron dextran was injected iptwice/wk for 8 wk. Acetaminophen and deferoxamine treatments were given on Mondays, Wednesdays, and Fridays during the same 8 wk and continued for 4 wk after completion of iron-overloading. Echocardiograms were performed after completion of the iron-overloading and drug treatments. Liver and cardiac iron contents were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Iron-overloaded controls had 232-fold and 16-fold increases in liver and cardiac iron content, respectively, compared to saline controls. In iron-overloaded controls, echocardiography showed cardiac hypertrophy, right and left ventricular distension, significant reduction in left ventricular ejection fraction (-22%), and fractional shortening (-31%) during systole. Treatments with acetaminophen (ip or oral) or deferoxamine (ip) were equally effective in reducing cardiac iron content and in preventing cardiac structural and functional changes. Both agents also significantly reduced excess hepatic iron content, although acetaminophen was less effective than deferoxamine. The results suggest that acetaminophen may be useful for treatment of iron-induced pathology.

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

    Science.gov (United States)

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

    2015-11-26

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

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

    Directory of Open Access Journals (Sweden)

    Irena Kasmi

    2015-09-01

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

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

    Science.gov (United States)

    AI-Nemrawi, Nusaiba K.

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

  9. Drug: D08696 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08696 Mixture, Drug Acetaminophen - ephedra herb - scopolia extract - caffeine and... sodium benzoate - magnesium oxide mixt; Asgen (TN) Acetaminophen [DR:D00217], Ephedra herb [DR:D06791], Scopolia extract

  10. Drug: D02153 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02153 Mixture, Drug Acetaminophen - oxycodone hydrochloride mixt; Percocet (TN); R...oxicet 5/500 (TN); Tylox (TN) Oxycodone hydrochloride [DR:D00847], Acetaminophen [DR:D00217] Analgesic PubChem: 7849214 ...

  11. Continuous multimechanistic postoperative analgesia: a rationale for transitioning from intravenous acetaminophen and opioids to oral formulations.

    Science.gov (United States)

    Pergolizzi, Joseph V; Raffa, Robert B; Tallarida, Ronald; Taylor, Robert; Labhsetwar, Sumedha A

    2012-02-01

    Good surgical outcomes depend in part on good pain relief, allowing for early mobilization, optimal recovery, and patient satisfaction. Postsurgical pain has multiple mechanisms, and multimechanistic approaches to postoperative analgesia are recommended and may be associated with improved pain relief, lowered opioid doses, and sometimes a lower rate of opioid-associated side effects. Acetaminophen (paracetamol) is a familiar agent for treating many types of pain, including postsurgical pain. Oral acetaminophen has been shown to be safe and effective in a variety of acute pain models. Combination products using a fixed-dose of acetaminophen and an opioid have also been effective in treating postsurgical pain. Combination products with acetaminophen have demonstrated an opioid-sparing effect, which inconsistently results in a reduced rate of opioid-associated side effects. Intravenous (IV) acetaminophen and an opioid analgesic administered in the perioperative period may be followed by an oral acetaminophen and opioid combination in the postoperative period. Transitioning from an IV acetaminophen and opioid formulation to a similar but oral formulation of the same drugs appears to be a reasonable step in that both analgesic therapies are known to be safe and effective. For postsurgical analgesia with any acetaminophen product, patient education is necessary to be sure that the patient does not concurrently take any over-the-counter products containing acetaminophen and accidentally exceed dose limits.

  12. Mechanisms of Acetaminophen-induced Hepatotoxicity and Targets for Drug Intervention%对乙酰氨基酚肝毒性机理及药物干预靶点

    Institute of Scientific and Technical Information of China (English)

    汪倩; 徐瑞娟; 杨劲

    2011-01-01

    Because of the wide use of non-steroidal anti-inflammatory drugs acetaminophen, its hepatotoxicity is paid more and more attention. This review introduces its metabolism, disposition in liver and endogenous regulation mechanism related to Keap1-Nrf2 pathway; explains its mechanisms of hepatotoxicity involving two theories: metabolic injury and oxidative stress injury. Important of all, we focus on its intervention targets related to absorption, metabolism and transport of drugs. Recent studies are interested in the relationships between acetaminophen toxicity and Keap1-Nrf2 detoxffying pathway especially hepatobiliary transporters, which is expected to search for new therapeutic targets and effective drugs.%由于对乙酰氨基酚用药普遍性和广泛性,其肝毒性问题日益引起人们的关注.本文介绍对乙酰氨基酚肝脏代谢、转运以及与Keap1-Nrf2通路有关的生理性调控机制,阐述对乙酰氨基酚的肝毒性机理,包括代谢损伤和氧化应激损伤两大理论.并以此为基础从吸收、代谢、转运等方面对其治疗靶点及干预药物加以综述.其中,Keap1-Nrf2抗氧化解毒通路和转运蛋白环节与对乙酰氨基酚肝毒性关系的研究在近几年逐渐增多,有望发现新的治疗靶点和对乙酰氨基酚肝毒性的有效治疗药物.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Julio R Chavez

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

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

    Science.gov (United States)

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

    2016-02-29

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

  16. Interventions for paracetamol (acetaminophen) overdoses

    DEFF Research Database (Denmark)

    Brok, J; Buckley, N; Gluud, C

    2002-01-01

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

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

    Directory of Open Access Journals (Sweden)

    John M D Thompson

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

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

    Science.gov (United States)

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

    2014-01-01

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

  19. Rapid assay of the comparative degradation of acetaminophen in binary and ternary combinations

    Directory of Open Access Journals (Sweden)

    Adnan Mujahid

    2014-09-01

    Full Text Available The study is intended to monitor the comparative degradation rates of acetaminophen in binary and ternary combinations by UV–vis spectroscopy. The drugs were exposed to UV-rays in blister packing. The exposition time was 24, 48 and 72 h for both shorter and longer wavelengths. The problem of overlapping UV bands of aspirin and caffeine with acetaminophen was solved by extracting them in diethylether, therefore, we developed a straightforward, rapid and accurate assay method for measuring acetaminophen concentration in binary and ternary mixtures and to monitor its degradation.

  20. Acetaminophen-Induced Acute Pancreatitis. A Case Report

    Directory of Open Access Journals (Sweden)

    Hisato Igarashi

    2009-09-01

    Full Text Available Context Drug-induced acute pancreatitis is rare but should not be overlooked in a patient who presents with idiopathic acute pancreatitis. More than 100 drugs have been implicated in causing the disease: acetaminophen has been associated with acute pancreatitis in cases where there has been an overdose of drugs; however, the frequency is rare. Case report We report the case of a 35-year-old woman who presented with acute pancreatitis and severe metabolic acidosis after overdosing on a drug containing acetaminophen. She improved dramatically after intensive care; however, she showed recurrent episodes after re-overdosing on the same drug. With her self re-challenge test, she was diagnosed as having acetaminophen-induced pancreatitis and metabolic acidosis. A review of the relevant literature is also presented. Conclusions Drug-induced acute pancreatitis is often challenging for clinicians and a detailed mechanism is unknown. It is very important to rule out drug-induced pancreatitis when treating pancreatitis with an unknown etiology.

  1. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    OpenAIRE

    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 increa...

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

    Directory of Open Access Journals (Sweden)

    Saul Shiffman

    2015-10-01

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

  3. The treatment of acetaminophen poisoning

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-01-01

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

  4. Efficacy and Safety of Duloxetine in Patients with Chronic Low Back Pain Who Used versus Did Not Use Concomitant Nonsteroidal Anti-Inflammatory Drugs or Acetaminophen: A Post Hoc Pooled Analysis of 2 Randomized, Placebo-Controlled Trials

    Directory of Open Access Journals (Sweden)

    Vladimir Skljarevski

    2012-01-01

    Full Text Available This subgroup analysis assessed the efficacy of duloxetine in patients with chronic low back pain (CLBP who did or did not use concomitant nonsteroidal anti-inflammatory drugs (NSAIDs or acetaminophen (APAP. Data were pooled from two 13-week randomized trials in patients with CLBP who were stratified according to NSAID/APAP use at baseline: duloxetine NSAID/APAP user (=137, placebo NSAID/APAP user (=82, duloxetine NSAID/APAP nonuser (=206, and placebo NSAID/APAP nonuser (=156. NSAID/APAP users were those patients who took NSAID/APAP for at least 14 days per month during 3 months prior to study entry. An analysis of covariance model that included therapy, study, baseline NSAID/APAP use (yes/no, and therapy-by-NSAID/APAP subgroup interaction was used to assess the efficacy. The treatment-by-NSAID/APAP use interaction was not statistically significant (=0.31 suggesting no substantial evidence of differential efficacy for duloxetine over placebo on pain reduction or improvement in physical function between concomitant NSAID/APAP users and non-users.

  5. Drug-induced hepatitis

    Science.gov (United States)

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  6. Intravenous paracetamol (acetaminophen).

    Science.gov (United States)

    Duggan, Sean T; Scott, Lesley J

    2009-01-01

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

  7. Transcriptomic studies on liver toxicity of acetaminophen.

    Science.gov (United States)

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

    2014-09-01

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

  8. Design of sustained release fine particles using two-step mechanical powder processing: particle shape modification of drug crystals and dry particle coating with polymer nanoparticle agglomerate.

    Science.gov (United States)

    Kondo, Keita; Ito, Natsuki; Niwa, Toshiyuki; Danjo, Kazumi

    2013-09-10

    We attempted to prepare sustained release fine particles using a two-step mechanical powder processing method; particle-shape modification and dry particle coating. First, particle shape of bulk drug was modified by mechanical treatment to yield drug crystals suitable for the coating process. Drug crystals became more rounded with increasing rotation speed, which demonstrates that powerful mechanical stress yields spherical drug crystals with narrow size distribution. This process is the result of destruction, granulation and refinement of drug crystals. Second, the modified drug particles and polymer coating powder were mechanically treated to prepare composite particles. Polymer nanoparticle agglomerate obtained by drying poly(meth)acrylate aqueous dispersion was used as a coating powder. The porous nanoparticle agglomerate has superior coating performance, because it is completely deagglomerated under mechanical stress to form fine fragments that act as guest particles. As a result, spherical drug crystals treated with porous agglomerate were effectively coated by poly(meth)acrylate powder, showing sustained release after curing. From these findings, particle-shape modification of drug crystals and dry particle coating with nanoparticle agglomerate using a mechanical powder processor is expected as an innovative technique for preparing controlled-release coated particles having high drug content and size smaller than 100 μm.

  9. Development of an Isotope-Dilution Liquid Chromatography/Mass Spectrometric Method for the Accurate Determination of Acetaminophen in Tablets

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Hyun Ju; Kim, Byung Joo; Lee, Joon Hee; Hwang, Eui Jin [Korea Research Institute of Standards and Science, Daejeon (Korea, Republic of)

    2010-12-15

    Acetaminophen (N-acetyl-p-aminophenol) is one of the most popular analgesic and antipyretic drugs. An isotope dilution mass spectrometric method based on LC/MS was developed as a candidate reference method for the accurate determination of acetaminophen in pharmaceutical product. After spiking an isotope labeled acetaminophen (acetyl-{sup 13}C{sub 2}, {sup 15}Nacetaminophen) as an internal standard, tablet extracts were analyzed by LC/MS in a selected reaction monitoring (SRM) mode to detect ions at m/z 152→110 and m/z 155→111 for acetaminophen and acetyl-{sup 13}C{sub 2}, {sup 15}N-acetaminophen, respectively. The repeatability and reproducibility of the developed ID/LC-MS method were tested for the validation and assessment of metrological quality of the method.

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

    Science.gov (United States)

    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.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kalantari H

    2000-11-01

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

  13. Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug-polymer mixtures

    DEFF Research Database (Denmark)

    Priemel, Petra A; Laitinen, Riikka; Barthold, Sarah;

    2013-01-01

    Surface coverage may affect the crystallisation behaviour of amorphous materials. This study investigates crystallisation inhibition in powder mixtures of amorphous drug and pharmaceutical excipients. Pure amorphous indomethacin (IMC) powder and physical mixtures thereof with Eudragit(®) E...... aggregated on the surface of IMC particles, whereas Soluplus(®) particles did not. The drug particles developed multiple crystallites at their surface with subsequent crystal growth. The intimate contact between the surface agglomerated Eudragit(®) particles and drug is believed to inhibit crystallisation...

  14. Drug: D09999 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09999 Mixture, Drug Tramadol hydrochloride - acetaminophen mixt; Tramcet (TN) Tramadol hydr...ic biomarker: CYP2D6 [HSA:1565] Therapeutic category of drugs in Japan [BR:br08301] 1 Agents affecting nervo...yretics and analgesics, anti-inflammatory agents 1149 Others D09999 Tramadol hydrochloride - acetaminophen m...PIOIDS N02AX Other opioids N02AX52 Tramadol, combinations D09999 Tramadol hydrochloride - acetaminophen mixt PubChem: 135626720 ...

  15. Acute interstitial nephritis with acetaminophen and alcohol intoxication

    Directory of Open Access Journals (Sweden)

    Alexopoulou Iakovina

    2011-04-01

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

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

    Science.gov (United States)

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

    2016-09-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Ahmadpour-Mobarakeh, Leila; Nezamzadeh-Ejhieh, Alireza, E-mail: arnezamzadeh@iaush.ac.ir

    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 (K{sub s}) of 0.44 s{sup −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 190 μmol L{sup −1} of acetaminophen [r{sup 2} = 0.9979, r = 0.9989 (n = 10)] with a detection limit of 0.04 μmol L{sup −1}. The method was successfully applied to the analysis of acetaminophen in some drugs. - Highlights: • Modified carbon paste electrode with Co(II)-zeolite A improved the voltammetric current in determination of acetaminophen. • Modified electrode is applicable for acetaminophen in real samples. • The proposed method has good reproducibility and repeatability.

  18. Treatment of acetaminophen-induced hepatitis and fulminant hepatic failure with extracorporeal sorbent-based devices.

    Science.gov (United States)

    Ash, Stephen R; Caldwell, Cary A; Singer, Greg G; Lowell, Jeff A; Howard, Todd K; Rustgi, Vinod K

    2002-01-01

    When a patient with acetaminophen overdose arrives in the emergency room more than 14 hours after ingestion, the value of N-acetylcysteine is unproven and patient mortality is at least 10%. Anecdotal case reports have indicated benefit of extracorporeal detoxification of these late-arriving patients with acetaminophen overdose. We identified 10 patients with serious acetaminophen overdose, 8 that arrived in the emergency room 16 to 44 hours after acetaminophen overdose with plasma levels predicting severe hepatic toxicity, and 2 that arrived in the emergency room 8 to 12 hours after overdose but with exceedingly high levels. All patients developed severe hepatitis (mean peak alanine aminotransferase, 4,052; mean peak protime, 25 seconds). At 16 to 68 hours after overdose, the patients were treated for 4 to 6 hours with the Liver Dialysis System (Hemocleanse Inc, W. Lafayette, IN), a single-access hemodiabsorption system indicated for treatment of serious drug overdose and for treatment of hepatic encephalopathy. Acetaminophen levels fell an average of 73% during treatment. Treatment was repeated 24 or 48 hours later if acetaminophen was still measurable in plasma. All 10 patients recovered intrinsic liver function and general health, with liver enzymes starting to normalize 24 hours after treatment, and were discharged 3 to 7 days after overdose. No patient required liver transplant. Because market introduction of Liver Dialysis, there have been 40 more patients with acetaminophen-induced hepatotoxicity treated with Liver Dialysis. All have recovered liver function without long-term sequelae. Though most of these patients with already established hepatic toxicity from acetaminophen would recover without extracorporeal blood therapy, treatment with the Liver Dialysis System should assure recovery from acute hepatic failure, and may shorten the clinical course of the illness.

  19. Compound list: acetaminophen [Open TG-GATEs

    Lifescience Database Archive (English)

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

  20. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    Science.gov (United States)

    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.

  1. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability

    Directory of Open Access Journals (Sweden)

    Prakash Khadka

    2014-12-01

    Full Text Available Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.

  2. Preparation and Drug Release Mechanism in Vitro of Acetaminophen Nasal Thermosensitive Gel%对乙酰氨基酚鼻用温敏凝胶的制备及其体外释药机制研究

    Institute of Scientific and Technical Information of China (English)

    赵亮; 苏畅

    2012-01-01

    目的:制备对乙酰氨基酚鼻用温敏凝胶,并对其体外释药机制进行研究.方法:以单用15%、16%、18%、20%、25%泊洛沙姆407(P407),及5%、10%P407与1%、1.5%、2%、2.5%、3%、4%聚乙烯醇(PVA)混合为凝胶基质制备对乙酰氨基酚鼻用温敏凝胶,根据胶凝温度筛选P407和PVA的最佳处方浓度,考察该凝胶的体外累积溶蚀量和体外释药行为并进行释放模型零级动力学、一级动力学、Higuchi方程、Riguchi-Peppas方程拟合.结果:单独使用P407作为凝胶基质,最佳处方浓度为16%~20%,凝胶的溶蚀和体外释药行为均符合零级动力学方程特征;选择混合基质,最佳处方浓度P407为10%,PVA为3%、4%,凝胶的溶蚀符合零级动力学方程特征,而体外释药遵从Higuchi方程,为骨架扩散释放机制.结论:PVA可显著降低P407的用量.单独使用P407作为凝胶基质,药物体外释药受凝胶溶蚀控制;而对于混合基质凝胶,溶蚀对体外释药并非决定性影响因素.%OBJECTIVE: To prepare Acetaminophen nasal thermosensitive gel, and to study drug release of it in vitro. METHODS: 15%, 16%, 18%, 20%, 25% poloxamer 407 (P407) alone, 5% and 10% P407 mixed with 1%、1.5%,2%、2.5% 、3%、 4% PVA were used as thermosensitive materials for gel. The best concentration of P407 and PVA in formulation was selected according to the gelating temperature. Drug release behavior and accumulative erosion amount of gel in vitro were investigated, and zero-order, first-order, Higuchi and Riguchi-Peppas equations were fitted. RESULTS: When use P407 alone as gel matrix, optimal concentration of P407 was from 16% to 20% ; erosion and in vitro drug release of gel were in line with zero-order equation. When use P407 and PVA as gel matrix, the best formulation included optimal concentration of P407 was 10% and PVA was 3% or 4%; the erosion pattern of gel showed zero-order kinetic characteristics and drug release was in

  3. Core-shell composite particles composed of biodegradable polymer particles and magnetic iron oxide nanoparticles for targeted drug delivery

    Science.gov (United States)

    Oka, Chiemi; Ushimaru, Kazunori; Horiishi, Nanao; Tsuge, Takeharu; Kitamoto, Yoshitaka

    2015-05-01

    Core-shell composite particles with biodegradability and superparamagnetic behavior were prepared using a Pickering emulsion for targeted drug delivery based on magnetic guidance. The composite particles were composed of a core of biodegradable polymer and a shell of assembled magnetic iron oxide nanoparticles. It was found that the dispersibility of the nanoparticles is crucial for controlling the core-shell structure. The addition of a small amount of dispersant into the nanoparticle's suspension could improve the dispersibility and led to the formation of composite particles with a thin magnetic shell covering a polymeric core. The composite particles were also fabricated with a model drug loaded into the core, which was released via hydrolysis of the core under strong alkaline conditions. Because the core can also be biodegraded by lipase, this result suggests that the slow release of the drug from the composite particles should occur inside the body.

  4. Acetaminophen induces apoptosis in rat cortical neurons.

    Directory of Open Access Journals (Sweden)

    Inmaculada Posadas

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

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

    Directory of Open Access Journals (Sweden)

    Gholamreza Faridaalaee

    2015-05-01

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

  6. Autoprotection in acetaminophen intoxication in rats

    DEFF Research Database (Denmark)

    Dalhoff, K; Laursen, H; Bangert, K;

    2001-01-01

    Autoprotection by acetaminophen, i.e. increased resistance to toxic effects caused by pretreatment, is a well-known phenomenon. The purpose of the present work was to identify mechanisms for increased acetaminophen tolerance induced by pretreatment of rats. One group of female Wistar rats (pretre...

  7. Solubility of Acetaminophen in Some Alcohol Free Solvent Systems

    OpenAIRE

    H. Barzegar-Jalali; H Rafati

    1990-01-01

    In an attempt to formulate an alcohol free acetaminophen solution for use in pediatrics, the effect of different concentra¬tions of polyethylene glycol 400 (PEG 400 ) and polysorbate 80 ( Iween 80 ) on the solubility of the drug in water .as well as in the vehicles composed of (propylene glycol 10?o V/V + glycerol 20% V/V in water ) and (propylene glycol 12?o V/V + glycerol 40?o V/V in water ) was investigated at 20 C. There was a linear relationship between the logarithm of the drug ...

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

    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.

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

    Institute of Scientific and Technical Information of China (English)

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

    2010-01-01

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

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

    Science.gov (United States)

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

    2014-02-01

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

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

    Science.gov (United States)

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

    2015-10-01

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

  13. Core–shell composite particles composed of biodegradable polymer particles and magnetic iron oxide nanoparticles for targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Oka, Chiemi; Ushimaru, Kazunori [Department of Innovative and Engineered Materials, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502 (Japan); Horiishi, Nanao [Bengala Techno Laboratory, 9-5-1006, 1-1 Kodai, Miyamae-ku, Kawasaki 216-0007 (Japan); Tsuge, Takeharu [Department of Innovative and Engineered Materials, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502 (Japan); Kitamoto, Yoshitaka, E-mail: kitamoto.y.aa@m.titech.ac.jp [Department of Innovative and Engineered Materials, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502 (Japan)

    2015-05-01

    Core–shell composite particles with biodegradability and superparamagnetic behavior were prepared using a Pickering emulsion for targeted drug delivery based on magnetic guidance. The composite particles were composed of a core of biodegradable polymer and a shell of assembled magnetic iron oxide nanoparticles. It was found that the dispersibility of the nanoparticles is crucial for controlling the core–shell structure. The addition of a small amount of dispersant into the nanoparticle's suspension could improve the dispersibility and led to the formation of composite particles with a thin magnetic shell covering a polymeric core. The composite particles were also fabricated with a model drug loaded into the core, which was released via hydrolysis of the core under strong alkaline conditions. Because the core can also be biodegraded by lipase, this result suggests that the slow release of the drug from the composite particles should occur inside the body. - Highlights: • Core−shell composites with biodegradability and magnetism are prepared. • O/W emulsion stabilized by iron oxide nanoparticles is utilized for the preparation. • The nanoparticle's dispersibility is crucial for controlling the composite structure. • Composites loading a model drug are also prepared. • The model drug is released with decomposition of the composites.

  14. Potentiation of cadmium nephrotoxicity by acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

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

    1988-10-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  17. Acetaminophen toxicity with concomitant use of carbamazepine.

    Science.gov (United States)

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

    2009-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Sudip Paul

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    M Mathew

    2011-01-01

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

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

    Science.gov (United States)

    Rybolt, Thomas R.; And Others

    1988-01-01

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

  1. Raman identification of drug of abuse particles collected with colored and transparent tapes.

    Science.gov (United States)

    Moreno, Victor Molina; López-López, María; Atoche, Juan-Carlos; García-Ruiz, Carmen

    2014-03-01

    Raman microscopy is a useful tool for the analysis of drug particles collected with adhesive tapes. In this work, first, the spectra of thirty drugs of abuse, degradation products, metabolites, and common cutting agent standards were recorded and the Raman bands observed were summarized providing the forensic analyst useful information for the identification of drug evidence. Then, the collection of different drug particles by a fingerprint lifting tape commonly used to remove and store fingerprints and fibers, and a white and green packaging tape, followed by the subsequent identification of the drugs by confocal Raman spectroscopy was performed. The particles were analyzed on top of the tapes, trapped between glass slides and the tapes, trapped in the tape folded over itself in the case of the transparent tape, and after folding and unfolding the tape in the case of the colored tape. The results obtained by the different approaches show that both tapes did not compromise the drugs spectra. However, the use of transparent tape is preferred because this tape allows the previous visual detection of the particles. Finally, several drug and sugar particles were spread over a clean table and inside a pocket, and the particles were collected with transparent tape and then properly identified. Although good results were obtained in both cases, the amount of fibers and other substances present in the collection area made the previous detection of the particles difficult and increases the analysis time.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-05-15

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

  3. Preparation and drug releasing property of magnetic chitosan-5-fluorouracil nano-particles

    Institute of Scientific and Technical Information of China (English)

    WANG Dong-sheng; LI Jian-guo; LI He-ping; TANG Fa-qing

    2009-01-01

    In order to synthesize the targeting drug carrier system, magnetic chitosan-5-fluorouracil nano-particles were prepared by using 5-fluorouracil (5-Fu) as model drug, Fe_3O_4 nano-particles as kernel, chitosan as enveloping material and glutaraldehyde as cross linking agent through ultrasonic technique. The morphology of the magnetic chitosan-5-Fu nano-particles was observed with a transmission electron microscope(TEM). The results showed that magnetic chitosan-5-Fu nano-particles were prepared in spherical structure with a size range of 50-60 nm. The delivering capacity and drug releasing properties of magnetic chitosan-5-Fu nano-particles were investigated by UV-vis spectrum analysis. The results showed that the loading capacity was 13.4% and the cumulative release percentage in the phosphate buffer (pH=7.2) solutions was 68% in 30 h. These data indicate that the wrapped drug of magnetic chitosan-5-Fu nano-particles was slowly-released. The magnetic response of magnetic chitosan-5-Fu nano-particles was studied by UV-vis spectrometer to detect the changes of solution absorbance. Without external magnetic field, the nano-particle deposition rate was slow. When being subjected to 8 mT magnetic field, the particle sedimentation rate was increased rapidly. The results showed that magnetic chitosan-5-Fu nano-particles have a magnetic stability and strong targeting characteristics.

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

    Science.gov (United States)

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

    2015-09-01

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

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

    Science.gov (United States)

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

    2009-08-01

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

  6. Don't Double Up on Acetaminophen

    Science.gov (United States)

    ... For Consumers Home For Consumers Consumer Updates Don't Double Up on Acetaminophen Share Tweet Linkedin Pin ... consumer organizations. AAC’s outreach campaign, "Double Check, Don't Double Up," is all about the safe use ...

  7. Pharm GKB: acetaminophen [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available . These individuals are poor metabolizers of debrisoquine, dextromethorphan, tricyclic antidepressants, amon...ion, dependence, tolerance and withdrawal. Acetaminophen is used on its own or in combination with pseudoephedrine, dextromethorphan

  8. Deafness associated with acetaminophen and codeine abuse.

    Science.gov (United States)

    Blakley, Brian W; Schilling, Heather

    2008-08-01

    Ototoxicity associated with narcotic-acetaminophen combinations is not widely recognized. This can be the cause of severe-to-profound hearing loss that may be overlooked. Otolaryngologists who encounter patients with progressive hearing loss with no apparent cause should specifically ask about overuse of medications containing acetaminophen and a narcotic. Many patients feel that this form of medication is "safe" because it can be purchased over-the-counter.

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

    Science.gov (United States)

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

    2011-01-01

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

  10. Microfabricated engineered particle systems for respiratory drug delivery and other pharmaceutical applications.

    Science.gov (United States)

    Garcia, Andres; Mack, Peter; Williams, Stuart; Fromen, Catherine; Shen, Tammy; Tully, Janet; Pillai, Jonathan; Kuehl, Philip; Napier, Mary; Desimone, Joseph M; Maynor, Benjamin W

    2012-01-01

    Particle Replication in Non-Wetting Templates (PRINT(®)) is a platform particle drug delivery technology that coopts the precision and nanoscale spatial resolution inherently afforded by lithographic techniques derived from the microelectronics industry to produce precisely engineered particles. We describe the utility of PRINT technology as a strategy for formulation and delivery of small molecule and biologic therapeutics, highlighting previous studies where particle size, shape, and chemistry have been used to enhance systemic particle distribution properties. In addition, we introduce the application of PRINT technology towards respiratory drug delivery, a particular interest due to the pharmaceutical need for increased control over dry powder characteristics to improve drug delivery and therapeutic indices. To this end, we have produced dry powder particles with micro- and nanoscale geometric features and composed of small molecule and protein therapeutics. Aerosols generated from these particles show attractive properties for efficient pulmonary delivery and differential respiratory deposition characteristics based on particle geometry. This work highlights the advantages of adopting proven microfabrication techniques in achieving unprecedented control over particle geometric design for drug delivery.

  11. Microfabricated Engineered Particle Systems for Respiratory Drug Delivery and Other Pharmaceutical Applications

    Directory of Open Access Journals (Sweden)

    Andres Garcia

    2012-01-01

    Full Text Available Particle Replication in Non-Wetting Templates (PRINT® is a platform particle drug delivery technology that coopts the precision and nanoscale spatial resolution inherently afforded by lithographic techniques derived from the microelectronics industry to produce precisely engineered particles. We describe the utility of PRINT technology as a strategy for formulation and delivery of small molecule and biologic therapeutics, highlighting previous studies where particle size, shape, and chemistry have been used to enhance systemic particle distribution properties. In addition, we introduce the application of PRINT technology towards respiratory drug delivery, a particular interest due to the pharmaceutical need for increased control over dry powder characteristics to improve drug delivery and therapeutic indices. To this end, we have produced dry powder particles with micro- and nanoscale geometric features and composed of small molecule and protein therapeutics. Aerosols generated from these particles show attractive properties for efficient pulmonary delivery and differential respiratory deposition characteristics based on particle geometry. This work highlights the advantages of adopting proven microfabrication techniques in achieving unprecedented control over particle geometric design for drug delivery.

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

    Science.gov (United States)

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

    2014-09-01

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

  13. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2014-01-01

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

  15. Supercritical fluid particle design for poorly water-soluble drugs (review).

    Science.gov (United States)

    Sun, Yongda

    2014-01-01

    Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water-soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio-drug particles) to improve solubility and dissolution rate of poorly water-soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review.

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

    Science.gov (United States)

    ... html Acetaminophen During Pregnancy May Up Risk of ADHD in Kids But only association found, and researchers ... their child will develop behavioral problems such as attention-deficit/hyperactivity disorder (ADHD), a new study suggests. Acetaminophen is generally ...

  17. [Effect of paracetamol (acetaminophen) on blood pressure in patients with coronary heart disease].

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2013-11-01

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

  19. Flash nanoprecipitation: prediction and enhancement of particle stability via drug structure.

    Science.gov (United States)

    Zhu, Zhengxi

    2014-03-01

    Flash nanoprecipitation (FNP) can generate hydrophobic drug nanoparticles in ∼ 100 nm with a much higher drug loading (e.g., > 40 wt %) than traditional nanocarriers (e.g., FNP and demonstrates that chemically bonding a drug compound (e.g., paclitaxel) with a cleavable hydrophobic moiety of organosilicate (e.g., triethoxysilicate) is able to enhance the particle size stability. A nonionic amphiphilic diblock copolymer, poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG), is used as a model surfactant to provide steric stabilization. The experiments here show that the lower the drug solubility in the aqueous medium, the more stable the particles in terms of Ostwald ripening, which are consistent with the prediction by the LSW theory. The initial particle size distribution is sufficiently narrow and of insignificance to Ostwald ripening. To correlate the particle stability with hydrophobicity, this study introduces the n-octanol/water partition coefficient (LogP), a hydrophobicity indication, into the FNP technique. A comparison of various drugs and their analogues shows that LogP of a drug is a better hydrophobicity indication than the solubility parameter (δ) and correlates well with the particle stability. Empirically, with ACDLogP > ∼ 12, nanoparticles have good stability; with ∼ 2 < ACDLogP < ∼ 9, nanoparticles show fast Ostwald ripening and interparticle recrystallization; with ACDLogP < ∼ 2, the drug is very likely difficult to form nanoparticles. This rule creates a quick way to predict particle stability for a randomly selected drug structure and helps to enable a fast preclinical drug screen.

  20. Transplacental Passage of Acetaminophen in Term Pregnancy.

    Science.gov (United States)

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

    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.

  1. Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug-polymer mixtures.

    Science.gov (United States)

    Priemel, Petra A; Laitinen, Riikka; Barthold, Sarah; Grohganz, Holger; Lehto, Vesa-Pekka; Rades, Thomas; Strachan, Clare J

    2013-11-18

    Surface coverage may affect the crystallisation behaviour of amorphous materials. This study investigates crystallisation inhibition in powder mixtures of amorphous drug and pharmaceutical excipients. Pure amorphous indomethacin (IMC) powder and physical mixtures thereof with Eudragit(®) E or Soluplus(®) in 3:1, 1:1 and 1:3 (w/w) ratios were stored at 30 °C and 23 or 42% RH. Samples were analysed during storage by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and scanning electron microscopy (SEM). IMC Eudragit(®) mixtures showed higher physical stability than pure IMC whereas IMC Soluplus(®) mixtures did not. Water uptake was higher for mixtures containing Soluplus(®) than for amorphous IMC or IMC Eudragit(®) mixtures. However, the Tg of amorphous IMC was unaffected by the presence (and nature) of polymer. SEM revealed that Eudragit(®) particles aggregated on the surface of IMC particles, whereas Soluplus(®) particles did not. The drug particles developed multiple crystallites at their surface with subsequent crystal growth. The intimate contact between the surface agglomerated Eudragit(®) particles and drug is believed to inhibit crystallisation through reduced IMC surface molecular mobility. Polymer particles may also mechanically hinder crystal growth outwards from the surface. This work highlights the importance of microparticulate surface coverage of amorphous drug particles on their stability.

  2. Microfluidic-Based Synthesis of Hydrogel Particles for Cell Microencapsulation and Cell-Based Drug Delivery

    Directory of Open Access Journals (Sweden)

    Jiandi Wan

    2012-04-01

    Full Text Available Encapsulation of cells in hydrogel particles has been demonstrated as an effective approach to deliver therapeutic agents. The properties of hydrogel particles, such as the chemical composition, size, porosity, and number of cells per particle, affect cellular functions and consequently play important roles for the cell-based drug delivery. Microfluidics has shown unparalleled advantages for the synthesis of polymer particles and been utilized to produce hydrogel particles with a well-defined size, shape and morphology. Most importantly, during the encapsulation process, microfluidics can control the number of cells per particle and the overall encapsulation efficiency. Therefore, microfluidics is becoming the powerful approach for cell microencapsulation and construction of cell-based drug delivery systems. In this article, I summarize and discuss microfluidic approaches that have been developed recently for the synthesis of hydrogel particles and encapsulation of cells. I will start by classifying different types of hydrogel material, including natural biopolymers and synthetic polymers that are used for cell encapsulation, and then focus on the current status and challenges of microfluidic-based approaches. Finally, applications of cell-containing hydrogel particles for cell-based drug delivery, particularly for cancer therapy, are discussed.

  3. Behavior of silica particles introduced into an isolated rat heart as potential drug carriers

    Energy Technology Data Exchange (ETDEWEB)

    Borak, B [Institute of Material Sciences and Applied Mechanics, Wroclaw University of Technology, Smoluchowskiego 25, 50-370 Wroclaw (Poland); Arkowski, J [Chair and Department of Cardiology, Medical University of Wroclaw, Pasteura 4, 50-367 Wroclaw (Poland); Skrzypiec, M [Chair and Department of Pharmacology, Medical University of Wroclaw, Mikulicza-Radeckiego 2, 50-345 Wroclaw (Poland); Ziolkowski, P [Chair and Department of Patomorphology, Medical University of Wroclaw, Marcinkowskiego 1, 50-368 Wroclaw (Poland); Krajewska, B [Chair and Department of Histology, Medical University of Wroclaw, Chalubinskiego 6a, 50-369 Wroclaw (Poland); Wawrzynska, M [Chair and Department of Cardiology, Medical University of Wroclaw, Pasteura 4, 50-367 Wroclaw (Poland); Grotthus, B [Chair and Department of Pharmacology, Medical University of Wroclaw, Mikulicza-Radeckiego 2, 50-345 Wroclaw (Poland); Gliniak, H [Chair and Department of Pharmacology, Medical University of Wroclaw, Mikulicza-Radeckiego 2, 50-345 Wroclaw (Poland); Szelag, A [Chair and Department of Pharmacology, Medical University of Wroclaw, Mikulicza-Radeckiego 2, 50-345 Wroclaw (Poland); Mazurek, W [Chair and Department of Cardiology, Medical University of Wroclaw, Pasteura 4, 50-367 Wroclaw (Poland); Bialy, D [Chair and Department of Cardiology, Medical University of Wroclaw, Pasteura 4, 50-367 Wroclaw (Poland); Maruszewski, K [Institute of Material Sciences and Applied Mechanics, Wroclaw University of Technology, Smoluchowskiego 25, 50-370 Wroclaw (Poland)

    2007-12-15

    Silica powders consisting of small spherical particles (50-200 nm) have been obtained by the sol-gel method. A suspension of such particles in the Krebs-Hanseleit solution has been introduced into the coronary circulation of a beating perfused rat heart. The influence of the suspension on the heart muscle and the coronary vessels in the rat body has been histopathologically examined. The particles have not left the lumen of the vessels and have not caused any side effects. These observations suggest the possibility of using such silica particles as a carrier for selected drugs.

  4. Irbesartan drug formulated as nanocomposite particles for the enhancement of the dissolution rate

    Institute of Scientific and Technical Information of China (English)

    Zhiliang Zhang; Yuan Le; Jiexin Wang; Hong Zhao; Jianfeng Chen

    2012-01-01

    Irbesartan (IBS),an angiotensin Ⅱ receptor antagonist,is a poorly water-soluble drug.To enhance the dissolution rate,IBS nanocomposite particles were produced via an anti-solvent precipitation combined with a spray drying process.Four pharmaceutically acceptable excipients,including three different polymers and one charged surfactant,were evaluated as stabilizers to control the particle size and to prevent the agglomeration of particles.The experiment results indicated that polyvinylpyrrolidone (PVP) combined with sodium dodecyl sulfate (SDS) significantly decreased the particle size and enhanced the stability of drug nanoparticles.As a result,we finally obtained stable IBS nanoparticles with an average size of approximately 55 nm.In the dissolution test,the IBS nanocomposite particles showed a significantly enhanced dissolution rate and 100% of the drug dissolved within 20 min.In contrast,the physical mixture with the same recipe as the IBS nanocomposite particles and the raw IBS reached only 8% and 40% of drug dissolved in 20 min,respectively,and both of them did not dissolve completely,even after 120 min.

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

    Science.gov (United States)

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

    2017-02-01

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

  6. Effect of supercritical fluid density on nanoencapsulated drug particle size using the supercritical antisolvent method.

    Science.gov (United States)

    Kalani, Mahshid; Yunus, Robiah

    2012-01-01

    The reported work demonstrates and discusses the effect of supercritical fluid density (pressure and temperature of supercritical fluid carbon dioxide) on particle size and distribution using the supercritical antisolvent (SAS) method in the purpose of drug encapsulation. In this study, paracetamol was encapsulated inside L-polylactic acid, a semicrystalline polymer, with different process parameters, including pressure and temperature, using the SAS process. The morphology and particle size of the prepared nanoparticles were determined by scanning electron microscopy and transmission electron microscopy. The results revealed that increasing temperature enhanced mean particle size due to the plasticizing effect. Furthermore, increasing pressure enhanced molecular interaction and solubility; thus, particle size was reduced. Transmission electron microscopy images defined the internal structure of nanoparticles. Thermal characteristics of nanoparticles were also investigated via differential scanning calorimetry. Furthermore, X-ray diffraction pattern revealed the changes in crystallinity structure during the SAS process. In vitro drug release analysis determined the sustained release of paracetamol in over 4 weeks.

  7. Effects of phosphate buffer in parenteral drugs on particle formation from glass vials.

    Science.gov (United States)

    Ogawa, Toru; Miyajima, Makoto; Wakiyama, Naoki; Terada, Katsuhide

    2013-01-01

    The characteristics of inorganic particles generated in glass vials filled with phosphate buffer solutions were investigated. During storage, particles were visually detected in the phosphate buffer solution in particular glass vials which pass compendial tests of containers for injectable drugs. These particles were considered to be different from ordinal glass delamination, which has been reported in a number of papers because the particles were mainly composed of Al, P and O, but not Si. The formation of the particles accelerated at higher storage temperatures. Among the surface treatments tested for the glass vials, sulfur treatment showed a protective effect on the particle formation in the vials, whereas the SiO(2) coating did not have any protective effects. It was found that the elution ratio of Al and Si in the solution stored in the glass vials after the heating was similar to the ratio of Al and Si in borosilicate glass. However, the Al concentration decreased during storage (5°C, 6 months), and consequently, particle formation was observed in the solution. Adding citrate, which is a chelating agent for Al, effectively suppressed the particle formation in the heated solution. When 50 ppb and higher concentrations of Al ion were added to the phosphate buffer solution, the formation of white particles containing Al, P and O was detected. It is suggested that a phosphate buffer solution in a borosilicate glass vial has the ability to form particles due to interactions with the Al that is eluted from the glass during storage.

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

    Science.gov (United States)

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

    2015-08-01

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

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

    Science.gov (United States)

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

    2010-06-01

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

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

    Science.gov (United States)

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

    Science.gov (United States)

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

    2008-01-01

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

  12. A sensor for acetaminophen in a blood medium using a Cu(II)-conducting polymer complex modified electrode

    Energy Technology Data Exchange (ETDEWEB)

    Boopathi, Mannan; Won, Mi-Sook; Shim, Yoon-Bo

    2004-06-11

    Complexation of Cu ions in a terthiophene carboxylic acid (TTCA) polymer film resulted an enhanced anodic current for acetaminophen oxidation when compared to polymer coated and bare glassy carbon electrodes in human blood and buffer media. Scanning electron microscopy (SEM) and ESCA experiments indicate the involvement of copper in the electrocatalytic oxidation of acetaminophen. No interference was observed from other biologically important and phenolic compounds used with this modified electrode. Especially, the non-interference from N-acetylcysteine, an antidote for the treatment of acetaminophen poisoning, reveals the proposed method's superiority in medicinal applications. In addition, the present modified electrode avoids surface fouling at higher concentrations of acetaminophen. The calibration range obtained with CV was based between 2.0x10{sup -5} and 5.0x10{sup -3} M [r{sup 2}=0.997 (n=5, R.S.D.=2.5%); DL=5.0x10{sup -6} M (S/N=3)]. The analytical utility of the modified electrode was achieved by analyzing the content of acetaminophen in different drugs without pretreatment using CV and amperometric techniques.

  13. Effects of the analgesic acetaminophen (Paracetamol) and its para-aminophenol metabolite on viability of mouse-cultured cortical neurons.

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Ngozi N Imasogie

    2009-01-01

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

  15. Biodegradable particle formation for drug and gene delivery using supercritical fluid and dense gas.

    Science.gov (United States)

    Mishima, Kenji

    2008-02-14

    Recent developments in biodegradable particle formation using supercritical fluids and dense gases have been reviewed with an emphasis on studies of micronizing and encapsulating poorly-soluble pharmaceuticals and gene. General review articles published in previous years have then been provided. A brief description of the operating principles of some types of particle formation processes is given. These include the rapid expansion of supercritical solutions (RESS), the particles from gas-saturated solution (PGSS) processes, the gas antisolvent process (GAS), and the supercritical antisolvent process (SAS). The papers have been reviewed under two groups, one involving the production of particles from pure biodegradable substances, and the other involving coating, capsule, and impregnation that contain active components, especially those that relate to pharmaceuticals. This review is a comprehensive review specifically focused on the formation of biodegradable particles for drug and gene delivery system using supercritical fluid and dense gas.

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

    Science.gov (United States)

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

    2016-06-01

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

  17. Microfluidic conceived drug loaded Janus particles in side-by-side capillaries device.

    Science.gov (United States)

    Khan, Ikram Ullah; Serra, Christophe A; Anton, Nicolas; Li, Xiang; Akasov, Roman; Messaddeq, Nadia; Kraus, Isabelle; Vandamme, Thierry F

    2014-10-01

    A side-by-side capillaries microfluidic device was developed to fabricate drug loaded poly(acrylamide)/poly(methyl acrylate) Janus particles in the range of 59-240 μm by UV-assisted free radical polymerization. This system was characterized in terms of continuous and dispersed phases flow rates (Qc/Qd), monomer composition of the two compartments, surfactant nature and concentration, outlet tube diameter and UV intensity. These factors were adequately controlled to get different particle shapes ranging from core-shell to bi-compartmental particles. For the latter, a low surfactant concentration (0.75 wt.%) was necessary when the two dispersed phases were pumped at equal flow rate, while at high surfactant concentration, dispersed phases flow rates have to be changed. FTIR analysis suggested complete polymerization of monomers and cytotoxicity test showed these particles were biocompatible having LD 50 of 9 mg/mL. Both ketoprofen and sodium fluorescein were released in sustained release manner at pH 6.8 by following a diffusion type release mechanism. Drug release was faster for bigger particles and found to result from the irregular distribution of the two phases and indentation on bigger particles as revealed by SEM analysis. In comparison, sodium fluorescein release was slower which was attributed to low encapsulation but could be modified by decreasing crosslinker concentration.

  18. Porous Silica-Supported Solid Lipid Particles for Enhanced Solubilization of Poorly Soluble Drugs.

    Science.gov (United States)

    Yasmin, Rokhsana; Rao, Shasha; Bremmell, Kristen E; Prestidge, Clive A

    2016-07-01

    Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.

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

    Science.gov (United States)

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

    2016-01-22

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

  20. Study on Preparation and in Vitro Drug Release of Acetaminophen/Acacia-chitosan Multilayer Microcapsule%对乙酰氨基酚/阿拉伯胶-壳聚糖多层微囊的制备及其体外释药研究

    Institute of Scientific and Technical Information of China (English)

    赵亮; 苏畅; 崔腾

    2012-01-01

    OBJECTIVE: To prepare Acetaminophen multilayer microcapsules and to investigate drug release property and mechanism of it. METHODS: Drug-loading (acetaminophen) multilayer (acacia-chitosan-acacia-chitosan) microcapsules were prepared by solution drying method (complex emulsion method) using chitosan and acacia as coating materials and glutaraldehyde as crosslinking agent. The preparation technology was optimized by orthogonal test with volume ratio of acacia solution to dichloro-methane (A), amount of chitosan (B), ratio of glutaraldehyde volume to total mass of coating material as factors and encapsulation efficiency as index. Drug release kinetic model was fitted and drug release mechanism was discussed by determining accumulative drug release rate in HC1 solution. RESULTS: The optimal preparation process was A 4:3, B 0.6 g and C 1:3. Prepared multilayer microcapsules were round completely and smooth with thick capsule wall. Significant burst effect was not found. The multilayer microcapsules released in 12 h completely, which followed Ritger-Peppas model. CONCLUSION: Prepared drug-loading multilayer microcapsules demonstrate lower burst release and longer drug delivery.%目的:制备对乙酰氨基酚多层微囊并考察其体外释药性能和机制.方法:以阿拉伯胶和壳聚糖为囊材,以戊二醛为交联剂,使用溶液干燥法(复合乳液法)制备载药(对乙酰氨基酚)多层(阿拉伯胶-壳聚糖-阿拉伯胶-壳聚糖)微囊.通过正交试验,以阿拉伯胶溶液-二氯甲烷体积比(A)、壳聚糖用量(B)、戊二醛-成壳材料总量比例(C)为因素,包封率为指标,优选制备工艺.通过测定其在盐酸溶液中的体外累积释药率并进行释放动力学模型拟合分析其释药机制.结果:最佳工艺条件为A4:3、B0.6 g、C1:3.所制备的多层微囊球形完整、光滑,囊壁较厚;突释效果不明显,药物在12h内全部释放,其体外释药机制符合Ritger-Peppas模型.结论:所制载药多层微

  1. Solubility of Acetaminophen in Some Alcohol Free Solvent Systems

    Directory of Open Access Journals (Sweden)

    H. Barzegar-Jalali

    1990-07-01

    Full Text Available In an attempt to formulate an alcohol free acetaminophen solution for use in pediatrics, the effect of different concentra¬tions of polyethylene glycol 400 (PEG 400 and polysorbate 80 ( Iween 80 on the solubility of the drug in water .as well as in the vehicles composed of (propylene glycol 10?o V/V + glycerol 20% V/V in water and (propylene glycol 12?o V/V + glycerol 40?o V/V in water was investigated at 20 C. There was a linear relationship between the logarithm of the drug solubility and volume fraction of PEG 400 in the vehicles. Also, a linear relation was established between the solubility of the drug in water and the volume fraction of Tween 80. After the solubilization studies, the appropriate concentration of the cosolvents and Tween 80 were chosen for the tolerance test of the solutions at a low temperature (4 C against crystalization. These studies led us to propose two alcohol free drug solutions with suitable sweetening and flavoring agents. Properties of the products including a simple method of determination of drug concentration, density and viscosity measure¬ments have been also reported.

  2. Acetaminophen toxicity and resistance in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Srikanth, Chittur V; Chakraborti, Asit K; Bachhawat, Anand K

    2005-01-01

    Acetaminophen (paracetamol), one of the most widely used analgesics, is toxic under conditions of overdose or in certain disease conditions, but the mechanism of acetaminophen toxicity is still not entirely understood. To obtain fresh insights into acetaminophen toxicity, this phenomenon was investigated in yeast. Acetaminophen was found to be toxic to yeast cells, with erg mutants displaying hypersensitivity. Yeast cells grown in the presence of acetaminophen were found to accumulate intracellular acetaminophen, but no metabolic products of acetaminophen could be detected in these extracts. The toxicity response did not lead to an oxidative stress response, although it did involve Yap1p. The cytochrome P450 enzymes of yeast, Erg5p and Erg11p, did not appear to participate in this process, unlike the mammalian systems. Furthermore, we could not establish a central role for glutathione depletion or the cellular glutathione redox status in acetaminophen toxicity, suggesting differences from mammalian systems in the pathways causing toxicity. Investigations of the resistance mechanisms revealed that deletion of the glutathione-conjugate pumps Ycf1p (a target of Yap1p) and Bpt1p, surprisingly, led to acetaminophen resistance, while overexpression of the multidrug resistance pumps Snq2p and Flr1p (also targets of Yap1p) led to acetaminophen resistance. The Yap1p-dependent resistance to acetaminophen required a functional Pdr1p or Pdr3p protein, but not a functional Yrr1p. In contrast, resistance mediated by Pdr1p/Pdr3p did not require a functional Yap1p, and revealed a distinct hierarchy in the resistance to acetaminophen.

  3. Vinyl polymer-coated lorazepam particles for drug delivery to the airways.

    Science.gov (United States)

    Traynor, Matthew J; Zhao, Yanjun; Brown, Marc B; Jones, Stuart A

    2011-05-30

    A particle engineering method that adsorbs a microfine vinyl polymer coat to crystalline drug microparticles has been shown to be an effective way to control delivery. However, the means by which the functional performance of such microparticles is altered by the behaviour of the polymers in the microparticle coat remains unclear. The aim of this study was to determine the influence of vinyl polymer coating on the in vitro delivery characteristics of intranasal lorazepam microparticles. A series of four, similarly sized (ca. 10 μm), lorazepam-rich microparticles with different polymer coats were generated. The absorption of the polymer coats appeared to disrupt lorazepam solid state dimer formation in the microparticles, which manifested in a reduction in drug melting point. Mildly cohesive particles (aerodynamic diameter of 32 μm) that allowed rapid drug release (ca. 80% in 5 min) were generated when partially hydrolysed PVA dominated the microparticle coat, whilst fully hydrolysed PVA reduced particle cohesion and retarded drug release (ca. 15% release in 5 min). Infrared analysis showed that the properties of the microparticles were dictated by the strength of the hydrogen bonding in the polymer coat and not the strength of coat adsorption that was facilitated by hydrogen bond formation between the hydroxyl groups of the PVA and the hydroxyl group at position C3 of the lorazepam diazepine ring.

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

    Directory of Open Access Journals (Sweden)

    Judge Bryan S

    2011-03-01

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

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

    Science.gov (United States)

    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)

  6. Apoferritin Modified Magnetic Particles as Doxorubicin Carriers for Anticancer Drug Delivery

    Directory of Open Access Journals (Sweden)

    Vojtech Adam

    2013-06-01

    Full Text Available Magnetic particle mediated transport in combination with nanomaterial based drug carrier has a great potential for targeted cancer therapy. In this study, doxorubicin encapsulation into the apoferritin and its conjugation with magnetic particles was investigated by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF. The quantification of encapsulated doxorubicin was performed by fluorescence spectroscopy and compared to CE-LIF. Moreover, the significant enhancement of the doxorubicin signal was observed by addition of methanol into the sample solution.

  7. Particle contamination of parenteralia and in-line filtration of proteinaceous drugs.

    Science.gov (United States)

    Werner, Benjamin Patrick; Winter, Gerhard

    2015-12-30

    Protein drug products play an important role in the treatment of severe diseases. However, due to the instability of these complex molecules, protein aggregates can form which can compromise drug safety and efficacy including immunogenic reactions. In-line filtration during the administration of these drugs can serve as a final safeguarding step to protect patients from risks associated with proteinaceous particles. A unique analysis of more than 300 marketed protein drug products revealed that already around 16% of all these products are filtered during preparation or administration. Further, the research revealed that no standardized filtration practice exists. Broad variances regarding filter membrane or pore size are found and sometimes no specifications are mentioned at all. The benefits as well as possible negative impacts of filtration like filter shedding, extractables or drug adsorption are critically assessed. Several proposals to improve the current filtration practice and to expand the number of in-line filtered protein drug products are made. The suggestions include the demand for the specific usage of one filter membrane type, the establishment of a filtration routine for unfiltered protein drugs and a statistical analysis between filtered and non-filtered products with similar formulations to identify possible differences in the immunogenicity rate.

  8. Expression of liver-specific functions in rat hepatocytes following sublethal and lethal acetaminophen poisoning

    DEFF Research Database (Denmark)

    Tygstrup, N; Jensen, S A; Krog, B;

    1996-01-01

    AIM: In order to study the short-term effect of moderate and severe reduction of liver function by acetaminophen poisoning of different severity on gene expression for liver-specific functions, rats were given 3.75 and 7.5 g per kg body weight acetaminophen intragastrically. The lower dose...... involved in metabolic liver functions, i.e. ureagenesis, gluconeogenesis, and drug metabolism, for acute phase proteins, "house-keeping" proteins, and for proteins related to liver regeneration. Results were expressed as per cent of the level in similarly fasted, untreated rats of the same stock RESULTS...... towards the end of the experiment. The greatest differences were seen for mRNA of arginase, beta-fibrinogen, alpha 1-acid glycoprotein, alpha-tubulin, histone 3, TGF beta, and cyclin d, i.e. proteins associated with acute phase response and liver cell replication and maintenance. CONCLUSIONS...

  9. Enteral exsorption of acetaminophen after intravenous injection in rats: influence of activated charcoal on this clearance path.

    Science.gov (United States)

    Eyer, Florian; Jung, Nicole; Neuberger, Heidi; Schulz, Roswitha; Steiner, Kurt; Ladstetter, Bernhard; Poethko, Thorsten; Henke, Julia; Zilker, Thomas

    2007-09-01

    The fate of acetaminophen after intravenous injection in whole bowel-irrigated rats (n = 40) and the influence of activated charcoal on the kinetics were investigated. After randomization to four groups (n = 10, each group), plasma concentration and the quantities of acetaminophen and metabolites excreted into bile, urine and intestine were determined using an in vivo model with or without orally administered activated charcoal and with or without bile duct cannulation. The cumulative amount of acetaminiphen and metabolites exsorbed into the small intestine within 3.5 hr after intravenous injection was about 20% of dose in the animals with bile duct cannulation and about 7% of dose in the animals without. Correspondingly, about 13% of dose was detected in the externalized bile. Activated charcoal did not influence the amount exsorbed into the small intestine. Terminal half-life in plasma ranged from 35 to 51 min. within the four treatment groups without statistically significant difference (P = 0.152). Correspondingly, the area under the curve did not vary much and ranged between 2.6 and 3.3 g/min./l (P = 0.392). Deposition of acetaminophen and metabolites in liver and kidney after 3.5 hr was marginal and ranged between 0.02% and 0.6% of the dose within all groups. The excretion of acetaminophen and metabolites into urine varied strikingly between 31% and 56% of the dose within all groups and correlated with diuresis. The lack of effect of activated charcoal on the elimination of acetaminophen and metabolites may be due to the small amount of the drug being exsorbed into the intestine or the reduced adsorbent capacity of activated charcoal to acetaminophen and metabolites, which also could be influenced by inadequate luminal stirring.

  10. The effect of carrier surface and bulk properties on drug particle detachment from crystalline lactose carrier particles during inhalation, as function of carrier payload and mixing time

    NARCIS (Netherlands)

    Dickhoff, B.H.J.; de Boer, Anne; Lambregts, D.; Frijlink, H.W.

    2003-01-01

    The effect of carrier payload and mixing time on the redispersion of drug particles from adhesive mixtures during inhalation for two different drugs (budesonide and disodium cromoglycate) has been investigated. A special test inhaler which retains carrier crystals during inhalation was used at 30 an

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

    Science.gov (United States)

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

    2015-01-01

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

  12. Role of particle size, shape, and stiffness in design of intravascular drug delivery systems: insights from computations, experiments, and nature.

    Science.gov (United States)

    Sen Gupta, Anirban

    2016-01-01

    Packaging of drug molecules within microparticles and nanoparticles has become an important strategy in intravascular drug delivery, where the particles are designed to protect the drugs from plasma effects, increase drug residence time in circulation, and often facilitate drug delivery specifically at disease sites. To this end, over the past few decades, interdisciplinary research has focused on developing biocompatible materials for particle fabrication, technologies for particle manufacture, drug formulation within the particles for efficient loading, and controlled release and refinement of particle surface chemistries to render selectivity toward disease site for site-selective action. Majority of the particle systems developed for such purposes are spherical nano and microparticles and they have had low-to-moderate success in clinical translation. To refine the design of delivery systems for enhanced performance, in recent years, researchers have started focusing on the physicomechanical aspects of carrier particles, especially their shape, size, and stiffness, as new design parameters. Recent computational modeling studies, as well as, experimental studies using microfluidic devices are indicating that these design parameters greatly influence the particles' behavior in hemodynamic circulation, as well as cell-particle interactions for targeted payload delivery. Certain cellular components of circulation are also providing interesting natural cues for refining the design of drug carrier systems. Based on such findings, new benefits and challenges are being realized for the next generation of drug carriers. The current article will provide a comprehensive review of these findings and discuss the emerging design paradigm of incorporating physicomechanical components in fabrication of particulate drug delivery systems.

  13. Electrophoretic particle guidance significantly enhances olfactory drug delivery: a feasibility study.

    Directory of Open Access Journals (Sweden)

    Jinxiang Xi

    Full Text Available BACKGROUND: Intranasal olfactory drug delivery provides a non-invasive method that bypasses the Blood-Brain-Barrier and directly delivers medication to the brain and spinal cord. However, a device designed specifically for olfactory delivery has not yet been found. METHODS: In this study, a new delivery method was proposed that utilized electrophoretic forces to guide drug particles to the olfactory region. The feasibility of this method was numerically evaluated in both idealized 2-D and anatomically accurate 3-D nose models. The influence of nasal airflow, electrode strength, and drug release position were also studied on the olfactory delivery efficiency. FINDINGS: Results showed that by applying electrophoretic forces, the dosage to the olfactory region was significantly enhanced. In both 2-D and 3-D cases, electrophoretic-guided delivery achieved olfactory dosages nearly two orders of magnitude higher than that without electrophoretic forces. Furthermore, releasing drugs into the upper half of the nostril (i.e., partial release led to olfactory dosages two times higher than releasing drugs over the entire area of the nostril. By combining the advantages of pointed drug release and appropriate electrophoretic guidance, olfactory dosages of more than 90% were observed as compared to the extremely low olfactory dosage (<1% with conventional inhaler devices. CONCLUSION: Results of this study have important implications in developing personalized olfactory delivery protocols for the treatment of neurological disorders. Moreover, a high sensitivity of olfactory dosage was observed in relation to different pointed release positions, indicating the importance of precise particle guidance for effective olfactory delivery.

  14. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

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

    2002-01-01

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

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

    DEFF Research Database (Denmark)

    Brok, J; Buckley, N; Gluud, C

    2001-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-30

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

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

    Science.gov (United States)

    Harris, Hope Elaine; Myers, Wade C.

    1997-01-01

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

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

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim; Poulsen, Henrik Enghusen

    2002-01-01

    The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were...

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

    Directory of Open Access Journals (Sweden)

    Wanqing eLiu

    2014-10-01

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

  20. Microfluidic conceived pH sensitive core-shell particles for dual drug delivery.

    Science.gov (United States)

    Khan, Ikram Ullah; Stolch, Lukas; Serra, Christophe A; Anton, Nicolas; Akasov, Roman; Vandamme, Thierry F

    2015-01-15

    In current study, we report on the synthesis of core-shell microparticles for dual drug delivery by means of a two co-axial microfluidic device and online UV assisted free radical polymerization. Before developing pH-sensitive particles, ketoprofen loaded poly(methyl acrylate) core-ranitidine HCl loaded poly(acrylamide) shell particles were produced. Influence of inner and outer phases flow rates on particle size, shape, core diameter, shell thickness, and drug release properties was studied. All the particles were monodispersed with coefficient of variation below 5%. Furthermore, their diameter ranged from 100 to 151 μm by increasing continuous (Qc) to middle (Qm) phase flow rate ratio (Qc/Qm). Core diameter varied from 58 to 115 μm by decreasing middle (Qm) to inner (Qi) phase flow rate ratio (Qm/Qi) at constant continuous phase flow rate as confirmed by SEM images. It was observed that an optimum concentration of acrylamide (30 wt%) and an appropriate combination of surfactants were necessary to get core-shell particles otherwise Janus structure was obtained. FTIR confirmed the complete polymerization of core and shell phases. MTT assay showed variation in viability of cells under non-contact and contact conditions with less cytotoxicity for the former. Under non-contact conditions LD50 was 3.1mg/mL. Release studies in USP phosphate buffer solution showed simultaneously release of ketoprofen and ranitidine HCl for non pH-sensitive particles. However, release rates of ranitidine HCl and ketoprofen were higher at low and high pH respectively. To develop pH-sensitive particles for colon targeting, the previous shell phase was admixed with few weight percentage of pH sensitive carboxyethyl acrylate monomer. Core and shell contained the same hydrophobic and hydrophilic model drugs as in previous case. The pH-sensitive shell prevented the release of the two entrapped molecules at low pH while increasing significantly their release rate at higher pH with a maximum

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

    Directory of Open Access Journals (Sweden)

    Bekhit MH

    2015-10-01

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

  2. Cadaveric liver transplantation for non-acetaminophen fulminant hepatic failure: A 20-year experience

    Institute of Scientific and Technical Information of China (English)

    Olivier Detry; Jacques Bela(i)che; Michel Meurisse; Pierre Honor; Arnaud De Roover; Carla Coimbra; Jean Delwaide; Marie-France Hans; Marie Hélène Delbouille; Joseé Monard; Jean Joris; Pierre Damas

    2007-01-01

    AIM: To investigate the long-term results of liver transplantation (LT) for non-acetaminophen fulminant hepatic failure (FHF).METHODS: Over a 20-year period, 29 FHF patients underwent cadaveric whole LT. Most frequent causes of FHF were hepatitis B virus and drug-related (not acetaminophen) liver failure. All surviving patients were regularly controlled at the out-patient clinic and none was lost to follow-up. Mean follow-up was 101 mo.RESULTS: One month, one-, five- and ten-year patient survival was 79%, 72%, 68% and 68%, respectively.One month, one-, five- and ten-year graft survival was 69%, 65%, 51% and 38%, respectively. Six patients needed early (< 2 mo) retransplantation, four for primary non-function, one for early acute refractory rejection because of ABO blood group incompatibility,and one for a malignant tumor found in the donor.Two patients with hepatitis B FHF developed cerebral lesions peri-transplantion: One developed irreversible and extensive brain damage leading to death, and one suffered from deep deficits leading to continuous medical care in a specialized institution.CONCLUSION: Long-term outcome of patients transplanted for non-acetaminophen FHF may be excellent. As the quality of life of these patients is also particularly good, LT for FHF is clearly justified, despite lower graft survival compared with LT for other liver diseases.

  3. Application of differential scanning calorimetry in evaluation of solid state interactions in tablets containing acetaminophen.

    Science.gov (United States)

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

    Directory of Open Access Journals (Sweden)

    Khoshkhoonejad AA.

    2004-07-01

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

  5. Fourier transform infared spectroscopic imaging for the identification of concealed drug residue particles and fingerprints

    Science.gov (United States)

    Ricci, Camilla; Chan, K. L. Andrew; Kazarian, Sergei G.

    2006-09-01

    Conventional FTIR spectroscopy and microscopy has been widely used in forensic science. New opportunities exist to obtain rapid chemical images and to enhance the sensitivity of detection of trace materials using attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy coupled with a focal-plane array (FPA) detector. In this work, the sensitivity of ATR-FTIR spectroscopic imaging using three different kinds of ATR crystals (Ge coupled with an infrared microscope, ZnSe and diamond) and resulting in three different optical arrangements for the detection of model drug particles is discussed. Model systems of ibuprofen and paracetamol particles having a size below 32 micrometers have been prepared by sieving. The sensitivity level in the three different approaches has been compared and it has been found that both micro and macro-ATR imaging methods have proven to be a promising techniques for the identification of concealed drug particles. To demonstrate the power and applicability of FTIR chemical imaging to forensic research, various examples are discussed. This includes investigation of the changes of chemical nature of latent fingerprint residue under controlled conditions of humidity and temperature studied by ATR-FTIR imaging. This study demonstrates the potential of spectroscopic imaging for visualizing the chemical changes of fingerprints.

  6. Particle designs for the stabilization and controlled-delivery of protein drugs by biopolymers: a case study on insulin.

    Science.gov (United States)

    Lim, Hui-Peng; Tey, Beng-Ti; Chan, Eng-Seng

    2014-07-28

    Natural biopolymers have attracted considerable interest for the development of delivery systems for protein drugs owing to their biocompatibility, non-toxicity, renewability and mild processing conditions. This paper offers an overview of the current status and future perspectives of particle designs using biopolymers for the stabilization and controlled-delivery of a model protein drug--insulin. We first describe the design criteria for polymeric encapsulation and subsequently classify the basic principles of particle fabrication as well as the existing particle designs for oral insulin encapsulation. The performances of these existing particle designs in terms of insulin stability and in vitro release behavior in acidic and alkaline media, as well as their in vivo performance are compared and reviewed. This review forms the basis for future works on the optimization of particle design and material formulation for the development of an improved oral delivery system for protein drugs.

  7. Paracetamol (acetaminophen) decreases hydrogen sulfide tissue concentration in brain but increases it in the heart, liver and kidney in mice.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2008-08-15

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

  9. Using Moessbauer spectroscopy as key technique in the investigation of nanosized magnetic particles for drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Morais, P. C., E-mail: pcmor@unb.br [Universidade de Brasilia, Nucleo de Fisica Aplicada, Instituto de Fisica (Brazil)

    2008-01-15

    This paper describes how cobalt ferrite nanoparticles, suspended as ionic or biocompatible magnetic fluids, can be used as a platform to built complex nanosized magnetic materials, more specifically magnetic drug delivery systems. In particular, the paper is addressed to the discussion of the use of the Moessbauer spectroscopy as an extremely useful technique in supporting the investigation of key aspects related to the properties of the hosted magnetic nanosized particle. Example of the use of the Moessbauer spectroscopy in accessing information regarding the nanoparticle modification due to the empirical process which provides long term chemical stability is included in the paper.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-15

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

  11. Poly(methyl methacrylate) particles for local drug delivery using shock wave lithotripsy: In vitro proof of concept experiment.

    Science.gov (United States)

    Shaked, Eliav; Shani, Yoav; Zilberman, Meital; Scheinowitz, Mickey

    2015-08-01

    To leverage current local drug delivery systems methodology, there is vast use of polymeric particles serving as drug carriers to assure minimal invasive therapy with little systemic distribution of the released drug. There is an increasing interest in poly(methyl methacrylate) (PMMA) serving as carriers in drug delivery. The study aims to develop PMMA carriers for localized drug delivery and release system, combining innovative biomaterial technology and shock wave lithotripsy (SWL), and to study the effect of SWL on various concentrations of PMMA particles. We prepared PMMA particles that contain horseradish peroxidase (HRP) using a double emulsion technique, and investigated the mechanism of in vitro drug release from the carriers following exposure to SWL. We investigated the correlation between production method modifications, concentrations of the carriers subjected to SWL, and shock wave patterns. We successfully produced PMMA particles as drug carriers and stimulated the release of their contents by SWL; their polymeric shell can be shattered externally by SWL treatment, leading to release of the encapsulated drug. HRP enzyme activity was maintained following the encapsulation process and exposure to high dose of SWL pulses. Increased shock wave number results in increased shattering and greater fragmentation of PMMA particles. The results demonstrate a dose-response release of HRP; quantitation of the encapsulated HRP from the carriers rises with the number of SWL. Moreover, increased concentration of particles subjected to the same dose of SWL results in a significant increase of the total HRP release. Our research offers novel technique and insights into new, site-specific drug delivery and release systems.

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

    Directory of Open Access Journals (Sweden)

    Shim Eugene

    2011-10-01

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

  13. Simultaneous measurements of glutathione and activated sulphate (PAPS) synthesis rates and the effects of selective inhibition of glutathione conjugation or sulphation of acetaminophen

    DEFF Research Database (Denmark)

    Dalhoff, K; Poulsen, H E

    1993-01-01

    The aim of the present study was to examine the effects of the hepatotoxic drug acetaminophen (AA) on the synthesis rates of glutathione (GSH), activated sulphate (PAPS; adenosine 3'-phosphate 5'-phosphosulphate) and the AA metabolites AA-GSH and AA-sulphate after selective inhibition of GSH bios...

  14. A poly(ethylene glycol)-based surfactant for formulation of drug-loaded mucus penetrating particles.

    Science.gov (United States)

    Mert, Olcay; Lai, Samuel K; Ensign, Laura; Yang, Ming; Wang, Ying-Ying; Wood, Joseph; Hanes, Justin

    2012-02-10

    Mucosal surfaces are protected by a highly viscoelastic and adhesive mucus layer that traps most foreign particles, including conventional drug and gene carriers. Trapped particles are eliminated on the order of seconds to hours by mucus clearance mechanisms, precluding sustained and targeted drug and nucleic acid delivery to mucosal tissues. We have previously shown that polymeric coatings that minimize adhesive interactions with mucus constituents lead to particles that rapidly penetrate human mucus secretions. Nevertheless, a particular challenge in formulating drug-loaded mucus penetrating particles (MPP) is that many commonly used surfactants are either mucoadhesive, or do not facilitate efficient drug encapsulation. We tested a novel surfactant molecule for particle formulation composed of Vitamin E conjugated to 5 kDa poly(ethylene glycol) (VP5k). We show that VP5k-coated poly(lactide-co-glycolide) (PLGA) nanoparticles rapidly penetrate human cervicovaginal mucus, whereas PLGA nanoparticles coated with polyvinyl alcohol or Vitamin E conjugated to 1 kDa PEG were trapped. Importantly, VP5k facilitated high loading of paclitaxel, a frontline chemo drug, into PLGA MPP, with controlled release for at least 4 days and negligible burst release. Our results offer a promising new method for engineering biodegradable, drug-loaded MPP for sustained and targeted delivery of therapeutics at mucosal surfaces.

  15. Encapsulation of anticancer drug and magnetic particles in biodegradable polymer nanospheres

    Energy Technology Data Exchange (ETDEWEB)

    Koneracka, M; Zavisova, V; Tomasovicova, N; Kopcansky, P; Timko, M; JurIkova, A; Csach, K; Kavecansky, V; Lancz, G [Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice (Slovakia); Muckova, M [Hameln rds a.s., Horna 36, Modra (Slovakia)], E-mail: konerack@saske.sk

    2008-05-21

    In this study, we have prepared PLGA (poly-D,L-lactide-co-glycolide) nanospheres loaded with biocompatible magnetic fluid and anticancer drug taxol by a modified nanoprecipitation technique and investigated their magnetic properties. A magnetic fluid, MF-PEG, with a biocompatible layer of polyethylene glycol (PEG), was chosen as a magnetic carrier. The PLGA, whose copolymer ratio of D,L-lactide to glycolide is 85:15, was utilized as a capsulation material. Taxol, as an important anticancer drug, was chosen for its significant role against a wide range of tumours. The morphology and particle size distributions of the prepared nanospheres were investigated by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed a spherical shape of prepared nanospheres with size 250 nm. Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetry (TGA) analysis confirmed incorporation of magnetic particles and taxol into the PLGA polymer. The results showed good encapsulation with magnetite content 21.5 wt% and taxol 0.5 wt%. Magnetic properties of magnetic fluids and taxol within the PLGA polymer matrix were investigated by SQUID magnetometry from 4.2 to 300 K. The SQUID measurements showed superparamagnetism of prepared nanospheres with a blocking temperature of 160 K and saturation magnetization 1.4 mT.

  16. [Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency].

    Science.gov (United States)

    Voloshchuk, O N; Kopylchuk, G P

    2016-01-01

    Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD(+)/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deprivation. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD(+)/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein caused a more pronounced decrease in the activity of NAD(+)-dependent dehydrogenases studied and a 2.2-fold increase of the mitochondrial NAD(+)/NADН ratio. This suggests that alimentary protein deprivation potentiated drug-induced liver damage.

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

    Directory of Open Access Journals (Sweden)

    Parvin Sajedi

    2014-01-01

    .002 respectively. Mean of recovery time, duration of agitation and 1 st time to agitation appearance, meperidine and midazolam consumption, nurse satisfaction and complication frequency were not statistically identical among groups (P < 0.001. Conclusions: Acetaminophen, dexamethasone and combination of them are superior to placebo for prevention of agitation after adenotonsillectomy in children. Furthermore combinations of both drugs are superior to acetaminophen or dexamethasone separately.

  18. Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways

    OpenAIRE

    Kalinec, GM; Thein, P; Parsa, A.; Yorgason, J; Luxford, W; Urrutia, R.; Kalinec, F

    2014-01-01

    Pain relievers containing N-acetyl-para-aminophenol, also called APAP, acetaminophen or paracetamol, in combination with opioid narcotics are top-selling pharmaceuticals in the U.S. Individuals who abuse these drugs for as little as sixty days can develop tinnitus and progressive bilateral sensorineural hearing loss. Recently published studies indicate that APAP and its metabolic product N-acetyl-p-benzoquinoneimine (NAPQI) are the primary ototoxic agents in this type of pain relievers. Howev...

  19. Thermal gelation of aqueous hydroxypropylmethylcellulose solutions with SDS and hydrophobic drug particles.

    Science.gov (United States)

    Acevedo, Aldo; Takhistov, Paul; de la Rosa, Carlos Pinzón; Florián, Vivian

    2014-02-15

    The thermal gelation of hydroxypropylmethylcellulose (HPMC) solutions has been studied as a function of sodium dodecyl sulfate (SDS) concentration with and without griseofulvin, a model particulate BCS Class II drug by rheological measurements of gelation temperature (Tgel), steady-state viscosity (η) at 25 °C, and ζ-potential. Polymer adsorption on the drug was demonstrated by a decrease in η and potential in the absence of SDS. Griseofulvin had a synergistic effect on gelation which was attributed to an effective spanning of associated hydrophobic polymeric regions through interactions with the adsorbed polymer. Adding SDS offsets this effect on Tgel shielding hydrophobic interactions. Higher SDS concentrations had no effect on the particles surface as evidenced by constant ζ-potential and Tgel. Yet, polymeric chains are saturated and larger surfactant aggregates account for the increase in viscosity. Understanding the gelation mechanism and complex interactions of HPMC with surfactants and drugs is necessary for the design of pharmaceutical products and optimization of their performance properties.

  20. Directed transport of bacteria-based drug delivery vehicles: bacterial chemotaxis dominates particle shape.

    Science.gov (United States)

    Sahari, Ali; Traore, Mahama A; Scharf, Birgit E; Behkam, Bahareh

    2014-10-01

    Several attenuated and non-pathogenic bacterial species have been demonstrated to actively target diseased sites and successfully deliver plasmid DNA, proteins and other therapeutic agents into mammalian cells. These disease-targeting bacteria can be employed for targeted delivery of therapeutic and imaging cargos in the form of a bio-hybrid system. The bio-hybrid drug delivery system constructed here is comprised of motile Escherichia coli MG1655 bacteria and elliptical disk-shaped polymeric microparticles. The transport direction for these vehicles can be controlled through biased random walk of the attached bacteria in presence of chemoattractant gradients in a process known as chemotaxis. In this work, we utilize a diffusion-based microfluidic platform to establish steady linear concentration gradients of a chemoattractant and investigate the roles of chemotaxis and geometry in transport of bio-hybrid drug delivery vehicles. Our experimental results demonstrate for the first time that bacterial chemotactic response dominates the effect of body shape in extravascular transport; thus, the non-spherical system could be more favorable for drug delivery applications owing to the known benefits of using non-spherical particles for vascular transport (e.g. relatively long circulation time).

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-04-01

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

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

    Science.gov (United States)

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

    2015-10-22

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

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

    Science.gov (United States)

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

    2014-05-01

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

  4. In Vitro antibacterial activity of ibuprofen and acetaminophen

    Directory of Open Access Journals (Sweden)

    Ali Abdul Hussein S AL-Janabi

    2010-01-01

    Full Text Available Background: Ibuprofen and acetaminophen are common chemical agents that have anti-inflammatory, antipyretic, and analgesic activity. Aims: To detect any potential antibacterial effects of ibuprofen and acetaminophen on pathogenic bacteria. Materials and methods: Ibuprofen and acetaminophen were tested for antibacterial activity against seven isolates of bacteria including gram positive bacteria (Staphylococci aureus and Bacillus subtilis and gram negative bacteria (E. coli, Enterobacter aerogenes, Enterobacter cloacae, Salmonella typhi and Paracoccus yeei. Spectrophotometer assay was applied to determine the antibacterial activities of ibuprofen and acetaminophen. Three controls were included in this study: Ampicilline sodium (20 μg/ml; cefotaxime sodium (20 μg/ml and chemical free medium. Results: Staphylococcus aureus and Paracoccus yeei were susceptible to lower concentrations of ibuprofen and acetaminophen (MIC=1.25 mg/ml, while two strains of Enterobacter exhibited resistance to these agents. Conclusions: Ibuprofen and acetaminophen showed a potential antibacterial effect on isolated strains of bacteria. They had the same ability to inhibit bacterial growth.

  5. Childhood suicide attempts with acetaminophen in Denmark

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  6. Influences of Organic Solvents on Particle Size and Drug-loading Efficiency for 5-Fluorouracil Poly(lactic acid) Nanoparticles

    Institute of Scientific and Technical Information of China (English)

    LIUXiao-yan; CHANGJin; GUOYan-shuang; YUANXu-bo; LIXiao-rong; LIUChun-ling; SONGCun-xian

    2004-01-01

    The objective of this study was to investigate the influences of organic solvents on particle size, drug content, loading efficiency and yield for 5-Fluorouracil Poly (lactic acid) nanoparticles . The 5-Fluorouracil was entrapped into poly(lactic acid)(PLA) nanoparticles using a water-in-oil-in-water solvent evaporation technique. During the preparation process, ethyl acetate and acetone were used as organic solvents since they are less toxic than the more commonly used dichloromethane. The effect of the three solvents on particle size, drug content, loading efficiency and yield of nanopartcles was compared. When the solvent of the oil phase was acetone, the highest drug content, smallest particle size and lowest yield were obtained for the PLA nanoparticles.

  7. Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles.

    Science.gov (United States)

    Li, Jiahe; Ai, Yiwei; Wang, Lihua; Bu, Pengcheng; Sharkey, Charles C; Wu, Qianhui; Wun, Brittany; Roy, Sweta; Shen, Xiling; King, Michael R

    2016-01-01

    Circulating tumor cells (CTCs) are responsible for metastases in distant organs via hematogenous dissemination. Fundamental studies in the past decade have suggested that neutralization of CTCs in circulation could represent an effective strategy to prevent metastasis. Current paradigms of targeted drug delivery into a solid tumor largely fall into two main categories: unique cancer markers (e.g. overexpression of surface receptors) and tumor-specific microenvironment (e.g. low pH, hypoxia, etc.). While relying on a surface receptor to target CTCs can be greatly challenged by cancer heterogeneity, targeting of tumor microenvironments has the advantage of recognizing a broader spectrum of cancer cells regardless of genetic differences or tumor types. The blood circulation, however, where CTCs transit through, lacks the same tumor microenvironment as that found in a solid tumor. In this study, a unique "microenvironment" was confirmed upon introduction of cancer cells of different types into circulation where activated platelets and fibrin were physically associated with blood-borne cancer cells. Inspired by this observation, synthetic silica particles were functionalized with activated platelet membrane along with surface conjugation of tumor-specific apoptosis-inducing ligand cytokine, TRAIL. Biomimetic synthetic particles incorporated into CTC-associated micro-thrombi in lung vasculature and dramatically decreased lung metastases in a mouse breast cancer metastasis model. Our results demonstrate a "Trojan Horse" strategy of neutralizing CTCs to attenuate metastasis.

  8. Regulation of human hepatic drug transporter activity and expression by diesel exhaust particle extract.

    Directory of Open Access Journals (Sweden)

    Marc Le Vee

    Full Text Available Diesel exhaust particles (DEPs are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC uptake transporters organic anion-transporting polypeptides (OATP 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP, whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP. Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a reference activator of the aryl hydrocarbon receptor (AhR pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute

  9. Ultrasound-mediated gene and drug delivery using a microbubble-liposome particle system.

    Science.gov (United States)

    Yoon, Young Il; Kwon, Yong-Su; Cho, Hee-Sang; Heo, Sun-Hee; Park, Kyeong Soon; Park, Sang Gyu; Lee, Soo-Hong; Hwang, Seung Il; Kim, Young Il; Jae, Hwan Jun; Ahn, Gook-Jun; Cho, Young-Seok; Lee, Hakho; Lee, Hak Jong; Yoon, Tae-Jong

    2014-01-01

    Theranostic agents present a promising clinical approach for cancer detection and treatment. We herein introduce a microbubble and liposome complex (MB-Lipo) developed for ultrasound (US) imaging and activation. The MB-Lipo particles have a hybrid structure consisting of a MB complexed with multiple Lipos. The MB components are used to generate high echo signals in US imaging, while the Lipos serve as a versatile carrier of therapeutic materials. MB-Lipo allows high contrast US imaging of tumor sites. More importantly, the application of high acoustic pressure bursts MBs, which releases therapeutic Lipos and further enhances their intracellular delivery through sonoporation effect. Both imaging and drug release could thus be achieved by a single US modality, enabling in situ treatment guided by real-time imaging. The MB-Lipo system was applied to specifically deliver anti-cancer drug and genes to tumor cells, which showed enhanced therapeutic effect. We also demonstrate the clinical potential of MB-Lipo by imaging and treating tumor in vivo.

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

    Directory of Open Access Journals (Sweden)

    Ben-Shachar Rotem

    2012-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Nesreen E.M. Mohammed

    2016-11-01

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

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

    Science.gov (United States)

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

    2014-04-01

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

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

    Science.gov (United States)

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

    2014-05-01

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

  14. Application of spray-drying and electrospraying/electospinning for poorly water-soluble drugs: a particle engineering approach.

    Science.gov (United States)

    Bohr, Adam; Boetker, Johan P; Rades, Thomas; Rantanen, Jukka; Yang, Mingshi

    2014-01-01

    Solid dispersions have been widely studied as an attractive formulation strategy for the increasingly prevalent poorly water-soluble drug compounds, including herbal medicines, often leading to improvements in drug dissolution rate and bioavailability. However, several challenges are encountered with solid dispersions, for instance regarding their physical stability, and the full potential of these formulations has yet to be reached. Solid dispersions have mainly been used to produce immediate release systems using water-soluble polymers but an extended release system may provide equal or better performance due to enhancement in the pharmacokinetics and low variability in plasma concentration. Progress in processing technologies and particle engineering provides new opportunities to prepare particle-based solid dispersions with control of physical characteristics and tailored drug release kinetics. Spray-drying and electrospraying are both technologies that allow production and continuous manufacturing of particle-based amorphous solid dispersions in a single step process and electrospinning further allows the production of fiber based systems. This review presents the use of spray drying and electrospraying/electrospinning as techniques for preparing particle-based solid dispersions, describes the particle formation processes via numerical and experimental models and discusses particle engineering using these techniques. Examples are given on the applications of these techniques for preparing solid dispersions and the challenges associated with the techniques such as stability, preparation of final dosage form and scale-up are also discussed.

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

    OpenAIRE

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

    2015-01-01

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

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

    OpenAIRE

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

    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 sho...

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

    Science.gov (United States)

    Cuzzolin, Laura; Antonucci, Roberto; Fanos, Vassilios

    2013-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Bohnen Arthur M

    2010-01-01

    Full Text Available Abstract Background Osteoarthritis is the most frequent chronic joint disease which causes pain and disability of especially hip and knee. According to international guidelines and the Dutch general practitioners guidelines for non-traumatic knee symptoms, acetaminophen should be the pain medication of first choice for osteoarthritis. However, of all prescribed pain medication in general practice, 90% consists of non-steroidal anti-inflammatory drugs compared to 10% of acetaminophen. Because general practitioners may lack evidence showing a similar efficacy of acetaminophen and non-steroidal anti-inflammatory drugs, we present the design of a randomized open-label trial to investigate the efficacy of a non-steroidal anti-inflammatory drug (diclofenac compared with acetaminophen in new consulters with knee osteoarthritis in general practice. Methods/Design Patients aged 45 years or older consulting their general practitioner with non-traumatic knee pain, meeting the clinical American College of Rheumatology criteria, and with a pain severity score of 2 or higher (on a 0-10 scale, will be randomly allocated to either diclofenac (maximum daily dose of 150 mg or acetaminophen (maximum daily dose of 3000 mg for 2 weeks and, if required, an additional 1-2 weeks, with a total follow-up period of 12 weeks. The primary outcomes are knee pain measured with a daily diary, and pain and function measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS at baseline, and at 3, 6, 9, and 12-weeks follow-up. Secondary outcomes are patients' perceived recovery, quality of life, medical, patient, and productivity costs, compliance to therapy, co-interventions, and adverse reactions. Discussion The successful completion of this trial would lead to a better understanding of which medication should be used in the treatment of primary care patients with mild knee osteoarthritis. Trial registration Dutch trial registry NTR1485.

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

    Science.gov (United States)

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

    2016-06-01

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

  20. 基于复合纳米微粒修饰丝网印刷电极的对乙酰氨基酚检测用电化学生物传感器%An electrochemical biosensor for determination of acetaminophen based on composite nano- particles modified screen- printed carbon electrodes

    Institute of Scientific and Technical Information of China (English)

    杨欣; 黄三镇; 邓强; 陈迪钊

    2011-01-01

    Objective: A sensitive electrochemical biosensor for determination of acetaminophen(ACOP) based on composite nano - particles modified screen - printed carbon electrodes (SPCEs) was fabricated ( SPCEs/Au/GS/β CD ). Methods; To construct the ACOP biosensor, graphene sheets (GS) was immobilized into biocompatible /3 - cyclodextrin(β -CD) ,then a SPCEs was modified by the biocomposite,followed by electroless plating of gold nanoparticles( Au) on the surface to fabricate SPCEs/Au/GS/yS - CD. Different technologies were employed to study the synthesis of GS, construction processes and the electrochemical properties of the biosensor. Results: Under optimum experimental conditions,the oxidation peak current(Ipa) is linear to ACOP concentration in the range from 3. 0 x 10-9-5. 0 x 10-6mol · L-1 (R2 =0. 9990) with a detection limit of 1. 6 × 10-9mol · L-1 Conclusion:The proposed electrochemical biosensor was sensitive, quickly, disposable with low cost, fewer sample volume and easy preparation, strong anti - interference, which is suitable for screen -determination of trace ACOP in real samples.%目的:构建一种复合纳米微粒修饰丝网印刷电极( SPC Es)的对乙酰氨基酚(ACOP)检测用电化学生物传感器(SPCEs/Au/GS/β - CD),建立ACOP测定方法.方法:采用化学镀方法于SPCEs表面形成纳米金颗粒(Au),然后将石墨烯(GS)和β-环糊精(β- CD)组成的复合物涂覆于SPCEs/Au表面,构建SPCEs/Au/GS/β - CD电极,采用扫描电镜(SEM)表征化学镀金、GS和电极的制备过程,采用循环伏安(CV)法和示差脉冲伏安(DPV)法研究ACOP的电化学性质.结果:在优化的实验条件下,ACOP浓度与DPV氧化峰电流(Ipa)在3.0×10-9~5.0 × 10-6 mol·L-1之间呈线性关系,线性相关系数为0.9990,检出限为1.6×10-9 mol·L-1.结论:该传感器灵敏快速、制备容易、样品用量少、可抛弃、抗干扰性强,有望用于痕量ACOP的检测.

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

    Directory of Open Access Journals (Sweden)

    Saul Shiffman

    2016-01-01

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

  2. Acetaminophen reduces social pain: behavioral and neural evidence.

    Science.gov (United States)

    Dewall, C Nathan; Macdonald, Geoff; Webster, Gregory D; Masten, Carrie L; Baumeister, Roy F; Powell, Caitlin; Combs, David; Schurtz, David R; Stillman, Tyler F; Tice, Dianne M; Eisenberger, Naomi I

    2010-07-01

    Pain, whether caused by physical injury or social rejection, is an inevitable part of life. These two types of pain-physical and social-may rely on some of the same behavioral and neural mechanisms that register pain-related affect. To the extent that these pain processes overlap, acetaminophen, a physical pain suppressant that acts through central (rather than peripheral) neural mechanisms, may also reduce behavioral and neural responses to social rejection. In two experiments, participants took acetaminophen or placebo daily for 3 weeks. Doses of acetaminophen reduced reports of social pain on a daily basis (Experiment 1). We used functional magnetic resonance imaging to measure participants' brain activity (Experiment 2), and found that acetaminophen reduced neural responses to social rejection in brain regions previously associated with distress caused by social pain and the affective component of physical pain (dorsal anterior cingulate cortex, anterior insula). Thus, acetaminophen reduces behavioral and neural responses associated with the pain of social rejection, demonstrating substantial overlap between social and physical pain.

  3. Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration.

    Science.gov (United States)

    Nguyen, Tri-Hung; Hanley, Tracey; Porter, Christopher J H; Boyd, Ben J

    2011-07-30

    This study is the first to demonstrate the ability of nanostructured liquid crystal particles to sustain the absorption of a poorly water soluble drug after oral administration. Cubic (V(2)) liquid crystalline nanostructured particles (cubosomes) formed from phytantriol (PHY) were shown to sustain the absorption of cinnarizine (CZ) beyond 48h after oral administration to rats. Plasma concentrations were sustained within the range of 21.5±1.5ng/mL from 12 to 48h. In stark contrast, cubosomes prepared using glyceryl monooleate (GMO) did not sustain the absorption of CZ and drug concentrations fell below quantifiable levels after 24h. Sustained absorption of CZ from PHY cubosomes lead to a significant enhancement (pdegradation of the LC nanostructure may limit sustained drug release. In addition, PHY cubosomes were shown to be extensively retained in the stomach (>24h) leading to the conclusion that in the case of non-digestible PHY cubosomes, the stomach may act as a non-sink reservoir that facilitates the slow release of poorly water soluble drugs, highlighting the potential use of non-digestible LC nanostructured particles as novel sustained oral drug delivery systems.

  4. Hydrophilic interaction chromatography of seized drugs and related compounds with sub 2 μm particle columns.

    Science.gov (United States)

    Lurie, Ira S; Li, Li; Toske, Steven G

    2011-12-30

    The use of hydrophilic interaction chromatography (HILIC) with sub 2 μm particle columns for the analysis of drugs and related compounds of forensic interest is described. This technique uses a high organic/low aqueous buffered mobile phase with a polar stationary phase, and is excellent for the separation of many of the charged solutes that are found in forensic drug exhibits. In this study, HILIC is investigated for 11 solutes of forensic interest, including weak bases, weak acids, and a neutral solute. In addition, for columns containing either ethylene bridged hybrid particles with or without an amide bonded phase, the effects of acetonitrile concentration, buffer type, buffer concentration, linear velocity, and sample concentration were studied. Based on these studies, HILIC with sub 2 μm particle columns can offer highly efficient, selective, and rapid isocratic separations of drugs and related compounds of forensic interest, with excellent peak shapes and low back pressures. This is in contrast to reverse phase chromatography (RPLC), where gradient elution is usually required, which can result in extensive overlap between acidic, neutral, and basic solutes. In addition, since HILIC exhibits a much greater loading capacity than RPLC, it could be a preferred technique for drug profiling. Furthermore, because high organic content mobile phases are highly amenable to mass spectrometric detection, the use of HILIC with tandem mass spectrometric detection for the analysis of seized drugs is described.

  5. Novel flower-shaped albumin particles as controlled-release carriers for drugs to penetrate the round-window membrane

    Directory of Open Access Journals (Sweden)

    Yu Z

    2014-07-01

    Full Text Available Zhan Yu,1,* Min Yu,2,* Zhimin Zhou,3 Zhibao Zhang,3 Bo Du,3 Qingqing Xiong3 1Second Artillery General Hospital, Beijing, 2Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, College of Basic Medicine, China Medical University, Shenyang, 3Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Key Laboratory of Biomedical Material of Tianjin, Tianjin, People’s Republic of China *These authors contributed equallyto this work Abstract: Controlled-release carriers for local drug delivery have attracted increasing attention for inner-ear treatment recently. In this paper, flower-shaped bovine serum albumin (FBSA particles were prepared by a modified desolvation method followed by glutaraldehyde or heat denaturation. The size of the FBSA particles varied from 10 µm to 100 µm, and most were 50–80 µm. Heat-denatured FBSA particles have good cytocompatibility with a prolonged survival time for L929 cells. The FBSA particles were utilized as carriers to investigate the release behaviors of the model drug – rhodamine B. Rhodamine B showed a sustained-release effect and penetrated the round-window membrane of guinea pigs. We also confirmed the attachment of FBSA particles onto the round-window membrane by microscopy. The FBSA particles, with good biocompatibility, drug-loading capacity, adhesive capability, and biodegradability, may have potential applications in the field of local drug delivery for inner-ear disease treatment. Keywords: bovine serum albumin (BSA, controlled release, local delivery, round-window membrane

  6. Erdosteine against acetaminophen induced renal toxicity.

    Science.gov (United States)

    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.

  7. Acetylsalicylic acid and acetaminophen protect against oxidative neurotoxicity.

    Science.gov (United States)

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

    2006-09-01

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

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

    Science.gov (United States)

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

    2016-01-28

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

  9. Melatonin prevents acetaminophen-induced nephrotoxicity in rats.

    Science.gov (United States)

    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.

  10. Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2.

    Science.gov (United States)

    Adams, M L; Pierce, R H; Vail, M E; White, C C; Tonge, R P; Kavanagh, T J; Fausto, N; Nelson, S D; Bruschi, S A

    2001-11-01

    Mitochondria play an important role in the cell death induced by many drugs, including hepatotoxicity from overdose of the popular analgesic, acetaminophen (APAP). To investigate mitochondrial alterations associated with APAP-induced hepatotoxicity, the subcellular distribution of proapoptotic BAX was determined. Based on the antiapoptotic characteristics of BCL-2, we further hypothesized that if a BAX component was evident then BCL-2 overexpression may be hepatoprotective. Mice, either with a human bcl-2 transgene (-/+) or wild-type mice (WT; -/-), were dosed with 500 or 600 mg/kg (i.p.) APAP or a nonhepatotoxic isomer, N-acetyl-m-aminophenol (AMAP). Immunoblot analyses indicated increased mitochondrial BAX-beta content very early after APAP or AMAP treatment. This was paralleled by disappearance of BAX-alpha from the cytosol of APAP treated animals and, to a lesser extent, with AMAP treatment. Early pathological evidence of APAP-induced zone 3 necrosis was seen in bcl-2 (-/+) mice, which progressed to massive panlobular necrosis with hemorrhage by 24 h. In contrast, WT mice dosed with APAP showed a more typical, and less severe, centrilobular necrosis. AMAP-treated bcl-2 (-/+) mice displayed only early microvesicular steatosis without progression to extensive necrosis. Decreased complex III activity, evident as early as 6 h after treatment, correlated well with plasma enzyme activities at 24 h (AST r(2) = 0.89, ALT r(2) = 0.87) thereby confirming a role for mitochondria in APAP-mediated hepatotoxicity. In conclusion, these data suggest for the first time that BAX may be an early determinant of APAP-mediated hepatotoxicity and that BCL-2 overexpression unexpectedly enhances APAP hepatotoxicity.

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

    Directory of Open Access Journals (Sweden)

    Soundharrajan Ilavenil

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    E Allahyry

    2006-04-01

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

  13. Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers.

    Science.gov (United States)

    Sosnik, Alejandro; Seremeta, Katia P

    2015-09-01

    Spray-drying is a rapid, continuous, cost-effective, reproducible and scalable process for the production of dry powders from a fluid material by atomization through an atomizer into a hot drying gas medium, usually air. Often spray-drying is considered only a dehydration process, though it also can be used for the encapsulation of hydrophilic and hydrophobic active compounds within different carriers without substantial thermal degradation, even of heat-sensitive substances due to fast drying (seconds or milliseconds) and relatively short exposure time to heat. The solid particles obtained present relatively narrow size distribution at the submicron-to-micron scale. Generally, the yield% of spray-drying at laboratory scale with conventional spray-dryers is not optimal (20-70%) due to the loss of product in the walls of the drying chamber and the low capacity of the cyclone to separate fine particles (spray-drying method for the production of pure drug particles and drug-loaded polymeric particles and discusses the potential of this technique and the more advanced equipment to pave the way toward reproducible and scalable processes that are critical to the bench-to-bedside translation of innovative pharmaceutical products.

  14. Preparation of Surfactant-free Core-Shell Poly(lactic acid) / Calcium Phosphate Hybrid Particles and Their Drug Release Characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Kuno, T; Hirao, K [Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya, 466-8555 (Japan); Nagata, F; Ohji, T; Kato, K, E-mail: katsuya-kato@aist.go.jp [Advanced Manufacturing Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8510 (Japan)

    2011-04-15

    We propose surfactant-free core-shell poly(lactic acid) (PLA) / calcium phosphate (CaP) hybrid particles as drug delivery carriers. These particles were prepared by biomineralization process using ultrasonic irradiation, and their drug release profiles were investigated. Drug release rate was earlier when particles were prepared by PLA with a low molecular weight, and/or by Ca(CH{sub 3}COO){sub 2} and (NH{sub 4}){sub 2}HPO{sub 4}. Also, these were shown good protein adsorption. This work indicates that these particles have sustained-release ability without initial burst and can do targeting capability by biomolecule conjugation.

  15. MIL-53(Fe), MIL-101, and SBA-15 porous materials: potential platforms for drug delivery.

    Science.gov (United States)

    Gordon, Jeff; Kazemian, Hossein; Rohani, Sohrab

    2015-02-01

    Conventional drug administration suffers from several drawbacks, including a lack of specificity for diseased tissue, the necessity of large and frequent doses, and adverse side effects. Great effort is currently being devoted to developing nanoparticle-based therapeutics capable of prolonging drug administration and providing better control. Here we demonstrate the use of flexible microporous MIL-53(Fe) and mesoporous MIL-101 and SBA-15 as matrices for the adsorption and in vitro drug delivery of acetaminophen, progesterone, and stavudine. A drug loading of 20 wt.% was achieved for each of the nanomaterials using an incipient wetness impregnation procedure. BET, DSC, and XRPD analyses indicated that the entire loaded amount of each of the model drugs had successfully been incorporated within the mesoporous channels of both MIL-101 and SBA-15. DSC analysis evidenced that a portion of each of the model drugs had deposited onto the outer surface of MIL-53(Fe) particles; however, the portion of each drug that had incorporated within the microporous channels was slowly delivered in a diffusion-controlled process, which occurred over a period of up to six days for acetaminophen. These results demonstrate the unique ability of MIL-53(Fe) to adapt its porosity and optimize drug-matrix interactions. Owing to its larger pore diameters and weaker host-guest interactions, MIL-101 release times were shorter, yet still prolonged, as evidenced by the complete release of stavudine after five days. Complete release of each of the drugs from SBA-15 occurred very quickly as a result of rapid drug dissolution and diffusion out of the mesopores.

  16. Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs

    Directory of Open Access Journals (Sweden)

    Rao S

    2011-06-01

    Full Text Available Shasha Rao, Yunmei Song, Frank Peddie, Allan M EvansSansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, South Australia, AustraliaAbstract: Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine–cyclodextrin complex and phenylephrine nanosuspensions were ­characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds.Keywords: buccal drug delivery, nanosuspension, solubility, permeation enhancement, mucoadhesion

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

    Directory of Open Access Journals (Sweden)

    Chee Ping Chong

    2017-01-01

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

  18. Simulation of magnetic drug targeting through tracheobronchial airways in the presence of an external non-uniform magnetic field using Lagrangian magnetic particle tracking

    Energy Technology Data Exchange (ETDEWEB)

    Pourmehran, O., E-mail: oveis87@yahoo.com; Rahimi-Gorji, M.; Gorji-Bandpy, M., E-mail: gorji@nit.ac.ir; Gorji, T.B.

    2015-11-01

    Drug delivery technologies are an important area within biomedicine. Targeted drug delivery aims to reduce the undesired side effects of drug usage by directing or capturing the active agents near a desired site within the body. Herein, a numerical investigation of magnetic drug targeting (MDT) using aerosol drugs named polystyrene particle (PMS40) in human lung is presented considering one-way coupling on the transport and capture of the magnetic particle. A realistic 3D geometry based on CT scan images is provided for CFD simulation. An external non-uniform magnetic field is applied. Parametric investigation is conducted and the influence of particle diameter, magnetic source position, and magnetic number (Mn) on the deposition efficiency and particle behavior is reported. According to the results, the magnetic field increased deposition efficiency of particles in a target region, the efficiency of deposition and MDT technique has a direct relation with increasing the particle diameter for magnetic number of 1 Tesla (T) and lower (Mn≤1(T)). Also it can be seen that there is an inverse relation between the particle diameter and deposition efficiency when Mn is more than 1 (T). - Highlights: • A realistic 3D geometry of human tracheobronchial airway based on CT scan image. • External non-uniform magnetic field applied to target the magnetic drug career. • Lagrangian particle tracking using discrete phase model applied. • The efficiency of deposition is dependent of magnetic number and particle diameter.

  19. Drug: D08695 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08695 Mixture, Drug dl-Methylephedrine hydrochloride - dihydrocodeine phosphate - ...diprophylline - diphenhydramine salicylate - acetaminophen - bromovalerylurea mixt; Coughcode N (TN) dl-Methylephedrine...2 Agents affecting individual organs 22 Respiratory organ agents 222 Antitussives 2229 Others D08695 dl-Methylephedrine...eine, combinations D08695 dl-Methylephedrine hydrochloride - dihydrocodeine phosp

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

    Directory of Open Access Journals (Sweden)

    Jean Matthieu Prot

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

  1. Acetaminophen, aspirin and progression of advanced chronic kidney disease

    NARCIS (Netherlands)

    Evans, Marie; Fored, Carl Michael; Bellocco, Rino; Fitzmaurice, Garrett; Fryzek, Jon P.; McLaughlin, Joseph K.; Nyren, Olof; Elinder, Carl-Gustaf

    2009-01-01

    Background. Although many studies have investigated the possible association between analgesic use (acetaminophen and aspirin) and the development of chronic kidney disease (CKD), the effect of analgesics on the progression of established CKD of any cause has not yet been investigated. Methods. In t

  2. Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450-independent mitochondrial toxicity of acetaminophen and amiodarone.

    Science.gov (United States)

    Prill, Sebastian; Bavli, Danny; Levy, Gahl; Ezra, Elishai; Schmälzlin, Elmar; Jaeger, Magnus S; Schwarz, Michael; Duschl, Claus; Cohen, Merav; Nahmias, Yaakov

    2016-05-01

    Prediction of drug-induced toxicity is complicated by the failure of animal models to extrapolate human response, especially during assessment of repeated dose toxicity for cosmetic or chronic drug treatments. In this work, we present a 3D microreactor capable of maintaining metabolically active HepG2/C3A spheroids for over 28 days in vitro under stable oxygen gradients mimicking the in vivo microenvironment. Mitochondrial respiration was monitored using two-frequency phase modulation of phosphorescent microprobes embedded in the tissue. Phase modulation is focus independent and unaffected by cell death or migration. This sensitive measurement of oxygen dynamics revealed important information on the drug mechanism of action and transient subthreshold effects. Specifically, exposure to antiarrhythmic agent, amiodarone, showed that both respiration and the time to onset of mitochondrial damage were dose dependent showing a TC50 of 425 μm. Analysis showed significant induction of both phospholipidosis and microvesicular steatosis during long-term exposure. Importantly, exposure to widely used analgesic, acetaminophen, caused an immediate, reversible, dose-dependent loss of oxygen uptake followed by a slow, irreversible, dose-independent death, with a TC50 of 12.3 mM. Transient loss of mitochondrial respiration was also detected below the threshold of acetaminophen toxicity. The phenomenon was repeated in HeLa cells that lack CYP2E1 and 3A4, and was blocked by preincubation with ascorbate and TMPD. These results mark the importance of tracing toxicity effects over time, suggesting a NAPQI-independent targeting of mitochondrial complex III might be responsible for acetaminophen toxicity in extrahepatic tissues.

  3. Simultaneous Determination of Acetaminophen and Synthetic Color(s) by Derivative Spectroscopy in Syrup Formulations and Validation by HPLC: Exposure Risk of Colors to Children

    OpenAIRE

    Rastogi, Shanya Das; Dixit, Sumita; Tripathi, Anurag; Das, Mukul

    2014-01-01

    Color additives are used in pediatric syrup formulations as an excipient; though not pre-requisite, but pediatric syrup formulations are normally colored. An attempt has been made to measure simultaneously the single drug, acetaminophen (AT), along with the colors, carmoisine (CA), erythrosine (ET), and sunset yellow FCF (SSY) added in it by three derivative spectroscopy methods namely, 1st order, ratio, and differential derivative methods. Moreover, evaluation has been made for the exposure ...

  4. Acetaminophen for self-reported sleep problems in an elderly population (ASLEEP): Study protocol of a randomized placebo-controlled double-blind trial

    OpenAIRE

    Glind, Esther; Hooft, Lotty; Tulner, Linda; Tulen, Joke; Kuper, Ingeborg; Hamburger, Hans; Rooij, Sophia de; van Munster, Barbara

    2014-01-01

    textabstractBackground: The prevalence of sleep disorders increases with age. Sleep disorders may have serious health implications and may be related to serious underlying diseases. Many older people use hypnotics, like benzodiazepines, although these medications have serious side effects and often lead to habituation. Acetaminophen is one of the most frequently used off-label drugs for sleep disorders, although little is known about its effects. Our objective is to investigate whether acetam...

  5. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs.

    Science.gov (United States)

    Kouznetsova, Jennifer; Sun, Wei; Martínez-Romero, Carles; Tawa, Gregory; Shinn, Paul; Chen, Catherine Z; Schimmer, Aaron; Sanderson, Philip; McKew, John C; Zheng, Wei; García-Sastre, Adolfo

    2014-12-01

    In light of the current outbreak of Ebola virus disease, there is an urgent need to develop effective therapeutics to treat Ebola infection, and drug repurposing screening is a potentially rapid approach for identifying such therapeutics. We developed a biosafety level 2 (BSL-2) 1536-well plate assay to screen for entry inhibitors of Ebola virus-like particles (VLPs) containing the glycoprotein (GP) and the matrix VP40 protein fused to a beta-lactamase reporter protein and applied this assay for a rapid drug repurposing screen of Food and Drug Administration (FDA)-approved drugs. We report here the identification of 53 drugs with activity of blocking Ebola VLP entry into cells. These 53 active compounds can be divided into categories including microtubule inhibitors, estrogen receptor modulators, antihistamines, antipsychotics, pump/channel antagonists, and anticancer/antibiotics. Several of these compounds, including microtubule inhibitors and estrogen receptor modulators, had previously been reported to be active in BSL-4 infectious Ebola virus replication assays and in animal model studies. Our assay represents a robust, effective and rapid high-throughput screen for the identification of lead compounds in drug development for the treatment of Ebola virus infection.

  6. Influence of particle size on drug delivery to rat alveolar macrophages following pulmonary administration of ciprofloxacin incorporated into liposomes.

    Science.gov (United States)

    Chono, Sumio; Tanino, Tomoharu; Seki, Toshinobu; Morimoto, Kazuhiro

    2006-09-01

    In order to confirm the efficacy of ciprofloxacin (CPFX) incorporated into liposomes (CPFX-liposomes) for treatment of respiratory intracellular parasite infections, the influence of particle size on drug delivery to rat alveolar macrophages (AMs) following pulmonary administration of CPFX-liposomes was investigated. CPFX-liposomes were prepared with hydrogenated soybean phosphatidylcholine (HSPC), cholesterol (CH) and dicetylphosphate (DCP) in a lipid molar ratio of 7/2/1 by the hydration method and then adjusted to five different particle sizes (100, 200, 400, 1000 and 2000 nm). In the pharmacokinetic experiment, the delivery efficiency of CPFX to rat AMs following pulmonary administration of CPFX-liposomes increased with the increase in the particle size over the range 100-1000 nm and became constant at over 1000 nm. The concentrations of CPFX in rat AMs until 24 h after pulmonary administration of CPFX-liposomes with a particle size of 1000 nm were higher than the minimum inhibitory concentration of CPFX against various intracellular parasites. In a cytotoxic test, no release of lactate dehydrogenase (LDH) from rat lung tissues by pulmonary administration of CPFX-liposomes with a particle size of 1000 nm was observed. These findings indicate that efficient delivery of CPFX to AMs by CPFX-liposomes with a particle size of 1000 nm induces an excellent antibacterial effect without any cytotoxic effects on lung tissues. Therefore, CPFX-liposomes may be useful in the development of drug delivery systems for the treatment of respiratory infections caused by intracellular parasites, such as Mycobacterium tuberculosis, Chlamydia pneumoniae and Listeria monocytogenes.

  7. Efficient drug delivery mechanisms of liposomes with tethered biopolymer brushes in aqueous solution using dissipative particle dynamics simulations

    CERN Document Server

    Goicochea, A Gama; Klapp, J; Pastorino, C

    2013-01-01

    We undertake the investigation of model liposomes covered with polyethylene glycol brushes as a case study for the mechanisms of efficient drug delivery in biologically relevant situations.Extensive non- equilibrium, coarse grained dissipative particle dynamics simulations of polymer brushes of various lengths and shear rates are performed, having in mind polymer brushes covering the surfaces of drug carrying liposomes in the human circulatory system.In particular, we calculate the viscosity and the friction coefficient for polymer brushes as functions of the shear rate and polymerization degree under theta solvent conditions, and find that the liposome brushes experience considerable shear thinning at large shear rates. The viscosity is shown to obey a scaling law at high shear rate irrespective of the brushes degree of polymerization. A new general scaling relation is obtained for the viscosity at high shear rates. These results reproduce very well trends in recent drug delivering experiments.

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

    Science.gov (United States)

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

    1984-10-01

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

  9. Synthesis and characterization of polymeric nanospheres loaded with the anticancer drug paclitaxel and magnetic particles

    Energy Technology Data Exchange (ETDEWEB)

    Zavisova, Vlasta [Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Kosice (Slovakia)], E-mail: zavisova@saske.sk; Koneracka, Martina [Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Kosice (Slovakia); Muckova, Marta [Hameln rds a.s., Horna 36, Modra (Slovakia); Kopcansky, Peter; Tomasovicova, Natalia; Lancz, Gabor; Timko, Milan [Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, 040 01 Kosice (Slovakia); Paetoprsta, Bozena; Bartos, Peter [Hameln rds a.s., Horna 36, Modra (Slovakia); Fabian, Martin [Institute of Geotechnics, Slovak Academy of Sciences, Watsonova 45, 040 01 Kosice (Slovakia)

    2009-05-15

    We describe the preparation (by nanoprecipitation) and characterization of nanospheres (NPs) for magnetic drug targeting made of a magnetic fluid with poly(ethylene glycol), poly(D,L-lactic-co-glycolic acid) (PLGA), and the anticancer drug paclitaxel (Taxol). Infrared spectroscopy confirmed the incorporation of the drug in the PLGA NPs, which were also characterized in terms of morphology, size (typical diameter 200-250 nm) and colloidal stability in aqueous solutions of NaCl. Drug release and in vivo toxicity experiments of the prepared samples were performed. Their stability, magnetic properties (superparamagnetism), and lethal dose were found to be acceptable for the proposed application in cancer therapy.

  10. Synthesis and characterization of polymeric nanospheres loaded with the anticancer drug paclitaxel and magnetic particles

    Science.gov (United States)

    Závišová, Vlasta; Koneracká, Martina; Múčková, Marta; Kopčanský, Peter; Tomašovičová, Natália; Lancz, Gábor; Timko, Milan; Pätoprstá, Božena; Bartoš, Peter; Fabián, Martin

    2009-05-01

    We describe the preparation (by nanoprecipitation) and characterization of nanospheres (NPs) for magnetic drug targeting made of a magnetic fluid with poly(ethylene glycol), poly( D, L-lactic- co-glycolic acid) (PLGA), and the anticancer drug paclitaxel (Taxol ®). Infrared spectroscopy confirmed the incorporation of the drug in the PLGA NPs, which were also characterized in terms of morphology, size (typical diameter 200-250 nm) and colloidal stability in aqueous solutions of NaCl. Drug release and in vivo toxicity experiments of the prepared samples were performed. Their stability, magnetic properties (superparamagnetism), and lethal dose were found to be acceptable for the proposed application in cancer therapy.

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

    Science.gov (United States)

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

    2012-01-25

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

  12. 影响对乙酰氨基酚用药因素的探讨%Exploration of Influential Factors on Acetaminophen Medication

    Institute of Scientific and Technical Information of China (English)

    李春福; 李燕; 李懂; 周建友; 李仲娟

    2014-01-01

    Objective:to discuss the rationality of the use of acetaminophen by changing the delivery and the drug combination.Method:The plasma concentrations in different time point were determined by colorimet-ric;Blood glucose levels was determined by Hexokinase -UV method.Result:Acetaminophen taken by mouth absorbs quickly and could produce a high blood drug concentration for a long time;The impact of combination ( with methionine or with polysaccharide ) on blood glucose level was observed .Blood sugar increase was showed at 1 hour after injecting methionine ,and at 2 hours after injecting polysaccharide .Conclusion:Oral ac-etaminophen is suitable for general patients;intramuscular injection acetaminophen is suitable for diabetics;Hepatoprotectants are not appropriate for the drug combination .%通过改变对乙酰氨基酚的给药途径和联合用药方式,探讨对乙酰氨基酚的临床合理用药。采用比色法测不同时间点的血药浓度,己糖激酶-UV 法测定血液中血糖浓度。结果为:不同给药方式中,口服对乙酰氨基酚吸收快、血药浓度维持时间长;联合用药(蛋氨酸、多糖)影响血糖值,蛋氨酸在注射1h后血糖值会升高,多糖则在注射2h后升高血糖。口服对乙酰氨基酚适合任何患者;肌注对乙酰氨基酚适合糖尿病患者;保肝类药物不适合与对乙酰氨基酚联合使用。

  13. Unexpected and pronounced antinociceptive synergy between spinal acetaminophen (paracetamol) and phentolamine.

    Science.gov (United States)

    Raffa, R B; Stone, D J; Tallarida, R J

    2001-01-26

    Acetaminophen was administered to mice by spinal (intrathecal, i.t.) injection alone or with phentolamine (11.3 microg = 0.03 micromol). Acetaminophen produced dose-related antinociception in the abdominal irritant test with an ED(50) value of 137.2 microg (0.9 micromol) Phentolamine had no effect. For combined administration, the potency of acetaminophen was significantly increased (ED50=24.4 vs. 137.2 microg), indicative of multiplicative interaction and strong synergism. These results reveal the significant and surprising interaction of spinal cord adrenoceptors or ion channel subtypes with acetaminophen-induced antinociception.

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

    DEFF Research Database (Denmark)

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

    1999-01-01

    We studied the association between acetaminophen exposure during pregnancy and the prevalence of congenital abnormalities and fetal growth. Our study included 123 women who had received a prescription of acetaminophen during pregnancy and/or 30 days before conception and 13,329 controls who did...... a prescription of acetaminophen during pregnancy and 30 days before conception and 7472 controls. We found no excess risk of malformation [OR = 0.7 (95% CI 0.1-5.5)], and no evidence that acetaminophen should influence fetal growth....

  15. Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK Modeling for Lesinurad Immediate Release Tablets.

    Science.gov (United States)

    Pepin, Xavier J H; Flanagan, Talia R; Holt, David J; Eidelman, Anna; Treacy, Don; Rowlings, Colin E

    2016-09-01

    In silico absorption modeling has been performed, to assess the impact of in vitro dissolution on in vivo performance for ZURAMPIC (lesinurad) tablets. The dissolution profiles of lesinurad tablets generated using the quality control method were used as an input to a GastroPlus model to estimate in vivo dissolution in the various parts of the GI tract and predict human exposure. A model was set up, which accounts for differences of dosage form transit, dissolution, local pH in the GI tract, and fluid volumes available for dissolution. The predictive ability of the model was demonstrated by confirming that it can reproduce the Cmax observed for independent clinical trial. The model also indicated that drug product batches that pass the proposed dissolution specification of Q = 80% in 30 min are anticipated to be bioequivalent to the clinical reference batch. To further explore the dissolution space, additional simulations were performed using a theoretical dissolution profile below the proposed specification. The GastroPlus modeling indicates that such a batch will also be bioequivalent to standard clinical batches despite having a dissolution profile, which would fail the proposed dissolution specification of Q = 80% in 30 min. This demonstrates that the proposed dissolution specification sits comfortably within a region of dissolution performance where bioequivalence is anticipated and is not near an edge of failure for dissolution, providing additional confidence to the proposed specifications. Finally, simulations were performed using a virtual drug substance batch with a particle size distribution at the limit of the proposed specification for particle size. Based on these simulations, such a batch is also anticipated to be bioequivalent to clinical reference, demonstrating that the proposed specification limits for particle size distribution would give products bioequivalent to the pivotal clinical batches.

  16. Effects of Formulation Variables on the Particle Size and Drug Encapsulation of Imatinib-Loaded Solid Lipid Nanoparticles.

    Science.gov (United States)

    Gupta, Biki; Poudel, Bijay Kumar; Pathak, Shiva; Tak, Jin Wook; Lee, Hee Hyun; Jeong, Jee-Heon; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2016-06-01

    Imatinib (IMT), an anticancer agent, inhibits receptor tyrosine kinases and is characterized by poor aqueous solubility, extensive first-pass metabolism, and rapid clearance. The aims of the current study are to prepare imatinib-loaded solid lipid nanoparticles (IMT-SLN) and study the effects of associated formulation variables on particle size and drug encapsulation on IMT-SLN using an experimental design. IMT-SLN was optimized by use of a "combo" approach involving Plackett-Burman design (PBD) and Box-Behnken design (BBD). PBD screening resulted in the determination of organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), and amount of Tween® 20 (Tw20) as three significant variables for particle size (S z), drug loading (DL), and encapsulation efficiency (EE) of IMT-SLN, which were used for optimization by BBD, yielding an optimized criteria of O/A = 0.04, D/L = 0.03, and Tw20 = 2.50% w/v. The optimized IMT-SLN exhibited monodispersed particles with a size range of 69.0 ± 0.9 nm, ζ-potential of -24.2 ± 1.2 mV, and DL and EE of 2.9 ± 0.1 and 97.6 ± 0.1% w/w, respectively. Results of in vitro release study showed a sustained release pattern, presumably by diffusion and erosion, with a higher release rate at pH 5.0, compared to pH 7.4. In conclusion, use of the combo experimental design approach enabled clear understanding of the effects of various formulation variables on IMT-SLN and aided in the preparation of a system which exhibited desirable physicochemical and release characteristics.

  17. FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF ACETAMINOPHEN

    Directory of Open Access Journals (Sweden)

    Abhay Kumar Mourya et al.

    2012-02-01

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

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

    Science.gov (United States)

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

    2014-07-01

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

  19. Influence of inspiratory flow rate, particle size, and airway caliber on aerosolized drug delivery to the lung.

    Science.gov (United States)

    Dolovich, M A

    2000-06-01

    A number of studies in the literature support the use of fine aerosols of drug, inhaled at low IFRs to target peripheral airways, with the objective of improving clinical responses to inhaled therapy (Fig. 8). Attempts have been made to separate response due to changes in total administered dose or the surface concentration of the dose from response due to changes in site of deposition--both are affected by the particle size of the aerosol, with IFR additionally influencing the latter. The tools for measuring dose and distribution have improved over the last 10-15 years, and thus we should expect greater accuracy in these measurements for assessing drug delivery to the lung. There are still issues, though, in producing radiolabeled (99m)technetium aerosols that are precise markers for the pharmaceutical product being tested and in quantitating absolute doses deposited in the lung. PET isotopes may provide the means for directly labelling a drug and perhaps can offer an alternative for making these measurements in the future, but deposition measurements should not be used in isolation; protocols should incorporate clinical tests to provide parallel therapeutic data in response to inhalation of the drug by the various patient populations being studied.

  20. Know Concentration Before Giving Acetaminophen to Infants

    Science.gov (United States)

    ... Consumers' Room: Medicines in My Home Daily Medicine Record for Your Child (PDF - 66KB) More in Consumer Updates Animal & Veterinary Children's Health Cosmetics Dietary Supplements Drugs Food Medical ...

  1. Examining drug hydrophobicity in continuous wet granulation within a twin screw extruder.

    Science.gov (United States)

    Li, H; Thompson, M R; O'Donnell, K P

    2015-12-30

    The influence of active pharmaceutical ingredient (API) hydrophobicity on continuous wet granulation was studied in twin screw granulation utilizing foamed binder delivery. The APIs examined were caffeine, acetaminophen, ibuprofen and griseofulvin and the drug load was maintained constant at 15 wt%. In order to understand the impact of these APIs on the granulation process, API and binder distribution, particle size, porosity, and fracture strength were analyzed on samples collected along the screw length. It was found that the API and binder distributions were uniform along the screws regardless of the hydrophobicity of the formulation, in contrast to literature results with liquid injection. The absence of de-mixing of the hydrophobic ingredient was hypothesized to be a result of the high spread-to-soak ratio of a foamed binder that 'cages' those particles within the mass of local hydrophilic solids.

  2. Post hemorrhoidectomy pain control: rectal Diclofenac versus Acetaminophen

    Directory of Open Access Journals (Sweden)

    Rahimi M

    2009-03-01

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

  3. Time to onset of analgesia and analgesic efficacy of effervescent acetaminophen 1000 mg compared to tablet acetaminophen 1000 mg in postoperative dental pain: a single-dose, double-blind, randomized, placebo-controlled study.

    Science.gov (United States)

    Møller, P L; Nørholt, S E; Ganry, H E; Insuasty, J H; Vincent, F G; Skoglund, L A; Sindet-Pedersen, S

    2000-04-01

    This randomized, double-blind, placebo-controlled study compared the time to onset of analgesia and the analgesic efficacy of two formulations of acetaminophen 1000 mg--an effervescent solution and tablet--in 242 patients with moderate or severe pain following dental surgery. Onset of analgesia was determined using a two-stopwatch procedure. Analgesia was assessed over a 4-hour period. Treatments were compared using standard indexes of pain intensity and pain relief and summary measures. Both acetaminophen formulations were significantly more effective than their corresponding placebo for all efficacy assessments. The median time to onset of analgesia was significantly shorter with effervescent acetaminophen (20 minutes) compared to tablet acetaminophen (45 minutes). During the first 45 minutes after administration, effervescent acetaminophen was significantly more effective at each scheduled assessment time than tablet acetaminophen. The median time to meaningful pain relief was significantly shorter with effervescent acetaminophen (45 minutes) compared to tablet acetaminophen (60 minutes). At 4 hours after administration, the pain relief was significantly better with tablet acetaminophen than with effervescent acetaminophen. No other significant differences were observed between the active treatments. In conclusion, effervescent acetaminophen produces a significantly faster onset of analgesia than tablet acetaminophen.

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

    Science.gov (United States)

    Langhammer, Astrid Jordet; Nilsen, Odd Georg

    2014-10-01

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

  5. Acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    Mossanen, J C; Tacke, F

    2015-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Francesco Di Pierro

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    S Saeedi Saravi

    2007-12-01

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

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

    Science.gov (United States)

    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. Protective activities of the aqueous root extract of Harungana madagascariensis in acute and repeated acetaminophen hepatotoxic rats

    Directory of Open Access Journals (Sweden)

    Adeneye AA

    2008-09-01

    Full Text Available In this study, the protective effects of 100 – 500 mg/kg/day of the aqueous root extract of Harungana madagascariensisLam. ex Poir were evaluated on the average body weight, relative liver-body weight, serum alanine (ALT and aspartateaminotransferases (AST, alkaline phosphatase (ALP, total (TB and conjugated bilirubin (CB, triglycerides (TG, total cholesterol(TC, cholesterol fractions (HDL-c, LDL-c, VLDL-c, fasting blood glucose (FBG, total protein (TP and albumin (ALB in the acuteand repeated dose acetaminophen hepatotoxic rats. Results showed that acute intraperitoneal injection of 800 mg/kg of acetaminopheninduced significant (p0.05 alterations in the serum levels oflipids, TB and CB. However, pretreatments with 100 - 500 mg/kg of Harungana madagascariensis significantly (p0.05 alterations in the serum lipids.Repeated acetaminophen hepatotoxicity caused similar effects in the measured parameters except that it was associated withsignificant (p<0.001 reduction in the FBG while inducing significant (p<0.05, p<0.001 increases in the serum TB and CB. Oralpretreatments with the extract significantly (p<0.001 enhanced acetaminophen induced hypoglycemia while significantly (p<0.05,p<0.01 attenuating significant elevations in the serum levels of TB and CB, in dose related fashion. The associated histopathologicfeatures of moderate-to-severe hepatic necrosis were also attenuated by the extract. Thus, the overall results of this study confirm thefolkloric use of the extract in the treatment of drug-induced hepatotoxicity.

  10. Crystallization of bifonazole and acetaminophen within the matrix of semicrystalline, PEO-PPO-PEO triblock copolymers.

    Science.gov (United States)

    Chen, Zhen; Liu, Zhengsheng; Qian, Feng

    2015-02-02

    The morphology and microstructure of crystalline drug/polymer solid dispersions could influence their physical stability and dissolution performance. In this study, the drug crystallization mechanism within PEG, PPG, and poloxamer matrix was investigated, and the resultant microstructure of various solid dispersions of acetaminophen (ACM) and bifonazole (BFZ) in the aforementioned polymers was characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and wide/small-angle X-ray diffraction (WAXD/SAXS). With a stronger molecular interaction with the PEG segments, ACM decreased the crystallization onset temperature and crystallinity of PEG and poloxamers much more than BFZ. The stronger molecular interaction and better miscibility between ACM and PEG also induced a more defective lamellar structure in the ACM solid dispersions compared with that in the BFZ systems, as revealed by DSC and SAXS investigation. Observed under polarized optical microscopy, PEG, PPG, and poloxamer could all significantly improve the crystallization rate of ACM and BFZ, because of the largely reduced Tg of the solid dispersions by these low Tg polymers. Moreover, when the drug loading was below 60%, crystallization of BFZ in PEG or poloxamer occurred preferably along the radial direction of PEG spherulite, rather than the perpendicular direction, which was attributed to the geometric restriction of well-ordered polymer lamellar structure in the BFZ solid dispersions. Similar phenomena were not observed in the ACM solid dispersions regardless of the drug loading, presumably because ACM could diffuse freely across the perpendicular direction of the PEG spherulite, through the well-connected interlamellar or interfibrillar spaces produced by the defective PEG lamellar structure. The different drug-polymer interaction also caused a difference in the microstructure of polymer crystal, as well as a difference in drug distribution within the polymer matrix, which

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

    Science.gov (United States)

    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.

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  14. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    NARCIS (Netherlands)

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absor

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

    Science.gov (United States)

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

    2014-11-01

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

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

    Science.gov (United States)

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

    2011-05-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-15

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

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

    DEFF Research Database (Denmark)

    Liu, Xiaoqin; Liew, Zeyan; Olsen, Jørn

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Josh eFoster

    2016-03-01

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

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

    Science.gov (United States)

    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.

  1. Drug –induced liver injury:a review

    OpenAIRE

    Sreya Kosanam; Revathi Boyina; Lakshmi Prasanthi N

    2015-01-01

    The incidence of drug induced liver injury (DILI) is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized ...

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

    Science.gov (United States)

    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.

  3. Nano-chitosan particles in anticancer drug delivery: An up-to-date review.

    Science.gov (United States)

    Kamath, Pooja R; Sunil, Dhanya

    2017-02-27

    Cancer is one of the most awful lethal diseases all over the world and the success of its current chemotherapeutic treatment strategies is limited due to several associated drawbacks. The exploration of cancer cell physiology and its microenvironment have exposed the potential of various classes of nanocarriers to deliver anticancer chemotherapeutic agents at the tumor target site. These nanocarriers must evade the immune surveillance system and achieve target selectivity. Besides, they must gain access in to the interior of cancerous cells, evade endosomal entrapment and discharge the drugs in a sustained manner. Chitosan, the second naturally abundant polysaccharide is a biocompatible, biodegradable and mucoadhesive cationic polymer which has been exploited extensively in the last few years in the effective delivery of anticancer chemotherapeutics to the target tumor cells. Therapeutic agent-loaded surface modified chitosan nanoparticles are established to be more stable, permeable and bioactive. This review will provide an up-to-date evidence-based background on recent pharmaceutical advancements in the transformation of chitosan nanoparticles for smart anticancer therapeutic drug delivery.

  4. Combined administration of silymarin and vitamin C stalls acetaminophen-mediated hepatic oxidative insults in Wistar rats

    Directory of Open Access Journals (Sweden)

    Saheed Sabiu

    2015-02-01

    Full Text Available Oxidative insult by free radicals has been implicated in drug-induced hepatic damage and this has resulted in frequent episodes of liver disorders. Therapeutic efficacy of antioxidants may provide a possible solution to this menace. This study was carried out to investigate the effect of combined administration of silymarin and vitamin C in rescuing acetaminophen-induced hepatotoxicity in rats. Hepatotoxic rats were orally administered with silymarin and vitamin C at 100 and 200 mg/kg body weight, respectively. At the end of the experiment, liver function indices, antioxidant parameters and histological analysis were evaluated. We observed that the significantly increased (p < 0.05 activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, as well as levels of thiobarbituric acid reactive substances and serum total bilirubin, were markedly reduced following co-administration of silymarin and vitamin C. The compounds also effectively reversed the reduced activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and total protein concentration in the hepatotoxic rats. These findings are indicative of hepatoprotective and antioxidant attributes of the two compounds which are also supported by the histological analysis. The available evidences in this study suggest that the complementary effects of silymarin and vitamin C proved to be capable of ameliorating acetaminophen-mediated hepatic oxidative damage and the probable mechanism is via antioxidative action.

  5. A particle swarm approach to solve vehicle routing problem with uncertain demand: A drug distribution case study

    Directory of Open Access Journals (Sweden)

    Babak Farhang Moghadam

    2010-07-01

    Full Text Available During the past few years, there have tremendous efforts on improving the cost of logistics using varieties of Vehicle Routing Problem (VRP models. In fact, the recent rise on fuel prices has motivated many to reduce the cost of transportation associated with their business through an improved implementation of VRP systems. We study a specific form of VRP where demand is supposed to be uncertain with unknown distribution. A Particle Swarm Optimization (PSO is proposed to solve the VRP and the results are compared with other existing methods. The proposed approach is also used for real world case study of drug distribution and the preliminary results indicate that the method could reduce the unmet demand significantly.

  6. Prolate spheroidal hematite particles equatorially belt with drug-carrying layered double hydroxide disks: Ring Nebula-like nanocomposites

    Directory of Open Access Journals (Sweden)

    Nedim Ay Ahmet

    2011-01-01

    Full Text Available Abstract A new nanocomposite architecture is reported which combines prolate spheroidal hematite nanoparticles with drug-carrying layered double hydroxide [LDH] disks in a single structure. Spindle-shaped hematite nanoparticles with average length of 225 nm and width of 75 nm were obtained by thermal decomposition of hydrothermally synthesized hematite. The particles were first coated with Mg-Al-NO3-LDH shell and then subjected to anion exchange with salicylate ions. The resulting bio-nanohybrid displayed a close structural resemblance to that of the Ring Nebula. Scanning electron microscope and transmission electron microscopy images showed that the LDH disks are stacked around the equatorial part of the ellipsoid extending along the main axis. This geometry possesses great structural tunability as the composition of the LDH and the nature of the interlayer region can be tailored and lead to novel applications in areas ranging from functional materials to medicine by encapsulating various guest molecules.

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

    Science.gov (United States)

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

    2015-01-01

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

  8. Sirtuin 1 modulation in rat model of acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Wojnarová, L; Kutinová Canová, N; Farghali, H; Kučera, T

    2015-01-01

    Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

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

    Science.gov (United States)

    Brune, K; Renner, B; Tiegs, G

    2015-08-01

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

  10. Simultaneous electrochemical determination of acetaminophen and metoclopramide at electrochemically pre-treated disposable graphite pencil electrode

    Directory of Open Access Journals (Sweden)

    Shreekant M Patil

    2016-09-01

    Full Text Available A sensitive and economic voltammetric method was developed for the simultaneous determination of acetaminophen (AMP and metoclopramide (MCP using pre-treated graphite pencil electrode (PTGPE. Compared to a graphite pencil electrode, the pre-treated electrode showed an apparent shift of the oxidation potentials in the positive direction and a notable enhancement in the current responses for both AMP and MCP. Cyclic voltammetry (CV was used to study the voltammetric behavior of the drugs, while differential pulse voltammetry (DPV was used to determine AMP and MCP simulta­neously. The dependence of the current on scan rate, pH and concentration was investi­gated to boost the experimental conditions for simultaneous determination. The calibra­tion curves were obtained over the range of 0.1×10-7 to 1.1×10-7 M, the concentration of each of both the drugs was varied by keeping the other constant, and achieved lower detection limit of 3.25 nM for AMP and 1.16 nM for MCP. The developed method was found to be selective and rapid for the simultaneous determination of AMP and MCP. The proposed method was applied simultaneously in real samples and pharmaceutical samples, with satisfactory results.

  11. Uniform surface modification of 3D Bioglass®-based scaffolds with mesoporous silica particles (MCM-41 for enhancing drug uptake capability

    Directory of Open Access Journals (Sweden)

    Elena eBoccardi

    2015-11-01

    Full Text Available The design and characterization of a new family of multifunctional scaffolds based on bioactive glass (BG of 45S5 composition for bone tissue engineering and drug delivery applications is presented. These BG-based scaffolds are developed via a replication method of polyurethane packaging foam. In order to increase the therapeutic functionality, the scaffolds were coated with mesoporous silica particles (MCM-41, which act as an in-situ drug delivery system. These sub-micron spheres are characterized by large surface area and pore volume with a narrow pore diameter distribution. The solution used for the synthesis of the silica mesoporous particles was designed to obtain at the same time a high ordered mesoporous structure and spherical shape, both are key factors for achieving the desired controlled drug release. The MCM-41 particles were synthesized directly inside the BG-based scaffolds and the drug release capability of this combined system was evaluated. Moreover the effect of MCM-41 particle coating on the bioactivity of the BG-based scaffolds was assessed. The results indicate that it is possible to obtain a multifunctional scaffold system characterized by high and interconnected porosity, high bioactivity and sustained drug delivery capability.

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Optimal structure of particles-based superparamagnetic microrobots: application to MRI guided targeted drug therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mellal, Lyès [INSA Centre Val de Loire, Université d’Orléans, PRISME EA 4229 (France); Belharet, Karim [Hautes Études d’Ingénieur campus Centre, PRISME EA 4229 (France); Folio, David; Ferreira, Antoine, E-mail: antoine.ferreira@insa-cvl.fr, E-mail: antoine.ferreira@ensi-bourges.fr [INSA Centre Val de Loire, Université d’Orléans, PRISME EA 4229 (France)

    2015-02-15

    This paper presents an optimal design strategy for therapeutic magnetic micro carriers (TMMC) guided in real time by a magnetic resonance imaging (MRI) system. As aggregates of TMMCs must be formed to carry the most amount of drug and magnetic actuation capability, different clustering agglomerations could be arranged. Nevertheless, its difficult to predict the hydrodynamic behavior of any arbitrary-shaped object due to the nonlinear hydrodynamic effects. Indeed, the drag effect is related not only to the properties of the bolus but also to its interaction with the fluid viscosity, the free-stream velocity and the container geometry. In this work, we propose a mathematical framework to optimize the TMMC aggregates to improve the steering efficiency in experimental endovascular conditions. The proposed analysis is carried out on various sizes and geometries of microcarrier: spherical, ellipsoid-like, and chain-like of microsphere structures. We analyze the magnetophoretic behavior of such designs to exhibit the optimal configuration. Based on the optimal design of the boluses, experimental investigations were carried out in mm-sized fluidic artery phantoms to demonstrate the steerability of the magnetic bolus using a proof-of-concept setup. The experiments demonstrate the steerability of the magnetic bolus under different velocity, shear-stress, and trajectory constraints with a laminar viscous fluidic environment. Preliminary experiments with a MRI system confirm the feasibility of the steering of these TMMCs in hepatic artery microchannel phantom.

  14. Dual functions of polyvinyl alcohol (PVA): fabricating particles and electrospinning nanofibers applied in controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Qin Xiaohong, E-mail: xhqin@dhu.edu.cn [Donghua University, College of Textiles (China); Wu Dequn; Chu Chihchang, E-mail: cc62@cornell.edu [Cornell University, Department of Fiber Science and Apparel Design (United States)

    2013-01-15

    The fabrication of submicron size microsphere from 8-Phe-4 poly(ester amide) (PEA) using polyvinyl alcohol (PVA) as the emulsion was reported. The biodegradable microspheres were prepared by an oil-in-water emulsion/solvent evaporation technique, and PVA was used as the emulsion. Furthermore, the emulsion PVA was electrospun into nanofibrous mats, and 8-Phe-4 PEA microspheres were entrapped in the resultant mats. The dual functions of PVA to fabricate ideal nanofibrous mats which can entrap microspheres in them and to obtain 8-Phe-4 microspheres as emulsion in their potential application were demonstrated. The anti-cancer drug doxorubicin (DOX) was encapsulated in the 8-Phe-4 amino acid-based PEA microspheres and the entrapment efficiency is almost 100 %. At the same time, the DOX can be controlled released in PBS solution and in {alpha}-chymotrypsin solution. The cytotoxicity of PVA, PVA mats-entrapped 8-Phe-4 microspheres and PVA mats-entrapped DOX-loaded 8-Phe-4 microspheres, was investigated. Hela cells were used to test the cytotoxicity of the DOX that released from the PVA mats-entrapped DOX-loaded 8-Phe-4 microspheres for 2 days, and the cell viability is below 30 % when the 8-Phe-4 microspheres concentration is 1 mg/mL. It demonstrated that the PVA mats-entrapped DOX-loaded 8-Phe-4 microspheres have a potential biomedical application.Graphical AbstractThe table of contents: DOX-loaded microspheres can be encapsulated in the PVA fibers by electrospinning and the DOX can be controlled released from the PVA fibers-entrapped microspheres. MTT assay indicated that the more than 70 % Hela cells were killed by the DOX released from DOX-loaded microspheres encapsulated in the PVA after 48 h.

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

    Science.gov (United States)

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

    2015-01-29

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

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

    Science.gov (United States)

    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.

  17. Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats.

    Science.gov (United States)

    Lee, Soo Hyun; An, Ji Hye; Lee, Hwa Jeong; Jung, Byung Hwa

    2012-09-01

    To evaluate the metabolic interaction between host and gut microflora on drug metabolism, pseudo germ-free rats were prepared with an antibiotics cocktail to change their gut conditions. The usefulness of the pseudo germ-free model was evaluated for observing the DMPK of acetaminophen (APAP). Pseudo germ-free rats were prepared by orally administering antibiotic cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered to control and pseudo germ-free rats. The plasma concentration of APAP and its six metabolites were quantified using a validated LC-MS/MS method. A non-compartment model estimated the pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve (AUC; AUC(metabolite) /AUC(APAP) ) were also observed to evaluate the change of APAP metabolism. The AUCs of APAP and APAP-Glth (glutathione) were higher and the AUC(APAP-Sul) /AUC(APAP) (metabolic efficiency of sulfate conjugation) was lower in pseudo germ-free rats than those in the control rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction of the sulphate supply, causing an increase of the AUC of APAP and APAP-Glth. The activities of gut microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic APAP metabolism. These results indicate that gut microflora may play an important role in the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and gut microflora should be considered upon drug administration and pseudo germ-free rats prepared in the present study can be competent for investigating the metabolic interaction between host and gut microflora on drug metabolism.

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

    Directory of Open Access Journals (Sweden)

    Carla Carnovale

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Maria Goretti R. Queiroz

    2008-10-01

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

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

    DEFF Research Database (Denmark)

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

    1991-01-01

    1. The combined antidote effect of N-acetylcysteine and ethanol on the toxicity of acetaminophen was investigated. 2. Fed male mice were given acetaminophen i.p. (600 mg kg-1) and after 5 min in addition ethanol i.p. (0.2 ml, 19% v/v), N-acetylcysteine i.p. (1.2 g kg-1, 0.2 ml), N-acetylcysteine ......1. The combined antidote effect of N-acetylcysteine and ethanol on the toxicity of acetaminophen was investigated. 2. Fed male mice were given acetaminophen i.p. (600 mg kg-1) and after 5 min in addition ethanol i.p. (0.2 ml, 19% v/v), N-acetylcysteine i.p. (1.2 g kg-1, 0.2 ml), N...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  4. Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation

    Science.gov (United States)

    Paluch, Andrew S.; Parameswaran, Sreeja; Liu, Shuai; Kolavennu, Anasuya; Mobley, David L.

    2015-01-01

    We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

  5. Kinetics of acetaminophen degradation by Fenton oxidation in a fluidized-bed reactor.

    Science.gov (United States)

    de Luna, Mark Daniel G; Briones, Rowena M; Su, Chia-Chi; Lu, Ming-Chun

    2013-01-01

    Acetaminophen (ACT), an analgesic and antipyretic substance, is one of the most commonly detected pharmaceutical compound in surface waters and wastewaters. In this study, fluidized-bed Fenton (FB-Fenton) was used to decompose ACT into its final degradation products. The 1.45-L cylindrical glass reactor had inlet, outlet and recirculating sections. SiO(2) carrier particles were supported by glass beads with 2-4 mm in diameter. ACT concentration was determined by high performance liquid chromatography (HPLC). During the first 40 min of reaction, a fast initial ACT removal was observed and the "two-stage" ACT degradation conformed to a pseudo reaction kinetics. The effects of ferrous ion dosage and [Fe(2+)]/[H(2)O(2)] (FH ratio) were integrated into the derived pseudo second-order kinetic model. A reaction pathway was proposed based on the intermediates detected through SPME/GC-MS. The aromatic intermediates identified were hydroquinone, benzaldehydes and benzoic acids while the non-aromatic substances include alcohols, ketones, aldehydes and carboxylic acids. Rapid initial ACT degradation rate can be accomplished by high initial ferrous ion concentration and/or low FH ratio.

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

    Science.gov (United States)

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

    2016-06-01

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

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

    OpenAIRE

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

    2014-01-01

    Background: Hepatotoxicity by acetaminophen is the most frequent cause of acute liver failure in many countries. Prosopis farcta beans extract (PFE) has some antioxidant property and may alleviate hepatotoxicity. Therefore, the aim of this study was to evaluate effects of PFE against acetaminophen-induced hepatotoxicity. Methods: Thirty-six male Wistar albino rats weighing 220 ± 30 g were distributed into six groups. Two groups were pretreated with PFE (50 and 75 mg/kg) for 7 days before ...

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

    Directory of Open Access Journals (Sweden)

    Sayyed Morteza Heidari Tabaei Zavareh

    2013-01-01

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

  9. Noninvasive analysis of hepatic glycogen kinetics before and after breakfast with deuterated water and acetaminophen

    OpenAIRE

    Jones, John G.; Fagulha, Ana; Barosa, Cristina; Bastos, Margarida; Barros, Luisa; Baptista, Carla; Caldeira, M. Madalena; Carvalheiro, Manuela

    2006-01-01

    The contributions of hepatic glycogenolysis to fasting glucose production and direct pathway to hepatic glycogen synthesis were quantified in eight type 1 diabetic patients and nine healthy control subjects by ingestion of (2)H(2)O and acetaminophen before breakfast followed by analysis of urinary water and acetaminophen glucuronide. After overnight fasting, enrichment of glucuronide position 5 relative to body water (G5/body water) was significantly higher in type 1 diabetic patients compare...

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

    OpenAIRE

    Abeer Hanafy; Aldawsari, Hibah M; Badr, Jihan M.; Amany K. Ibrahim; Seham El-Sayed Abdel-Hady

    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 acetaminophe...

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

    OpenAIRE

    Daniela Rodrigues; Themis Reverbel Da Silveira; Ursula Matte

    2012-01-01

    CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) ...

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  13. Lupeol protects against acetaminophen-induced oxidative stress and cell death in rat primary hepatocytes.

    Science.gov (United States)

    Kumari, Archana; Kakkar, Poonam

    2012-05-01

    Drug induced hepatotoxicity is a major problem where phytochemicals hold promise for its abrogation. This study was carried out to explore cytoprotective potential of lupeol, a triterpene, against acetaminophen (AAP)-induced toxicity in rat hepatocytes. AAP exposure significantly (p<0.05) reduced cell viability, disturbed Bcl-2 family pro/anti-apoptotic protein balance, increased ROS production and altered redox homeostasis. It also induced mitochondria-mediated hepatocellular injury by significant mitochondrial depolarization, caspase-9/3 activation and subsequent DNA fragmentation. Our results suggest that lupeol pre-treatment effectively restored antioxidant enzyme levels, decreased lipid peroxidation, inhibited ROS generation and depolarization of mitochondria. Lupeol also attenuated mitochondria-mediated signaling pathway and DNA damage as evident from TUNEL assay and cell cycle studies leading to prevention of cytotoxicity. This study confirms the efficacy of lupeol, a food derived antioxidant, in abrogating ROS generation, maintaining redox balance and providing significant protection against mitochondria-mediated cell death during AAP-induced toxicity.

  14. UV-induced photocatalytic degradation of aqueous acetaminophen: the role of adsorption and reaction kinetics.

    Science.gov (United States)

    Basha, Shaik; Keane, David; Nolan, Kieran; Oelgemöller, Michael; Lawler, Jenny; Tobin, John M; Morrissey, Anne

    2015-02-01

    Nanostructured titania supported on activated carbon (AC), termed as integrated photocatalytic adsorbents (IPCAs), were prepared by ultrasonication and investigated for the photocatalytic degradation of acetaminophen (AMP), a common analgesic and antipyretic drug. The IPCAs showed high affinity towards AMP (in dark adsorption studies), with the amount adsorbed proportional to the TiO2 content; the highest adsorption was at 10 wt% TiO2. Equilibrium isotherm studies showed that the adsorption followed the Langmuir model, indicating the dependence of the reaction on an initial adsorption step, with maximum adsorption capacity of 28.4 mg/g for 10 % TiO2 IPCA. The effects of initial pH, catalyst amount and initial AMP concentration on the photocatalytic degradation rates were studied. Generally, the AMP photodegradation activity of the IPCAs was better than that of bare TiO2. Kinetic studies on the photocatalytic degradation of AMP under UV suggest that the degradation followed Langmuir-Hinshelwood (L-H) kinetics, with an adsorption rate constant (K) that was considerably higher than the photocatalytic rate constant (k r), indicating that the photocatalysis of AMP is the rate-determining step during the adsorption/photocatalysis process.

  15. Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

    Science.gov (United States)

    van der Westhuizen, J; Kuo, P Y; Reed, P W; Holder, K

    2011-03-01

    Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

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

    Science.gov (United States)

    Fakurazi, S; Hairuszah, I; Nanthini, U

    2008-08-01

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

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

    Science.gov (United States)

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

    2013-12-01

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

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Science.gov (United States)

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

    2000-01-01

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

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Science.gov (United States)

    Fouad, Amr A; Jresat, Iyad

    2012-03-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  3. Direct Protection Against Acetaminophen Hepatotoxicity by Propylthiouracil: IN VIVO AND IN VITRO STUDIES IN RATS AND MICE

    OpenAIRE

    1981-01-01

    Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [3H]acetam...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-06-30

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

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

    Indian Academy of Sciences (India)

    Gholamhossein Rounaghi; Roya Mohammadzadeh Kakhki

    2012-10-01

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

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

    Science.gov (United States)

    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.

  7. Determination of surface-adsorbed excipients of various types on drug particles prepared by antisolvent precipitation using HPLC with evaporative light scattering detection.

    Science.gov (United States)

    Zimmermann, Anne; Elema, Michiel Ringkjøbing; Hansen, Tue; Müllertz, Anette; Hovgaard, Lars

    2007-08-15

    A common challenge in the development of new drug substances is poor dissolution characteristics related to low aqueous solubility. One approach to overcome this problem is antisolvent precipitation in the presence of polymers or surfactants, which may enhance the dissolution rate through reduced particle size and increased wettability. In this study, a simple method based on size exclusion chromatography (SEC) with evaporative light scattering detection (ELSD) was developed for the determination of polymers and surfactants adsorbed to drug particles prepared by antisolvent precipitation of the poorly water-soluble model drug Lu 28-179. Detection of many polymeric excipients and surfactants is problematic due to the lack of UV-absorbing chromophores, but ELSD proved successful for the direct determination of the investigated compounds. A mixed mode column was used to effectively separate each of the excipient structures from the drug. The mobile phase comprised acetonitrile-ammonium formate (20mM; pH 6.5) (50:50, v/v) at a flow-rate of 0.6 ml/min. Qualification studies showed that the method was adequately sensitive and precise with limits of detection between 0.72 and 4.32 microg/ml. Linearity of the calibration curves was achieved by log-log modelling. The method was applied for determination of nine polymeric excipients and surfactants adsorbed to particles of the model drug. The extent of excipient adsorption varied between 0.07 and 1.39% (w/w) of the total particle weight.

  8. Drug –induced liver injury:a review

    Directory of Open Access Journals (Sweden)

    Sreya Kosanam

    2015-03-01

    Full Text Available The incidence of drug induced liver injury (DILI is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized based on the pattern of liver enzyme alteration (hepatocellular, cholestatic or mixed pattern, the mechanism of hepatotoxicity (direct, immune mediated or idiosyncratic and histologic findings on liver biopsy (steatosis or sinusoidal obstruction syndrome. Treatment options for DILI include discontinuing the drug, conservative measurements and liver transplantation in the case of non-acetaminophen induced hepatotoxicity.

  9. Folic acid-functionalized magnetic ZnFe2O4 hollow microsphere core/mesoporous silica shell composite particles: synthesis and application in drug release.

    Science.gov (United States)

    Yang, Dandan; Wei, Kaiwei; Liu, Qi; Yang, Yong; Guo, Xue; Rong, Hongren; Cheng, Mei-Ling; Wang, Guoxiu

    2013-07-01

    A drug delivery system was designed by deliberately combining the useful functions into one entity, which was composed of magnetic ZnFe2O4 hollow microsphere as the core, and mesoporous silica with folic acid molecules as the outer shell. Amine groups coated magnetic ZnFe2O4 hollow microsphere core/mesoporous silica shell (MZHM-MSS-NH2) composite particles were first synthesized by a one-pot direct co-condensation method. Subsequently a novel kind of folic acid-functionalized magnetic ZnFe2O4 hollow microsphere core/mesoporous silica shell (MZHM-MSS-NHFA) composite particles were synthesized by conjugating folic acid as targeted molecule to MZHM-MSS-NH2. Ibuprofen, a well-known antiphlogistic drug, was used as a model drug to assess the loading and releasing behavior of the composite microspheres. The results show that the MZHM-MSS-NHFA system has the higher capacity of drug storage and good sustained drug-release property.

  10. Simultaneous voltammetric determination of tramadol and acetaminophen using carbon nanoparticles modified glassy carbon electrode

    Energy Technology Data Exchange (ETDEWEB)

    Ghorbani-Bidkorbeh, Fatemeh [Department of Chemistry, Sharif University of Technology, Tehran 11155-9516 (Iran, Islamic Republic of); Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Shahrokhian, Saeed, E-mail: shahrokhian@sharif.ed [Department of Chemistry, Sharif University of Technology, Tehran 11155-9516 (Iran, Islamic Republic of); Institute for Nanoscience and Technology, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Mohammadi, Ali [Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Dinarvand, Rassoul [Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of)

    2010-03-01

    A sensitive and selective electrochemical sensor was fabricated via the drop-casting of carbon nanoparticles (CNPs) suspension onto a glassy carbon electrode (GCE). The application of this sensor was investigated in simultaneous determination of acetaminophen (ACE) and tramadol (TRA) drugs in pharmaceutical dosage form and ACE determination in human plasma. In order to study the electrochemical behaviors of the drugs, cyclic and differential pulse voltammetric studies of ACE and TRA were carried out at the surfaces of the modified GCE (MGCE) and the bare GCE. The dependence of peak currents and potentials on pH, concentration and the potential scan rate were investigated for these compounds at the surface of MGCE. Atomic force microscopy (AFM) was used for the characterization of the film modifier and its morphology on the surface of GCE. The results of the electrochemical investigations showed that CNPs, via a thin layer model based on the diffusion within a porous layer, enhanced the electroactive surface area and caused a remarkable increase in the peak currents. The thin layer of the modifier showed a catalytic effect and accelerated the rate of the electron transfer process. Application of the MGCE resulted in a sensitivity enhancement and a considerable decrease in the anodic overpotential, leading to negative shifts in peak potentials. An optimum electrochemical response was obtained for the sensor in the buffered solution of pH 7.0 and using 2 muL CNPs suspension cast on the surface of GCE. Using differential pulse voltammetry, the prepared sensor showed good sensitivity and selectivity for the determination of ACE and TRA in wide linear ranges of 0.1-100 and 10-1000 muM, respectively. The resulted detection limits for ACE and TRA was 0.05 and 1 muM, respectively. The CNPs modified GCE was successfully applied for ACE and TRA determinations in pharmaceutical dosage forms and also for the determination of ACE in human plasma.

  11. Determination of Log K[subscript ow] Values for Four Drugs

    Science.gov (United States)

    Harris, Mark F.; Logan, Jennifer L.

    2014-01-01

    Though many undergraduates are interested in medicine, relatively few experiments related to drug design and development are included in introductory chemistry laboratory courses. In this experiment, aqueous solutions of four different drugs (acetaminophen, caffeine, phenacetin, and sulfanilamide) are extracted using 1-octanol, a mimic of the…

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

    Directory of Open Access Journals (Sweden)

    Geeta

    2015-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Christophe Mallet

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

  14. Studies on the compressibility of wax matrix granules of acetaminophen and their admixtures with various tableting bases.

    Science.gov (United States)

    Uhumwangho, M U; Okor, R S

    2006-04-01

    Matrix granules of acetaminophen have been formed by a melt granulation process whereby the acetaminophen powder was triturated with the melted wax--goat wax, glyceryl monostearate or carnuba wax. The compressibility of the matrix granules and their admixture, with diluent granules (lactose, alpha-cellulose or microcrystalline cellulose) was investigated. The granules were compressed to tablets at a constant load (30 arbitrary units on the load scale) of a manesty single punch machine. Resulting tablets were evaluated for tensile strength (T) and disintegration times (DT). Granule flow was determined by measuring their angle of repose when allowed to fall freely on a level surface. Matrix granules prepared by melt granulation with goat wax or glyceryl monostearate were too sticky and therefore did not flow at all. They were also poorly compressible (T values = 0.20MN/m2). Inclusion of the diluent remarkably improved granule flow property and compressibility. The T values of the tablets (measure of compressibility) increased from about 0.24 to 0.65 MN/m2 during increase in diluent (lactose) content from 20 to 80 %w/w. Microcrystalline cellulose and alpha-cellulose were more effective than lactose in promoting compressibility of the granules. By contrast the matrix granules formed with carnuba wax were free flowing (angle of repose, 18.60). Addition of the diluent further improved flowability slightly. The matrix granules (without a diluent) were readily compressible (T value, 1.79MN/m2). Addition of the diluent (80%w/w) reduced T values (MN/m2) slightly to 1.32 (lactose), 1.48 (alpha-cellulose) and 1.74 (microcrystalline cellulose). Tablets of the matrix granules only, disintegrated rapidly within 3 minutes. DT was further reduced to wax proved most promising in the melt granulation of the test drug for sustained release applications.

  15. Tramadol/acetaminophen combination as add-on therapy in the treatment of patients with ankylosing spondylitis.

    Science.gov (United States)

    Chang, Jhi-Kai; Yu, Chen-Tung; Lee, Ming-Yung; Yeo, Kj; Chang, I-Chang; Tsou, Hsi-Kai; Wei, James Cheng-Chung

    2013-03-01

    This study aimed to determine the safety and efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (Ultracet®) in patients with ankylosing spondylitis (AS). This was a 12-week, randomized, double-blind, placebo-controlled study. Sixty patients with active AS according to the Modified New York Criteria were enrolled. Active disease was defined by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for more than 3 at randomization. Subjects were randomized equally into two groups: the treatment group received aceclofenac plus Ultracet® one tablet twice a day, and the control group received aceclofenac plus placebo for 12 weeks. The primary endpoint was a difference of Assessment in Ankylosing Spondylitis (ASAS20) response criteria between two groups at week 12. At week 12, ASAS20 was achieved by 53.3 % of the aceclofenac plus Ultracet group and 31 % of the aceclofenac alone group (p = 0.047). For the pain visual analogue scale at week 12, there was a reduction of 45.6 % in aceclofenac plus Ultracet group and 25.7 % in the aceclofenac alone group (p = 0.087). There was no statistically significant difference between two groups in BASDAI, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Global Index, Physician Global Assessment, spinal mobility, ESR, hs-CRP, and Ankylosing Spondylitis Quality of Life Questionnaire. A slight increase in total adverse events was noted with dizziness (7.5 vs 1.5 %), vertigo (4.5 vs 1.5 %), and nausea/vomiting (6 vs 0 %) in the Ultracet arm compared to placebo. The tramadol 37.5 mg/acetaminophen 325 mg combination tablet (Ultracet®) might has additional effect to nonsteroidal anti-inflammatory drugs in the treatment of patients with ankylosing spondylitis. It showed marginal benefit in pain and disease activity. However, a slight increase in minor adverse events was noted.

  16. Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

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    Isaac Mohar

    2014-01-01

    Full Text Available The mechanism by which acetaminophen (APAP causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD compared to male C57BL/6 mice in order to identify the cause(s of sensitivity. Furthermore, we use mice that are either heterozygous (HZ or null (KO for glutamate cysteine ligase modifier subunit (Gclm, in order to titrate the toxicity relative to wild-type (WT mice. Gclm is important for efficient de novo synthesis of glutathione (GSH. APAP (300 mg/kg, ip or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  18. Comparação da eficácia de doses iguais de acetaminofeno retal e oral em crianças Comparison of antipyretic effectiveness of equal doses of rectal and oral acetaminophen in children

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    Sedigha Akhavan Karbasi

    2010-06-01

    Full Text Available OBJETIVO: Comparar uma dose de acetaminofeno oral e retal e avaliar a aceitabilidade do acetaminofeno retal, uma vez que o acetaminofeno oral e retal é amplamente usado como agente antipirético em crianças com febre e a eficiência comparativa dessas duas preparações não está bem estabelecida. MÉTODOS: Neste estudo prospectivo de grupos paralelos, foram incluídas 60 crianças admitidas na emergência ou clínica ambulatorial pediátrica em um hospital terciário, com idade entre 6 meses e 6 anos e com temperatura retal acima de 39 °C. Os pacientes foram distribuídos aleatoriamente em dois grupos de mesmo tamanho. O grupo 1 recebeu 15 mg/kg de acetaminofeno retal, e o grupo 2 recebeu a mesma dose oralmente. A temperatura foi registrada no tempo zero e 1 e 3 horas após administração da droga. RESULTADOS: No primeiro grupo, a redução média de temperatura, 1 e 3 horas após administração do acetaminofeno, foi de 1,07±0,16 (p 0,05. CONCLUSÃO: As preparações oral e retal de acetaminofeno têm eficácia antipirética equivalente em crianças. A via retal mostrou ser tão aceitável quanto a oral entre os pais.OBJECTIVE: To compare a dose of oral and rectal acetaminophen and to evaluate acceptability of rectal acetaminophen, since oral and rectal acetaminophen is widely used as an antipyretic agent in febrile children and the comparative effectiveness of these two preparations is not well established. METHODS: In this prospective parallel group designed study, 60 children who presented to the emergency department or outpatient pediatric clinic at a tertiary hospital and aged from 6 months to 6 years with rectal temperature over 39 °C were enrolled. Patients were randomly assigned to two equal-sized groups. Group 1 received 15 mg/kg acetaminophen rectally and group 2 received the same dose orally. Temperature was recorded at baseline and 1 and 3 hours after drug administration. RESULTS: In the first group, mean decrease in

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

    DEFF Research Database (Denmark)

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

    2003-01-01

    an indirect measure of gastric emptying. Emulsified fats with added acetaminophen were fed by gavage to rats, and the plasma concentration of acetaminophen was followed for 3 h by repeated blood sampling from the carotid artery. The fats administered included rapeseed, corn, and fish oils, lard, and cocoa...

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

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    Kopylchuk G.P.

    2015-09-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Nnodim Johnkennedy; Emejulu Adamma

    2011-01-01

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

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

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    Narayanan Kannan

    2013-01-01

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

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

    Science.gov (United States)

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

    2015-12-01

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

  4. Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways.

    Science.gov (United States)

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

    2014-07-01

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

  5. Evaluation of protective effect of hydroalcoholic extract of saffron petals in prevention of acetaminophen-induced renal damages in rats

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    Arash Omidi

    2015-03-01

    Full Text Available In recent years more attention has been given to herbal drugs in the treatment and prevention of drug toxicity because of the harmful effects of chemical drugs. In this study, directed for this purpose, research was conducted on the protective effect of hydro-ethanolic extract of saffron petals (SPE against acetaminophen (APAP induced acute nephrotoxicity. Twenty-four male Wistar rats were distributed into four groups of six each. Group I, as a control group, received normal saline (0.09% orally (PO. Group II, as an intoxicated group was treated with APAP, PO (600 mg/kg. In the groups III and IV, SPE in a dose of 10 and 20 mg/kg along with APAP (600 mg/kg was administered, respectively. At the end of the trial (8th day, blood was taken from the heart of rats for assessment of biochemical parameters and the right kidney was placed in 10% buffered formalin for histopathological evaluations. In the APAP treatment group, higher serum creatinine and uric acid were observed. SPE in a dose of 20 mg/kg significantly reduced serum creatinine and uric acid. In pathologic evaluation, a dose of 20 mg/kg of SPE prevented the kidney injuries induced by APAP. Tissues changes were in accordance with biochemical findings. It is likely that the SPE contributed to the prevention of acute nephrotoxicity induced by APAP.

  6. Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    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.

  7. Effects of kale ingestion on pharmacokinetics of acetaminophen in rats.

    Science.gov (United States)

    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.

  8. Protective role of p53 in acetaminophen hepatotoxicity.

    Science.gov (United States)

    Huo, Yazhen; Yin, Shutao; Yan, Mingzhu; Win, Sanda; Aung Than, Tin; Aghajan, Mariam; Hu, Hongbo; Kaplowitz, Neil

    2017-02-11

    p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout. Mice were treated with APAP (300mg/kg) i.p. and after 24h in all three conditions, the liver injury was more severe as reflected in higher ALT levels and great area of necrosis in histology of the liver. Conversely, a p53 activator, nutlin-3a, decreased the liver injury induced by APAP. In the p53 inhibition models, enhanced sustained JNK activation was seen in the early time course, while the JNK was suppressed with the p53 activator. In conclusion, p53 plays a novel protective role in APAP induced liver injury through inhibiting the activation of JNK, a key mediator in APAP-induced oxidative stress.

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

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    Xiaoyan Lu

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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Abeer Hanafy

    2016-01-01

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

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

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    Daniela Rodrigues

    2012-12-01

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

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

    Science.gov (United States)

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

    2015-11-01

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

  14. Activation of GR but not PXR by dexamethasone attenuated acetaminophen hepatotoxicities via Fgf21 induction.

    Science.gov (United States)

    Vispute, Saurabh G; Bu, Pengli; Le, Yuan; Cheng, Xingguo

    2017-03-01

    Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity. Our results showed that DEX dose/concentration- and time-dependently increased Fgf21 mRNA and protein expression in mouse liver as well as cultured mouse and human hepatoma cells. By using PXR-null mouse model, we demonstrated that DEX induced Fgf21 expression by a PXR-independent mechanism. In cultured mouse and human hepatoma cells, inhibition of GR signaling, by RU486 (Mifepristone) or GR silencing using GR-specific siRNA, attenuated DEX-induced Fgf21 expression. In addition, DEX increased luciferase reporter activity driven by the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Further, ChIP-qPCR assays demonstrated that DEX increased the binding of GR to the specific cis-regulatory elements located in the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Pretreatment of 2mg/kg DEX ameliorated APAP-induced liver injury in wild-type but not Fgf21-null mice. In conclusion, via GR activation, DEX induced Fgf21 expression in mouse liver and human hepatoma cells.

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Liwen eZhang

    2012-09-01

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

  18. Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.

    Science.gov (United States)

    Tran, A; Tréluyer, J M; Rey, E; Barbet, J; Ferracci, G; d'Athis, P; Vincent, J; Pons, G

    2001-02-01

    Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.

  19. Regulating Drug Release Behavior and Kinetics from Matrix Tablets Based on Fine Particle-Sized Ethyl Cellulose Ether Derivatives: An In Vitro and In Vivo Evaluation

    Directory of Open Access Journals (Sweden)

    Kifayat Ullah Shah

    2012-01-01

    Full Text Available The design and fabrication of sustained/controlled release dosage forms, employing new excipients capable of extending/controlling the release of drugs from the dosage forms over prolonged periods, has worked well in achieving optimally enhanced therapeutic levels of the drugs. In this sense, the objective of this study was to investigate the suitability of selected cellulose ether derivatives for use in direct compression (DC and as efficient drug release controlling agents. Controlled release matrix tablets of ciprofloxacin were prepared at different drug-to-polymer (D : P ratios by direct compression using a fine particle sized ethylcellulose ether derivative (ETHOCEL Standard Premium 7FP as rate controlling polymer. The tablets obtained were evaluated for various physico-chemical characteristics and in-vitro drug release studies were conducted in phosphate buffer (pH 7.4 using PharmaTest dissolution apparatus at constant temperature of 37∘C±0.1. Similarity factor 2 was employed to the release profiles of test formulations and were compared with marketed ciprofloxacin conventional tablets. Drug release mechanism and the kinetics involved were investigated by fitting the release profile data to various kinetic models. It was found that with increasing the proportion of ethylcellulose ether derivative in the matrix, the drug release was significantly extended up to 24 hours. The tablets exhibited zero order or nearly zero order drug transport mechanism. In vivo drug release performance of the developed controlled release tablets and reference conventional tablets containing ciprofloxacin were determined in rabbit serum according to randomized two-way crossover study design using High Performance Liquid Chromatography. Several bioavailability parameters of both the test tablets and conventional tablets including max, max and AUC0- were compared which showed an optimized max and max (<0.05. A good correlation was obtained between in vitro

  20. Regulating drug release behavior and kinetics from matrix tablets based on fine particle-sized ethyl cellulose ether derivatives: an in vitro and in vivo evaluation.

    Science.gov (United States)

    Shah, Kifayat Ullah; Khan, Gul Majid

    2012-01-01

    The design and fabrication of sustained/controlled release dosage forms, employing new excipients capable of extending/controlling the release of drugs from the dosage forms over prolonged periods, has worked well in achieving optimally enhanced therapeutic levels of the drugs. In this sense, the objective of this study was to investigate the suitability of selected cellulose ether derivatives for use in direct compression (DC) and as efficient drug release controlling agents. Controlled release matrix tablets of ciprofloxacin were prepared at different drug-to-polymer (D : P) ratios by direct compression using a fine particle sized ethylcellulose ether derivative (ETHOCEL Standard Premium 7FP) as rate controlling polymer. The tablets obtained were evaluated for various physico-chemical characteristics and in-vitro drug release studies were conducted in phosphate buffer (pH 7.4) using PharmaTest dissolution apparatus at constant temperature of 37 °C ± 0.1. Similarity factor f(2) was employed to the release profiles of test formulations and were compared with marketed ciprofloxacin conventional tablets. Drug release mechanism and the kinetics involved were investigated by fitting the release profile data to various kinetic models. It was found that with increasing the proportion of ethylcellulose ether derivative in the matrix, the drug release was significantly extended up to 24 hours. The tablets exhibited zero order or nearly zero order drug transport mechanism. In vivo drug release performance of the developed controlled release tablets and reference conventional tablets containing ciprofloxacin were determined in rabbit serum according to randomized two-way crossover study design using High Performance Liquid Chromatography. Several bioavailability parameters of both the test tablets and conventional tablets including C(max⁡), T(max⁡) and AUC(0-t) were compared which showed an optimized C(max⁡) and T(max⁡) (P < 0.05). A good correlation was obtained

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

    Science.gov (United States)

    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 hepatotoxicity. Liver histopathological examination showed that pioglitazone administration antagonized acetaminophen -induced liver pathological damage. Various biochemical estimations of different hepatic markers and antioxidant enzymes and histopathological studies of liver tissues glimpse a support to its significant hepatoprotective activity on acetaminophen -induced hepatotoxicity.

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-15

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

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

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    . Prospectively, serial measurements of serum phosphate were performed in 125 patients with severe acetaminophen poisoning. The optimum threshold value of serum phosphate to discriminate nonsurvivors was identified. Prognostic value and speed of identification were compared with those of the King's College...... after acetaminophen overdose is seen exclusively in nonsurvivors, which makes it a highly specific as well as sensitive predictor of nonsurvival. We propose that hyperphosphatemia is caused by renal dysfunction in the absence of hepatic regeneration, as the latter appears to be associated with lowering...

  5. Undifferentiated Altered Mental Status: A Late Presentation of Toxic Acetaminophen Ingestion

    Directory of Open Access Journals (Sweden)

    Thomas E. Robey

    2012-01-01

    Full Text Available Altered mental status is a common undifferentiated presentation in the emergency department. We describe a case of acetaminophen-induced acute liver failure that was diagnosed and treated prior to obtaining definitive historical or laboratory information about the etiology. The physical exam finding of scleral icterus in this case was a key element to rapid identification and treatment of this life-threatening condition. A discussion of appropriate N-acetylcysteine treatment for acute liver failure and acetaminophen intoxication is included.

  6. Formulation and evaluation of gelatin micropellets of aceclofenac: Effect of process variables on encapsulation efficiency, particle size and drug release

    Directory of Open Access Journals (Sweden)

    Sahoo S

    2008-01-01

    Full Text Available In the present study aceclofenac-gelatin micropellets were prepared by the cross linking technique using gluteraldehyde as cross linking agent and characterized by X-ray diffractometry, differential scanning calorimetry and scanning electron microscopy. The effect of drug: polymer ratio, temperature of oil phase, amount of gluteraldehyde and stirring time was studied with respect to entrapment efficiency, micropellet size and drug release characteristics. Spherical micropellets having an entrapment efficiency of 57% to 97% were obtained. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The micromeritic studies of micropellets show improved flow property. The entrapment efficiency, micropellet size and drug release profile was altered significantly by changing various processing parameters.

  7. Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen

    Directory of Open Access Journals (Sweden)

    Vittorio Vellani

    2017-01-01

    Full Text Available Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKCε translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs. We found that gabapentin significantly reduced PKCε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen, a very commonly used analgesic drug, also produces inhibition of PKCε. We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

  8. Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen)

    Science.gov (United States)

    2017-01-01

    Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKCε) translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs). We found that gabapentin significantly reduced PKCε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen), a very commonly used analgesic drug, also produces inhibition of PKCε. We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

  9. Design and characterization of a device to quantify the magnetic drug targeting efficiency of magnetic nanoparticles in a tube flow phantom by magnetic particle spectroscopy

    Science.gov (United States)

    Radon, Patricia; Löwa, Norbert; Gutkelch, Dirk; Wiekhorst, Frank

    2017-04-01

    The aim of magnetic drug targeting (MDT) is to transfer a therapeutic drug coupled to magnetic nanoparticles (MNP) to desired disease locations (e.g. tumor region) with the help of magnetic field gradients. To transfer the MDT approach into clinical practice a number of important issues remain to be solved. We developed and characterized an in-vitro flow phantom to provide a defined and reproducible MDT environment. The tube system of the flow phantom is directed through the detection coil of a magnetic particle spectroscopy (MPS) device to determine the targeting efficiency. MPS offers an excellent temporal resolution of seconds and an outstanding specific sensitivity of some nanograms of iron. In the flow phantom different MNP types, magnet geometries and tube materials can be employed to vary physical parameters like diameter, flow rate, magnetic targeting gradient, and MNP properties.

  10. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity.

    Science.gov (United States)

    Yohe, Herbert C; O'Hara, Kimberley A; Hunt, Jane A; Kitzmiller, Tamar J; Wood, Sheryl G; Bement, Jenna L; Bement, William J; Szakacs, Juliana G; Wrighton, Steven A; Jacobs, Judith M; Kostrubsky, Vsevolod; Sinclair, Peter R; Sinclair, Jacqueline F

    2006-06-01

    The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-alpha. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-alpha. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity.

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

    Directory of Open Access Journals (Sweden)

    Inmaculada Posadas

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

  12. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    Directory of Open Access Journals (Sweden)

    Miriam S. N. Hohmann

    2013-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  14. Short-term treatment with alcohols causes hepatic steatosis and enhances acetaminophen hepatotoxicity in Cyp2e1(-/-) mice.

    Science.gov (United States)

    Sinclair, J F; Szakacs, J G; Wood, S G; Walton, H S; Bement, J L; Gonzalez, F J; Jeffery, E H; Wrighton, S A; Bement, W J; Sinclair, P R

    2000-10-15

    CYP2E1 has been reported to have an essential role in alcohol-mediated increases in hepatic steatosis and acetaminophen hepatotoxicity. We found that pretreatment of Cyp2e1(-/-) mice with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, for 7 days resulted in micro- and macrovesicular steatosis in the livers of all mice, as well as a dramatic increase in acetaminophen hepatotoxicity. In Cyp2e1(-/-) mice administered up to 600 mg acetaminophen/kg alone and euthanized 7 h later, there was no increase in serum levels of ALT. In Cyp2e1(-/-) mice pretreated with ethanol and isopentanol, subsequent exposure to 400 or 600 mg acetaminophen/kg resulted in centrilobular necrosis in all mice with maximal elevation in serum levels of ALT. Acetaminophen-mediated liver damage was similar in males and females. Hepatic microsomal levels of APAP activation in untreated females were similar to those in males treated with the alcohols. However, the females, like the males, required pretreatment with the alcohols in order to increase APAP hepatotoxicity. These findings suggest that, in the Cyp2e1(-/-) mice, the alcohol-mediated increase in acetaminophen hepatotoxicity involves the contribution of other factors, in addition to induction of CYP(s) that activate acetaminophen. Alternatively, CYP-mediated activation of acetaminophen measured in vitro may not reflect the actual activity in vivo. Our findings that a 7-day treatment with ethanol and isopentanol causes extensive hepatic steatosis and increases acetaminophen hepatotoxicity in Cyp2e(-/-) mice indicate that CYP2E1 is not essential for either response.

  15. Screening strategy to avoid toxicological hazards of inhaled nanoparticles for drug delivery: The use of a-quartz and nano zinc oxide particles as benchmark

    Energy Technology Data Exchange (ETDEWEB)

    Beyerle, Andrea; Schulz, Holger; Stoeger, Tobias [Institute of Inhalation Biology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstrasse 1, D - 85764 Neuherberg (Germany); Kissel, Thomas, E-mail: tobias.stoeger@helmholtz-muenchen.d [Department of Pharmaceutical Technology and Biopharmacy, Philipps- University Marburg (Germany)

    2009-02-01

    Nanotechnology is a broad, revolutionary field with promising advantages for new medicine. In this context the rapid development and improvement of so called nanocarriers is of high pharmaceutical interest and some devices are already on the market. In our project we aim to develop well characterized nanoscaled drug delivery systems for an inhalative application. To this end, we focus on the most adverse side-effects within the lung, the cytotoxic and the proinflammatory responses to these nanoparticles (NPs). Before performing any animal experiments, we start with an in vitro screening for analyzing the cytotoxic and proinflammatory effects of the investigated particles on two murine lung target cell lines, the alveolar epithelial like typ II cell line (LA4) and the alveolar macrophage cell line (MH-S). Three different endpoints were estimated, (i) cellular metabolic activity, determined by the WST-1 assay, (ii) membrane integrity, by detection of LDH release and hemolytic activity, and (iii) secretion of inflammatory mediators. To analyze the relative particle toxicity we choose two reference particles as benchmarks, (i) fine a-quartz, and (ii) ultrafine ZnO particles. The investigation of dose-response and kinetics of proinflammatory and toxic effects caused to the named cell lines provide an insight to a close evaluation of our cell based screening strategy. oc-quartz is well known for its inflammatory and toxic potential caused by inhalation, and nanosized ZnO particles - used in a broad field of nanotechnology like electronics, but also cosmetics and pharmaceuticals - is to a high degree cytotoxic and proinflammatory in vitro. Preliminary experiments indicated not only particle and cell specific inflammatory responses, but also different susceptibilities of the cell types being exposed to our benchmark particles regarding their size and surface activities. Exposure to the mum-sized a-quartz particles affected the viability of epithelia cells less than that of

  16. Screening strategy to avoid toxicological hazards of inhaled nanoparticles for drug delivery: The use of a-quartz and nano zinc oxide particles as benchmark

    Science.gov (United States)

    Beyerle, Andrea; Schulz, Holger; Kissel, Thomas; Stoeger, Tobias

    2009-02-01

    Nanotechnology is a broad, revolutionary field with promising advantages for new medicine. In this context the rapid development and improvement of so called nanocarriers is of high pharmaceutical interest and some devices are already on the market. In our project we aim to develop well characterized nanoscaled drug delivery systems for an inhalative application. To this end, we focus on the most adverse side-effects within the lung, the cytotoxic and the proinflammatory responses to these nanoparticles (NPs). Before performing any animal experiments, we start with an in vitro screening for analyzing the cytotoxic and proinflammatory effects of the investigated particles on two murine lung target cell lines, the alveolar epithelial like typ II cell line (LA4) and the alveolar macrophage cell line (MH-S). Three different endpoints were estimated, (i) cellular metabolic activity, determined by the WST-1 assay, (ii) membrane integrity, by detection of LDH release and hemolytic activity, and (iii) secretion of inflammatory mediators. To analyze the relative particle toxicity we choose two reference particles as benchmarks, (i) fine a-quartz, and (ii) ultrafine ZnO particles. The investigation of dose-response and kinetics of proinflammatory and toxic effects caused to the named cell lines provide an insight to a close evaluation of our cell based screening strategy. oc-quartz is well known for its inflammatory and toxic potential caused by inhalation, and nanosized ZnO particles - used in a broad field of nanotechnology like electronics, but also cosmetics and pharmaceuticals - is to a high degree cytotoxic and proinflammatory in vitro. Preliminary experiments indicated not only particle and cell specific inflammatory responses, but also different susceptibilities of the cell types being exposed to our benchmark particles regarding their size and surface activities. Exposure to the μm-sized a-quartz particles affected the viability of epithelia cells less than that of

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

    Science.gov (United States)

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

    2013-11-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Khan Hira

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kappelle L Jaap

    2008-11-01

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

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

    NARCIS (Netherlands)

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

    2013-01-01

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

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

    OpenAIRE

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2014-03-01

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

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

    Science.gov (United States)

    Dewprashad, Brahmadeo

    2009-01-01

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

  8. Free radical scavenging activity of Berberine in acetaminophen induced liver injury

    Directory of Open Access Journals (Sweden)

    Suhail Ahmed Almani

    2017-01-01

    Full Text Available Objective: Evaluation of free radical scavenging activity of Berberine (BBR in acetaminophen (AAP induced liver injury. Study design: Experimental study Place and Duration: Animal house, Isra University Hyderabad from October 2015 to March 2016. Methodology: A sample of 80 male Wistar rats was selected according to inclusion and exclusion criteria and was divided into a control and three experimental groups. Acetaminophen, N-acetyl cysteine (NAC and BBR were administered in standard doses. Blood samples were collected by cardiac puncture after 18 hours of post experiment period. Liver function test, anti oxidant enzymes and malondialdehyde (MDA were detected by ELISA assay kit (Fortress Diagnostics. The data was analyzed on Statistix 10.0 software (USA at 95% CI (P≤ 0.05. Results: The BBR showed anti oxidant and anti peroxidant activity against acetaminophen induced liver injury. BBR treated animals showed increased serum and tissue SOD, GPX, CAT, and GSSH with a reduction in tissue MDA (p=0.0001. Liver injury ameliorating effect of BBR was superior to N-acetyl cysteine. Conclusion: The present study suggests Berberine protects against acetaminophen-induced liver injury by its free radical scavenging activity.

  9. Protective effects of pterostilbene against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    El-Sayed, El-Sayed M; Mansour, Ahmed M; Nady, Mohamed E

    2015-01-01

    The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase-3, hydroxyproline, with significant decreases in serum HDL-cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

  10. An Experiment in Physical Chemistry: Polymorphism and Phase Stability in Acetaminophen (Paracetamol)

    Science.gov (United States)

    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,…

  11. Effect of single dose intraoperative IV acetaminophen in pediatric tonsillectomy or adenotonsillectomy

    Directory of Open Access Journals (Sweden)

    Christopher A. Roberts

    2017-01-01

    Conclusion: Intraoperative intravenous acetaminophen may lead to improved pain scores in the early postoperative period and decreased time in the recovery room, but this group also had a longer hospital stay. This information should instigate randomized controlled trials of this intervention.

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  14. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose.

    Science.gov (United States)

    Spiller, Henry A; Winter, Mark L; Klein-Schwartz, Wendy; Bangh, Stacey A

    2006-01-01

    To evaluate whether administration of activated charcoal, in addition to standard N-acetylcysteine (NAC) therapy, after acetaminophen overdose provides additional patient benefit over NAC therapy alone, a 1-year non-randomized prospective, multi-center, observational case series was performed at three poison centers and one poison center system. Entrance criteria were all acute acetaminophen overdoses with: 1) an acetaminophen blood concentration determined to be in the toxic range by the Rumack-Matthew nomogram; and 2) all therapies, including NAC and activated charcoal, initiated between 4 and 16 h post-ingestion. There were 145 patients meeting entrance criteria, of whom 58 patients (40%) received NAC only and 87 patients (60%) received NAC and activated charcoal. Overall, 23 patients had elevations of AST or ALT greater than 1000 IU/L, of which 21 patients received NAC only (38% of total NAC only group) and 2 patients received NAC and activated charcoal (2% of total NAC+AC group). Administration of activated charcoal in this series of patients with toxic acetaminophen concentrations treated with NAC was associated with reduced incidence of liver injury, as measured by elevated serum transaminases and prothrombin times.

  15. Raspberry-like poly(γ-glutamic acid hydrogel particles for pH-dependent cell membrane passage and controlled cytosolic delivery of antitumor drugs

    Directory of Open Access Journals (Sweden)

    Cho SH

    2016-10-01

    Full Text Available Sun-Hee Cho,1,* Ji Hyeon Hong,2,* Young-Woock Noh,1 Eunji Lee,2 Chang-Soo Lee,3 Yong Taik Lim1 1SKKU Advanced Institute of Nanotechnology, School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do, 2Graduate School of Analytical Science and Technology, Chungnam National University, 3Hazards Monitoring Bionano Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea *These authors contributed equally to this work Abstract: In this research, we synthesized bioderived poly(amino acid hydrogel particles that showed pH-dependent membrane-disrupting properties and controlled cytosolic delivery of antitumor drugs. Poly(γ-glutamic acid (γ-PGA that has been produced extensively using bacteria, especially those of Bacillus subtilis species, was modified with cholesterol (γ-PGA/Chol, and the γ-PGA/Chol conjugates were used to form polymeric nanoparticles the size of 21.0±1.1 nm in aqueous solution. When the polymeric nanoparticles were mixed with doxorubicin (Dox, raspberry-like hydrogel particles (RBHPs were formed by the electrostatic interaction between the cationically charged Dox and the anionically charged nanoparticles. The average size and surface charge of the RBHPs in aqueous solution were 444.9±122.5 nm and -56.44 mV, respectively. The loaded amount of Dox was approximately 63.9 µg/mg of RBHPs. The RBHPs showed controlled drug release behavior in both in vitro and ex vivo cell-based experiments. Through fluorescence microscopy and fluorescence-activated cell sorting, the cellular uptake of RBHPs into human cervical cancer cells (HeLa was analyzed. The cytotoxic effect, evaluated by the methyl tetrazolium salt assay, was dependent on both the concentration of RBHPs and the treatment time. The pH-dependent membrane-disrupting properties of the RBHPs and the subsequent cytosolic delivery of Dox were evaluated using a standard hemolysis assay. Upon an increase in

  16. Photocatalytic degradation of acetaminophen in modified TiO2 under visible irradiation.

    Science.gov (United States)

    Dalida, Maria Lourdes P; Amer, Kristine Marfe S; Su, Chia-Chi; Lu, Ming-Chun

    2014-01-01

    This study investigated the photocatalytic degradation of acetaminophen (ACT) in synthetic titanium dioxide (TiO2) solution under a visible light (λ >440 nm). The TiO2 photocatalyst used in this study was synthesized via sol-gel method and doped with potassium aluminum sulfate (KAl(SO4)2) and sodium aluminate (NaAlO2). The influence of some parameters on the degradation of acetaminophen was examined, such as initial pH, photocatalyst dosage, and initial ACT concentration. The optimal operational conditions were also determined. Results showed that synthetic TiO2 catalysts presented mainly as anatase phase and no rutile phase was observed. The results of photocatalytic degradation showed that LED alone degraded negligible amount of ACT but with the presence of TiO2/KAl(SO4)2, 95% removal of 0.10-mM acetaminophen in 540-min irradiation time was achieved. The synthetic TiO2/KAl(SO4)2 presented better photocatalytic degradation of acetaminophen than commercially available Degussa P-25. The weak crystallinity of synthesized TiO2/NaAlO2 photocatalyst showed low photocatalytic degradation than TiO2/KAl(SO4)2. The optimal operational conditions were obtained in pH 6.9 with a dose of 1.0 g/L TiO2/KAl(SO4)2 at 30 °C. Kinetic study illustrated that photocatalytic degradation of acetaminophen fits well in the pseudo-first order model. Competitive reactions from intermediates affected the degradation rate of ACT, and were more obvious as the initial ACT concentration increased.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1990-09-01

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

  18. Sustain-release of various drugs from leucaena leucocephala polysaccharide.

    Science.gov (United States)

    Jeevanandham, S; Sekar, M; Dhachinamoorthi, D; Muthukumaran, M; Sriram, N; Joysaruby, J

    2010-01-01

    This study examines the sustained release behavior of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water-insoluble (indomethacin) drugs from Leucaena leucocephala seed Gum isolated from Leucaena leucocephala kernel powder. It further investigates the effect of incorporation of diluents like microcrystalline cellulose and lactose on release of caffeine and partial cross-linking of the gum (polysaccharide) on release of acetaminophen. Applying exponential equation, the mechanism of release of soluble drugs was found to be anomalous. The insoluble drug showed near case II or zero-order release mechanism. The rate of release was in the decreasing order of caffeine, acetaminophen, theophylline, salicylic acid and indomethacin. An increase in release kinetics of drug was observed on blending with diluents. However, the rate of release varied with type and amount of blend in the matrix. The mechanism of release due to effect of diluents was found to be anomalous. The rate of release of drug decreased on partial cross-linking and the mechanism of release was found to be super case II.

  19. pH-sensitive drug loading/releasing in amphiphilic copolymer PAE-PEG: integrating molecular dynamics and dissipative particle dynamics simulations.

    Science.gov (United States)

    Luo, Zhonglin; Jiang, Jianwen

    2012-08-20

    Molecular dynamics (MD) and dissipative particle dynamics (DPD) simulations are integrated to investigate the loading/releasing of anti-cancer drug camptothecin (CPT) in pH-sensitive amphiphilic copolymer, composed of hydrophobic poly(β-amino ester) (PAE) and hydrophilic methyl ether-capped poly(ethylene glycol) (PEG). MD simulation is used to estimate the Flory-Huggins interaction parameters and miscibility of binary components. On this basis, DPD simulation is applied to examine the micellization of PAE-PEG, CPT loading in PAE-PEG, and CPT releasing in PAEH-PEG. With increasing concentration, PAE-PEG forms spherical then disk-like micelles and finally vesicles, as a competitive counterbalance of free energies for the formation of shell, interface and core. CPT loading in PAE-PEG micelles/vesicles is governed by adsorption-growth-micellization mechanism, and CPT is loaded into both hydrophobic core and interface of hydrophobic core/hydrophilic shell. The predicted loading efficiency is close to experimental value. Similar to literature reports, the loading of high concentration of CPT is observed to cause morphology transition from micelles to vesicles. Upon protonation, CPT is released from micelles/vesicles by swelling-demicellization-releasing mechanism. This multi-scale simulation study provides microscopic insight into the mechanisms of drug loading and releasing, and might be useful for the design of new materials for high-efficacy drug delivery.

  20. The impact of preparation parameters on typical attributes of chitosan-heparin nanohydrogels: particle size, loading efficiency, and drug release.

    Science.gov (United States)

    Shahbazi, Mohammad-Ali; Hamidi, Mehrdad

    2013-11-01

    Today, developing an optimized nanoparticle (NP) preparation procedure is of paramount importance in all nanoparticulate drug delivery researches, leading to expanding more operative and clinically validated nanomedicines. In this study, a one-at-a-time experimental approach was used for evaluating the effect of various preparation factors on size, loading, and drug release of hydrogel NPs prepared with ionotropic gelation between heparin and chitosan. The size, loading efficiency (LE) and drug release profile of the NPs were evaluated when the chitosan molecular weight, chitosan concentration, heparin addition time to chitosan solution, heparin concentration, pH value of chitosan solution, temperature, and mixing rate were changed separately while other factors were in optimum condition. The results displayed that size and LE are highly influenced by chitosan concentration, getting an optimum of 63 ± 0.57 and 75.19 ± 2.65, respectively, when chitosan concentration was 0.75 mg/ml. Besides, heparin addition time of 3 min leaded to 74.1 ± 0.79 % LE with no sensible effect on size and release profile. In addition, pH 5.5 showed a minimum size of 63 ± 1.87, maximum LE of 73.81 ± 3.13 and the slowest drug release with 63.71 ± 3.84 % during one week. Although LE was not affected by temperature, size and release reduced to 63 ± 0 and 74.21 ± 1.99% when temperature increased from 25°C to 55°C. Also, continuous increase of mixer rate from 500 to 3500 rpm resulted in constant enhancement of LE from 58.3 ± 3.6 to 74.4 ± 2.59 as well as remarkable decrease in size from 148 ± 4.88 to 63 ± 2.64.

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

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  2. Preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Yamada, S; Murawaki, Y; Kawasaki, H

    1993-09-14

    The preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats was examined by histological and biochemical analysis. Acetaminophen at a dose of 750 mg/kg was administered to male Wistar rats with or without pretreatment with 50 mg/kg of gomisin A. Gomisin A inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxides content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration and necrosis of hepatocytes. However, gomisin A did not affect the decrease in liver glutathione content. These results suggest that gomisin A protects the liver from injury after administration of acetaminophen through the suppression of lipid peroxidation.

  3. Effect of venous dexamethasone, oral caffeine and acetaminophen on relative frequency and intensity of postdural puncture headache after spinal anesthesia

    Directory of Open Access Journals (Sweden)

    Mehrdad Masoudifar

    2016-01-01

    Conclusions: Though the taking of acetaminophen + caffeine + dexamethasone is associated with a decrease in headache intensity and duration and decrease in PDPH incidence, compared with placebo, however, no essentially and statistically significant effect was produced.

  4. Validation Thin Layer Chromatography for the Determination of Acetaminophen in Tablets and Comparison with a Pharmacopeial Method

    Directory of Open Access Journals (Sweden)

    Alina Pyka

    2013-01-01

    Full Text Available Adsorption thin layer chromatography (NP-TLC with densitometry has been established for the identification and the quantification of acetaminophen in three leading commercial products of pharmaceutical tablets coded as brand: P1 (Product no. 1, P2 (Product no. 2, and P3 (Product no. 3. Applied chromatographic conditions have separated acetaminophen from its related substances, namely, 4-aminophenol and and 4′-chloroacetanilide. UV densitometry was performed in absorbance mode at 248 nm. The presented method was validated by specificity, range, linearity, accuracy, precision, detection limit, quantitative limit, and robustness. The TLC-densitometric method was also compared with a pharmacopeial UV-spectrophotometric method for the assay of acetaminophen, and the results confirmed statistically that the NP-TLC-densitometric method can be used as a substitute method. It could be said that the validated NP-TLC-densitometric method is suitable for the routine analysis of acetaminophen in quantity control laboratories.

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

    Directory of Open Access Journals (Sweden)

    Kanwal Zahra

    2012-02-01

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

  6. Adsorption of Selected Pharmaceutical Compounds onto Activated Carbon in Dilute Aqueous Solutions Exemplified by Acetaminophen, Diclofenac, and Sulfamethoxazole.

    Science.gov (United States)

    Chang, E-E; Wan, Jan-Chi; Kim, Hyunook; Liang, Chung-Huei; Dai, Yung-Dun; Chiang, Pen-Chi

    2015-01-01

    The adsorption of three pharmaceuticals, namely, acetaminophen, diclofenac, and sulfamethoxazole onto granular activated carbon (GAC), was investigated. To study competitive adsorption, both dynamic and steady-state adsorption experiments were conducted by careful selection of pharmaceuticals with various affinities and molecular size. The effective diffusion coefficient of the adsorbate was increased with decease in particle size of GAC. The adsorption affinity represented as Langmuir was consistent with the ranking of the octanol-water partition coefficient, K(ow). The adsorption behavior in binary or tertiary systems could be described by competition adsorption. In the binary system adsorption replacement occurred, under which the adsorbate with the smaller K(ow) was replaced by the one with larger K(ow). Results also indicated that portion of the micropores could be occupied only by the small target compound, but not the larger adsorbates. In multiple-component systems the competition adsorption might significantly be affected by the macropores and less by the meso- or micropores.

  7. Electrochemical preparation of nickel and copper oxides-decorated graphene composite for simultaneous determination of dopamine, acetaminophen and tryptophan.

    Science.gov (United States)

    Liu, Bingdi; Ouyang, Xiaoqian; Ding, Yaping; Luo, Liqing; Xu, Duo; Ning, Yanqun

    2016-01-01

    In the present work, transition metal oxides decorated graphene (GR) have been fabricated for simultaneous determination of dopamine (DA), acetaminophen (AC) and tryptophan (Trp) using square wave voltammetry. Electro-deposition is a facile preparation strategy for the synthesis of nickel oxide (NiO) and copper oxide (CuO) nanoparticles. GR can be modified by using citric acid to produce more functional groups, which is conducive to the deposition of dispersed metal particles. The morphologies and interface properties of the obtained NiO-CuO/GR nanocomposite were examined by scanning electron microscopy, energy dispersive X-ray spectroscopy and Raman spectroscopy. Moreover, the electrochemical performances of the composite film were investigated by cyclic voltammetry and electrochemical impedance spectroscopy. The modified electrode exhibited that the linear response ranges for detecting DA, AC and Trp were 0.5-20 μM, 4-400 μM and 0.3-40 μM, respectively, and the detection limits were 0.17 μM, 1.33 μM and 0.1 μM (S/N=3). Under optimal conditions, the sensor displayed high sensitivity, excellent stability and satisfactory results in real samples analysis.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-15

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

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

    Directory of Open Access Journals (Sweden)

    Zeinab M. Gebaly* and Gamal M. Aboul Hassan

    2012-10-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2014-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Haider Raza

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

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

    Science.gov (United States)

    Raza, Haider; John, Annie

    2015-01-01

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

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

    DEFF Research Database (Denmark)

    Dalhoff, K; Poulsen, H E

    1992-01-01

    are dependent on sulphur deriving from cysteine. The effect of cysteine on the syntheses was investigated at non-toxic and toxic concentrations of the hepatotoxic drug acetaminophen (AA). Administration of AA trapped radioactivity (35S) in the pre-labelled PAPS and GSH pools by formation of the metabolites, AA...... in increased median PAPS and GSH syntheses (8 to 11 and 311 to 2218 nmol/10(6) cells/min, respectively) (P less than 0.05). Addition of cysteine did not alter median PAPS synthesis (5 to 3 nmol/10(6) cells/min) but decreased median GSH synthesis (666 to 261 nmol/10(6) cells/min) (P less than 0.......05) in experiments with non-toxic AA concentrations. In experiments with toxic AA concentrations opposite effects of cysteine were seen, i.e. median PAPS synthesis was reduced (3 to 2 nmol/10(6) cells/min) (P less than 0.05) while median GSH synthesis was unchanged (23 to 16 nmol/10(6) cells/min). The present method...

  14. Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

    Directory of Open Access Journals (Sweden)

    Takeshi Yamamotoya

    2017-02-01

    Full Text Available Linear ubiquitin chain assembly complex (LUBAC, composed of SHARPIN (SHANK-associated RH domain-interacting protein, HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1, and HOIP (HOIL-1L interacting protein, forms linear ubiquitin on nuclear factor-κB (NF-κB essential modulator (NEMO and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4 or acetaminophen (APAP, both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

  15. Oxidative removal of acetaminophen using zero valent aluminum-acid system:Efficacy, influencing factors, and reaction mechanism

    Institute of Scientific and Technical Information of China (English)

    Honghua Zhang; Beipei Cao; Wanpeng Liu; Kunde Lin; Jun Feng

    2012-01-01

    Commercial available zero valent aluminum under air-equilibrated acidic conditions (ZVA1/H+/air system) demonstrated an excellent capacity to remove aqueous organic compounds.Acetaminophen (ACTM),the active ingredient of the over-the-counter drug Tylenol(R),is widely present in the aquatic environment and therefore the treatment of ACTM-contaminated water calls for further research.Herein we investigated the oxidative removal of ACTM by ZVAl/H+/air system and the reaction mechanism.In acidic solutions (pH < 3.5),ZVAl displayed an excellent capacity to remove ACTM.More than 99% of ACTM was eliminated within 16 hr in pH 1.5 reaction solutions initially containing 2.0 g/L aluminum and 2.0 mg/L ACTM at 25 ± 1℃.Higher temperature and lower pH facilitated ACTM removal.The addition of different iron species Fe0,Fe2+ and Fe3+ into ZVAl/H+/air system dramatically accelerated the reaction likely due to the enhancing transformation of H2O2 to HO·via Fenton's reaction.Furthermore,the primary intermediate h.ydroquinone and the anions formate,acetate and nitrate,were identified and a possible reaction scheme was proposed.This work suggested that ZVA1/H+/air system may be potentially employed to treat ACTM-contaminated water.

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

    Directory of Open Access Journals (Sweden)

    Bruno da Cruz Pádua

    2014-01-01

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

  17. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers

    Science.gov (United States)

    Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

    2013-01-01

    Aims Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. Methods A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Results Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively). Conclusion The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. PMID:22725836

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

    Science.gov (United States)

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

    2014-06-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-06-15

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-09-15

    Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5 mM, 10 mM or 20 mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24 h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3 h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12 h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3 h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24 h and 48 h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6 h after APAP and a partial protection when given at 15 h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic. - Highlights: • APAP reproducibly causes cell death in freshly isolated primary human hepatocytes. • APAP induces adduct formation, JNK activation and mitochondrial dysfunction in PHH. • Mitochondrial adducts and JNK translocation are delayed in PHH compared to

  1. In vitro validation of drug-induced phospholipidosis.

    Science.gov (United States)

    Park, Sora; Choi, You-Jin; Lee, Byung-Hoon

    2012-01-01

    Intracellular accumulation of phospholipids with lamellar bodies is a hallmark of drug-induced phospholipidosis (PLD) which is caused by impaired phospholipid metabolism of the lysosome. Although it remains uncertain whether PLD is associated with the adverse effects, sponsors generally terminate the development of a candidate drug when PLD is observed in an organ. For drugs that are used without serious adverse events, there should be labels indicating that the drug can induce PLD. We conducted LipidTox and NBD-PE assays for detecting PLD to compare and validate the methods. In the case of contrary results in both assays, electron microscopy was performed to confirm the data. We selected 12 chemicals and divided them into 4 categories: P+S+, PLD and steatosis positive; P+/S-, PLD positive and steatosis negative; P-S+, PLD negative and steatosis positive; P-/S-, PLD and steatosis negative. In general, results showed very good agreement with the known information with some minor discrepancies. LipidTox assay is proven to be a very sensitive method. Considering the contrary results of acetaminophen and menadione in LipidTox and the NBD-PE assay, the combination of two methods using different phospholipids is advantageous to reduce false positives. The finding that acetaminophen was positive in LipidTos assay and increased the frequency of lamellar body implies that acetaminophen is a weak inducer of PLD.

  2. Drug stability analyzer for long duration spaceflights

    Science.gov (United States)

    Shende, Chetan; Smith, Wayne; Brouillette, Carl; Farquharson, Stuart

    2014-06-01

    Crewmembers of current and future long duration spaceflights require drugs to overcome the deleterious effects of weightlessness, sickness and injuries. Unfortunately, recent studies have shown that some of the drugs currently used may degrade more rapidly in space, losing their potency well before their expiration dates. To complicate matters, the degradation products of some drugs can be toxic. Consequently there is a need for an analyzer that can determine if a drug is safe at the time of use, as well as to monitor and understand space-induced degradation, so that drug types, formulations, and packaging can be improved. Towards this goal we have been investigating the ability of Raman spectroscopy to monitor and quantify drug degradation. Here we present preliminary data by measuring acetaminophen, and its degradation product, p-aminophenol, as pure samples, and during forced degradation reactions.

  3. Drug stability analysis by Raman spectroscopy.

    Science.gov (United States)

    Shende, Chetan; Smith, Wayne; Brouillette, Carl; Farquharson, Stuart

    2014-12-22

    Pharmaceutical drugs are available to astronauts to help them overcome the deleterious effects of weightlessness, sickness and injuries. Unfortunately, recent studies have shown that some of the drugs currently used may degrade more rapidly in space, losing their potency before their expiration dates. To complicate matters, the degradation products of some drugs can be toxic. Here, we present a preliminary investigation of the ability of Raman spectroscopy to quantify mixtures of four drugs; acetaminophen, azithromycin, epinephrine, and lidocaine, with their primary degradation products. The Raman spectra for the mixtures were replicated by adding the pure spectra of the drug and its degradant to determine the relative percent contributions using classical least squares. This multivariate approach allowed determining concentrations in ~10 min with a limit of detection of ~4% of the degradant. These results suggest that a Raman analyzer could be used to assess drug potency, nondestructively, at the time of use to ensure crewmember safety.

  4. Drug Stability Analysis by Raman Spectroscopy

    Directory of Open Access Journals (Sweden)

    Chetan Shende

    2014-12-01

    Full Text Available Pharmaceutical drugs are available to astronauts to help them overcome the deleterious effects of weightlessness, sickness and injuries. Unfortunately, recent studies have shown that some of the drugs currently used may degrade more rapidly in space, losing their potency before their expiration dates. To complicate matters, the degradation products of some drugs can be toxic. Here, we present a preliminary investigation of the ability of Raman spectroscopy to quantify mixtures of four drugs; acetaminophen, azithromycin, epinephrine, and lidocaine, with their primary degradation products. The Raman spectra for the mixtures were replicated by adding the pure spectra of the drug and its degradant to determine the relative percent contributions using classical least squares. This multivariate approach allowed determining concentrations in ~10 min with a limit of detection of ~4% of the degradant. These results suggest that a Raman analyzer could be used to assess drug potency, nondestructively, at the time of use to ensure crewmember safety.

  5. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2005-01-01

    An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...... performed in 239 patients with acetaminophen intoxication and a peak alanine aminotransferase (ALT) level above 1000 U/L. AFP was measured using an enzyme-linked immunoassay (EIA) with a detection limit below 0.4 microg/L. The optimum threshold of AFP to discriminate nonsurvivors was identified. An increase...... in AFP above 4 microg/L occurred in 158 (79%) of 201 survivors compared with 11 of 33 nonsurvivors (33%; P AFP occurred a mean of 1.0 days (range, -2 to +6 days) after peak ALT in survivors compared with 4.1 days (range, +2 to +7 days) in nonsurvivors (P

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

    Science.gov (United States)

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

    2011-12-08

    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?

  7. Simplified analysis of acetaminophen glucuronide for quantifying gluconeogenesis and glycogenolysis using deuterated water.

    Science.gov (United States)

    Jones, J; Kahl, S; Carvalho, F; Barosa, C; Roden, M

    2015-06-15

    Measurement of acetaminophen glucuronide (AG) (2)H enrichment from deuterated water ((2)H2O) by (2)H nuclear magnetic resonance (NMR) analysis of its monoacetone glucose (MAG) derivative provides estimation of gluconeogenic and glycogenolytic contributions to endogenous glucose production (EGP). However, AG derivatization to MAG is laborious and unsuitable for high-throughput studies. An alternative derivative, 5-O-acetyl monoacetone glucuronolactone (MAGLA), was tested. Eleven healthy subjects ingested (2)H2O to 0.5% body water enrichment and 500 mg of acetaminophen. Plasma glucose and urinary glucuronide positional (2)H enrichments were measured by (2)H NMR spectroscopy of MAG and MAGLA, respectively. A Bland-Altman analysis indicated agreement at the 95% confidence level between glucose and glucuronide estimates.

  8. The Effect of Piroxicam Administration before Surgical Removal of Mandibular Mesioangular Third Molar Compared with Acetaminophen.

    Directory of Open Access Journals (Sweden)

    Refoua Y

    2000-05-01

    Full Text Available : 32 patients were entered in randomized double blind clinical research. The patients were"ndivided into two groups. Group A(18 patients were given a single dose of 20 mg Piroxicam one hour"npre-surgery. Group B(14 patients were received 325 mg Acetaminophen every six hours immediately"nafter surgery. The mouth opening was measured pre-surgical treatment. Pain relief was evaluated in both"ngroups lsl and 8th hour after surgery. The mouth opening was measured lsl and 7,b day after surgery. The"nresults showed that the analgesic effects of Piroxicam were higher than acetaminophen, however, the"ncomparison of trismus means revealed no significant difference.

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

    Directory of Open Access Journals (Sweden)

    Godrat Akhavanakbari

    2013-01-01

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

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

    Science.gov (United States)

    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

  11. Altered Regulation of Hepatic Efflux Transporters Disrupts Acetaminophen Disposition in Pediatric Nonalcoholic Steatohepatitis

    OpenAIRE

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

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and health...

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

    Directory of Open Access Journals (Sweden)

    Babak Mahshidfar

    2016-01-01

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

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

    Science.gov (United States)

    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.

  14. Data on expression of lipoxygenases-5 and -12 in the normal and acetaminophen-damaged liver

    Directory of Open Access Journals (Sweden)

    Maria Suciu

    2016-06-01

    Mice were injected with acetaminophen, and at 48 h their livers were processed for immunohistochemistry with anti-mouse lipoxygenase-5 and -12 antibodies. At the same time point, the RNA was also extracted from the liver to assess the expression of lipoxygenase-5 and -12 genes via qPCR analysis. Our results show that lipoxygenase-5 expression, but not that of lipoxygenase-12, changes significantly in the acetominophen-damaged liver.

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

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-03-01

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

  17. Preparation and pharmaceutical evaluation of acetaminophen nano-fiber tablets: Application of a solvent-based electrospinning method for tableting.

    Science.gov (United States)

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

    Science.gov (United States)

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

    2012-07-01

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

  19. Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR.

    Science.gov (United States)

    Kanno, Syu-ichi; Tomizawa, Ayako; Yomogida, Shin

    2016-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Drug-induced liver injury from agents such as APAP is known to vary between individuals within a species. To avoid liver injury and ensure the proper use of pharmaceutical products, it is important to be able to predict such risks using genetic information. This study evaluated the use of quantitative real-time polymerase chain reaction (RT-qPCR) to identify mRNAs (carried in the blood of male ddY mice) capable of predicting susceptibility to APAP-induced hepatotoxicity. Screening was performed on samples obtained at 18 h after treatment from mice that had been orally treated with 500 mg/kg APAP. APAP-induced hepatotoxicity was seen in 60% of the mice, and the mortality rate was 12%. Blood APAP concentration did not differ significantly between mice with and without APAP-induced hepatotoxicity. We compared blood mRNA expression levels between mice with (positive, serious or lethal injury) and without hepatotoxicity in the APAP-treated group. The transcript levels of interleukin-encoding loci Il1β, Il10, and tumor necrosis factor (Tnf) were increased in the lethal injury group. Transcripts of the loci encoding transthyretin (Ttr) and metallothionein 1 (Mt1) showed increases in the liver injury group, while those of the glutathione peroxidase 3-encoding locus (Gpx3) were decreased. APAP hepatotoxicity was potentiated in fasted animals, although fasting did not appear to affect the level of expression of these genes. These results indicate that mRNA expression of Il1β, Il10, Tnf, Ttr, Mt1, and Gpx3 in mouse blood may provide useful surrogate markers of APAP-induced hepatotoxicity.

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Directory of Open Access Journals (Sweden)

    John Carlo O. Macuja

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Science.gov (United States)

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

    2014-06-15

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2010-09-01

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

  6. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-04-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5-2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-12-01

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

  8. 氨酚羟考酮依赖性及滥用风险分析%Oxycodone and Acetaminophen Dependence and Abuse Risk Analysis

    Institute of Scientific and Technical Information of China (English)

    马军丽; 逄立艳; 周立新; 张黎明

    2012-01-01

    Oxycodone hydrochloride is a derivative of morphine. The pharmacological effects of the oxycodone hy— drochloride is similar to morphine. There has been animal experiments show that oxycodone and morphine are similar in strengthening effect, and they have the same potential for psychological dependence. In the United States and Australia, oxycodone products are one of the most common drugs being diverted and abused. Although the single and compound preparations of oxycodone hydrochloride are both likely to cause abuse, In China, oxycodone acetaminophen(oxycodone hydrochloride compound) is managed in accordance with prescription drug, so it is more likely to be lossed and abused compared to the single preparation of oxycodone hydrochloride which is managed in accordance with narcotic drugs. Medical institutions and drug regulatory departments shall strengthen the management and monitoring of oxycodone acetaminophen to prevent loss and abuse.%盐酸羟考酮是盐酸吗啡的衍生物,药理作用与吗啡相似,已有动物实验表明羟考酮与吗啡的强化效应相似,具有相同的精神依赖性潜力.在美国和澳大利亚等国,羟考酮类产品是最常被遭到转移和滥用的药品之一.虽然盐酸羟考酮的单方和复方制剂都有可能引发滥用,但在我国盐酸羟考酮的复方制剂即氨酚羟考酮是按照处方药管理,相对于按照麻醉药品管理的单方制剂流失和滥用的可能性更大.医疗机构和药品监管部门应当加强对氨酚羟考酮的管理和监测,积极避免流失和滥用的发生.

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

    Directory of Open Access Journals (Sweden)

    Ahmadi Koorosh

    2014-07-01

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

  10. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Sreenivasan Sasidharan

    2012-11-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2011-12-01

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

  14. Amperometric detection of acetaminophen by an electrochemical sensor based on cobalt oxide nanoparticles in a flow injection system

    Energy Technology Data Exchange (ETDEWEB)

    Razmi, Habib, E-mail: h.razmi@azaruniv.ed [Electrochemistry Research Laboratory, Faculty of Sciences, Azarbaijan University of Tarbiat Moallem, P.O. Box 53714-161, Tabriz (Iran, Islamic Republic of); Habibi, Esmaeil [Electrochemistry Research Laboratory, Faculty of Sciences, Azarbaijan University of Tarbiat Moallem, P.O. Box 53714-161, Tabriz (Iran, Islamic Republic of)

    2010-12-01

    This paper reports the use of a carbon ceramic electrode as a highly-porous substrate for the electrochemical formation of cobalt oxide nanoparticles. The electrocatalyst was characterized by energy dispersive X-ray (EDX) spectroscopy, scanning electron microscopy (SEM) and cyclic voltammetry techniques, and it was used in a homemade flow injection analysis (FIA) system for acetaminophen determination using 0.1 M KOH as the carrier solution. The rate constant (k{sub s}) and charge transfer coefficient ({alpha}) were calculated for the electron exchange reaction of the modified film. The kinetic parameters and the mechanism of acetaminophen electrooxidation at the electrode surface were studied by cyclic voltammetry and chronoamperometry. The effects of working potential and flow rate on the performance of the FIA system were studied. Under optimized conditions, the electrode response due to the electrocatalytic oxidation of acetaminophen at 450 mV (vs. SCE) is proportional to the concentration of acetaminophen over a 5-35 {mu}M range with an associated detection limit (S/N = 3) of 0.37 {mu}M and a sensitivity of 0.0296 {mu}A/{mu}M. The relative standard deviation (RSD) was 1.6% for eight replicate measurements. The modified electrode was used to determine the acetaminophen content in tablet samples.

  15. AC electrokinetic drug delivery in dentistry using an interdigitated electrode assembly powered by inductive coupling.

    Science.gov (United States)

    Ivanoff, Chris S; Wu, Jie Jayne; Mirzajani, Hadi; Cheng, Cheng; Yuan, Quan; Kevorkyan, Stepan; Gaydarova, Radostina; Tomlekova, Desislava

    2016-10-01

    AC electrokinetics (ACEK) has been shown to deliver certain drugs into human teeth more effectively than diffusion. However, using electrical wires to power intraoral ACEK devices poses risks to patients. The study demonstrates a novel interdigitated electrode arrays (IDE) assembly powered by inductive coupling to induce ACEK effects at appropriate frequencies to motivate drugs wirelessly. A signal generator produces the modulating signal, which multiplies with the carrier signal to produce the amplitude modulated (AM) signal. The AM signal goes through the inductive link to appear on the secondary coil, then rectified and filtered to dispose of its carrier signal, and the positive half of the modulating signal appears on the load. After characterizing the device, the device is validated under light microscopy by motivating carboxylate-modified microspheres, tetracycline, acetaminophen, benzocaine, lidocaine and carbamide peroxide particles with induced ACEK effects. The assembly is finally tested in a common dental bleaching application. After applying 35 % carbamide peroxide to human teeth topically or with the IDE at 1200 Hz, 5 Vpp for 20 min, spectrophotometric analysis showed that compared to diffusion, the IDE enhanced whitening in specular optic and specular optic excluded modes by 215 % and 194 % respectively. Carbamide peroxide absorbance by the ACEK group was two times greater than diffusion as measured by colorimetric oxidation-reduction and UV-Vis spectroscopy at 550 nm. The device motivates drugs of variable molecular weight and structure wirelessly. Wireless transport of drugs to intraoral targets under ACEK effects may potentially improve the efficacy and safety of drug delivery in dentistry.

  16. Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers.

    Science.gov (United States)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline; Weaver, Richard John; Gesson, Charlotte; Brian Houston, J; Oosterhuis, Berend; Bjerrum, Ole J; Grynkiewicz, Grzegorz; Alder, Jane; Rowland, Malcolm; Garner, Colin

    2011-06-14

    A clinical study was conducted to assess the ability of a microdose (100 μg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 μg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 μg iv (14)C-doses were

  17. Excretion of drugs in human breast milk

    Energy Technology Data Exchange (ETDEWEB)

    Welch, R.M.; Findlay, J.W.

    1981-01-01

    The present report briefly discusses some of the morphological, physiological, and compositional aspects of animal and human breast milk and how these characteristics might be important for the accumulation of drugs and foreign compounds. In addition, a study is described confirming the presence of caffeine, codeine, morphine, phenacetin, acetaminophen, and salicylic acid in the breast milk of a lactating mother following oral administration of a combination analgesic containing aspirin, phenacetin, caffeine, and codeine. Although the study is limited to one subject, it has provided critically needed data on the rates of appearance in, and elimination of these drugs from, breast milk. A similar amount of information is presented on phenacetin, also a component of the analgesic mixture, which has not been previously reported to enter human milk. The distribution of these drugs between the slightly more acidic breast milk and the relatively neutral plasma is consistent with their weakly basic, acidic, or relatively neutral properties. In general, the study shows that codeine and morphine milk concentrations are higher than, salicylic acid milk levels are much lower than, and phenacetin, caffeine, and acetaminophen milk concentrations are relatively similar to their respective plasma levels. It is projected, from estimated steady-state milk concentrations of the drugs and their metabolites studied, that very low percentages of the therapeutic dosages (less than 0.7%) would be excreted in mother's milk, too low an amount to be clinically significant to the infant.

  18. Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors.

    Science.gov (United States)

    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.

  19. 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.

    Science.gov (United States)

    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 (ion-sources of mass spectrometers may form intermediates that are produced from activated drugs in enzyme-catalyzed reactions.

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

    Science.gov (United States)

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

    2014-02-01

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

  1. Differential regulation of mitogen-activated protein kinase pathways by acetaminophen and its nonhepatotoxic regioisomer 3'-hydroxyacetanilide in TAMH cells.

    Science.gov (United States)

    Stamper, Brendan D; Bammler, Theo K; Beyer, Richard P; Farin, Frederico M; Nelson, Sidney D

    2010-07-01

    Acetaminophen (APAP), a widely used analgesic and antipyretic that is considered to be relatively safe at recommended doses, is the leading cause of drug-induced liver failure in the United States. 3'-Hydroxyacetanilide (AMAP), a regioisomer of APAP, is useful as a comparative tool for studying APAP-induced toxicity because it is nontoxic relative to APAP. Transforming growth factor-alpha transgenic mouse hepatocytes were treated with both isomers to investigate mitogen-activated protein kinase (MAPK) cascades in order to differentiate their toxicological outcomes. Posttranslational modifications of MAPK signaling were assessed using immunoblotting and Bioplex technology, whereas gene expression changes were measured using Affymetrix Mouse Gene 1.0 ST arrays. APAP treatment led to higher levels of glutathione depletion at 6 and 24 h compared with AMAP in mitochondria. Glutathione depletion was preceded by increased levels of c-Jun N-terminal kinase (JNK) phosphorylation at 2 and 6 h after APAP treatment compared with AMAP, whereas AMAP treatment led to increased extracellular signal-regulated protein kinase (ERK) phosphorylation at 2 and 6 h compared with APAP. Furthermore, APAP treatment significantly upregulated jun oncogene (c-Jun) gene expression, which was confirmed by Western blotting for both the phosphorylated and the nonphosphorylated forms of c-Jun protein. Transfection with JNK siRNA attenuated APAP toxicity after 24 h, suggesting that higher levels of APAP-induced activation of JNK were related to higher rates of cell death. In summary, genomic regulation of MAPK-related transcription factors coupled with posttranslational activation of their upstream kinases is critical in differentiating the toxicities of APAP and AMAP.

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

    Directory of Open Access Journals (Sweden)

    Rachel P L van Swelm

    Full Text Available Drug-induced liver injury (DILI is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP. Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw followed by 24 h urine collection. Doses of ≥275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT values (p<0.0001. Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001, including superoxide dismutase 1 (SOD1, carbonic anhydrase 3 (CA3 and calmodulin (CaM, as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001 in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury.

  3. Degradation of Acetaminophen and Its Transformation Products in Aqueous Solutions by Using an Electrochemical Oxidation Cell with Stainless Steel Electrodes

    Directory of Open Access Journals (Sweden)

    Miguel Ángel López Zavala

    2016-09-01

    Full Text Available In this study, a novel electrochemical oxidation cell using stainless steel electrodes was found to be effective in oxidizing acetaminophen and its transformation products in short reaction times. Aqueous solutions of 10 mg/L-acetaminophen were prepared at pH 3, 5, 7, and 9. These solutions were electrochemically treated at direct current (DC densities of 5.7 mA/cm2, 7.6 mA/cm2, and 9.5 mA/cm2. The pharmaceutical and its intermediates/oxidation products were determined by using high pressure liquid chromatography (HPLC. The results showed that electrochemical oxidation processes occurred in the cell. Acetaminophen degradation rate constants increased proportionally with the increase of current intensity. High current densities accelerated the degradation of acetaminophen; however, this effect diminished remarkably at pH values greater than 5. At pH 3 and 9.5 mA/cm2, the fastest degradation of acetaminophen and its intermediates/oxidation products was achieved. To minimize the wear down of the electrodes, a current density ramp is recommended, first applying 9.5 mA/cm2 during 2.5 min or 7.6 mA/cm2 during 7.5 min and then continuing the electrochemical oxidation process at 5.7 mA/cm2. This strategy will hasten the acetaminophen oxidation, extend the electrode’s life, and shorten the reaction time needed to degrade the pharmaceutical and its intermediates/oxidation products. DC densities up to 9.5 mA/cm2 can be supplied by photovoltaic cells.

  4. Humanizing π-class glutathione S-transferase regulation in a mouse model alters liver toxicity in response to acetaminophen overdose.

    Directory of Open Access Journals (Sweden)

    Matthew P Vaughn

    Full Text Available BACKGROUND: Glutathione S-transferases (GSTs metabolize drugs and xenobiotics. Yet despite high protein sequence homology, expression of π-class GSTs, the most abundant of the enzymes, varies significantly between species. In mouse liver, hepatocytes exhibit high mGstp expression, while in human liver, hepatocytes contain little or no hGSTP1 mRNA or hGSTP1 protein. π-class GSTs are known to be critical determinants of liver responses to drugs and toxins: when treated with high doses of acetaminophen, mGstp1/2+/+ mice suffer marked liver damage, while mGstp1/2-/- mice escape liver injury. METHODOLOGY/PRINCIPAL FINDINGS: To more faithfully model the contribution of π-class GSTs to human liver toxicology, we introduced hGSTP1, with its exons, introns, and flanking sequences, into the germline of mice carrying disrupted mGstp genes. In the resultant hGSTP1+mGstp1/2-/- strain, π-class GSTs were regulated differently than in wild-type mice. In the liver, enzyme expression was restricted to bile duct cells, Kupffer cells, macrophages, and endothelial cells, reminiscent of human liver, while in the prostate, enzyme production was limited to basal epithelial cells, reminiscent of human prostate. The human patterns of hGSTP1 transgene regulation were accompanied by human patterns of DNA methylation, with bisulfite genomic sequencing revealing establishment of an unmethylated CpG island sequence encompassing the gene promoter. Unlike wild-type or mGstp1/2-/- mice, when hGSTP1+mGstp1/2-/- mice were overdosed with acetaminophen, liver tissues showed limited centrilobular necrosis, suggesting that π-class GSTs may be critical determinants of toxin-induced hepatocyte injury even when not expressed by hepatocytes. CONCLUSIONS: By recapitulating human π-class GST expression, hGSTP1+mGstp1/2-/- mice may better model human drug and xenobiotic toxicology.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    training. Thirty-six individuals were randomly assigned to a placebo (67 ± 2 yr old), acetaminophen (64 ± 1 yr old; 4,000 mg/day), or ibuprofen (64 ± 1 yr old; 1,200 mg/day) group in a double-blind manner and completed 12 wk of knee extensor resistance training. Before and after training in vivo patellar...... adults induces modest changes in the mechanical properties of the patellar tendon. Over-the-counter doses of acetaminophen, but not ibuprofen, have a strong influence on tendon mechanical and material property adaptations to resistance training. These findings add to a growing body of evidence...

  6. Paracetamol (acetaminophen): a blessing or a hidden curse?

    Science.gov (United States)

    Whitehouse, M W; Butters, D E

    2014-02-01

    This Journal has recently published a splendid review of all you need to know about paracetamol (Graham et al. 2013), an analgesic widely used in the long-term management of arthritis. It clearly presents the science and hard facts. This commentary, by contrast, discusses some aspects of the metapharmacology of paracetamol; particularly by asking questions of how we might extract more benefit and suffer less adverse reactions when using this analgesic in the context of non-transient inflammation. As both a drug and a toxin, paracetamol exemplifies how beneficial and/or deleterious responses may be conditioned by circumstances (disease stress, nutritional status, fasting, etc.).

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

    Science.gov (United States)

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

    2015-06-01

    Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back-extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP-CYS, suggesting approximate APAP-protein adduct molecular weights ≥ 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal adduct production and protein shedding into urine rather than elimination of serum adducts.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-09-15

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

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

  11. Comparative release studies on suppositories using the basket, paddle, dialysis tubing and flow-through cell methods I. Acetaminophen in a lipophilic base suppository.

    Science.gov (United States)

    Hori, Seiichi; Kawada, Tsubasa; Kogure, Sanae; Yabu, Shinako; Mori, Kenji; Akimoto, Masayuki

    2017-02-01

    The release characteristics of lipophilic suppositories containing acetaminophen (AAP) were examined using four types of dissolution methods: the basket, paddle, dialysis tubing (DT) and flow-through cell (FTC) methods. The suitability of each apparatus for quality control in AAP compounded suppositories was evaluated using statistical procedures. More than 80% of the drug was released over 60 min in all the release methods studied, with the exception of the basket method. Reproducible and faster release was achieved using the paddle method at 100 and 200 rpm, whereas poor release occurred with the basket method. The mean dissolution time (MDT), maximum dissolved quantity of AAP at the end of the sampling time (Q) and dissolution efficiency (DE) were calculated by model-independent methods. The FTC method with a single chamber used in this study was also appreciable for AAP suppositories (Q of 100%, MDT of 71-91 min and DE of 75-80%). The DT apparatus is considered similar to the FTC apparatus from a quality control perspective for judging the release properties of lipophilic base suppositories containing AAP. However, even the single chamber FTC used in this study has potential as an in vitro drug release test for suppositories. The comparative dissolution method is expected to become one of the valuable tools for selecting an adequate dissolution test.

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

    Science.gov (United States)

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

    2014-06-01

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

  13. Estudio termodinámico de la transferencia de acetaminofén desde el agua hasta el octanol Thermodynamic study of acetaminophen's transfer from water to octanol

    Directory of Open Access Journals (Sweden)

    Yolima Baena

    2004-09-01

    Full Text Available Se determinó el coeficiente de reparto octanol/agua y la solubilidad de acetaminofén (paracetamol en octanol, agua y los solventes mutuamente saturados a 25.0, 30.0, 35.0 y 40.0 °C. Mediante el análisis termodinámico de Gibbs y van't Hoff se observa que el proceso de transferencia del fármaco desde el agua hasta el octanol es espontáneo y de conducción principalmente entálpica. Se encuentra que la saturación mutua de las fases juega un papel importante en el reparto y la solubilidad de este fármaco, lo cual se ha demostrado para otras sustancias semipolares tales como algunos derivados de la guanina y algunas sulfonamidas.The partition coefficients and solubilities in octanol, water and mutually saturated octanol-water phases were determined for acetaminophen at 25.0, 30.0, 35.0, and 40.0 °C. By means of Gibbs and van't Hoff thermodynamic analyses it may observe that the transfer of this drug from water to octanol is spontaneous and mainly driven enthalpically. As in other studies made with guanine derivatives and sulfonamides, it has been shown that the mutual saturation of the octanol and aqueous phases plays an important role in the partitioning and solubility of this drug.

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

    Science.gov (United States)

    Emmett, Michael

    2014-01-01

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

  15. Paracetamol (acetaminophen) - a popular and widely used nonopioid analgesic.

    Science.gov (United States)

    Klotz, U

    2012-08-01

    For several decades paracetamol has proven its clinical efficacy and safety in the treatment of various acute and chronic pain states. Whereas its pharmacokinetic properties (high oral bioavailability, good penetration into the brain, relative rapid hepatic elimination) are well known, its exact central mode of action remains to be elucidated. According to many international guidelines/recommendations paracetamol is a drug of first choice for relieving mild to moderate pain. It has been successfully combined with opioids for severe pain. Due to its cardiovascular, renal and gastrointestinal safety paracetamol offers several advantages vs. NSAIDs. It should be realized that the maximum daily dose is restricted to 4 g to avoid unnecessary hepatic complications. Keeping this limitation in mind paracetamol still represents a valuable first-line agent in the pharmacological management of pain.

  16. Validation of ICD-9-CM/ICD-10 coding algorithms for the identification of patients with acetaminophen overdose and hepatotoxicity using administrative data

    Directory of Open Access Journals (Sweden)

    Shaheen Abdel

    2007-10-01

    Full Text Available Abstract Background Acetaminophen overdose is the most common cause of acute liver failure (ALF. Our objective was to develop coding algorithms using administrative data for identifying patients with acetaminophen overdose and hepatic complications. Methods Patients hospitalized for acetaminophen overdose were identified using population-based administrative data (1995–2004. Coding algorithms for acetaminophen overdose, hepatotoxicity (alanine aminotransferase >1,000 U/L and ALF (encephalopathy and international normalized ratio >1.5 were derived using chart abstraction data as the reference and logistic regression analyses. Results Of 1,776 potential acetaminophen overdose cases, the charts of 181 patients were reviewed; 139 (77% had confirmed acetaminophen overdose. An algorithm including codes 965.4 (ICD-9-CM and T39.1 (ICD-10 was highly accurate (sensitivity 90% [95% confidence interval 84–94%], specificity 83% [69–93%], positive predictive value 95% [89–98%], negative predictive value 71% [57–83%], c-statistic 0.87 [0.80–0.93]. Algorithms for hepatotoxicity (including codes for hepatic necrosis, toxic hepatitis and encephalopathy and ALF (hepatic necrosis and encephalopathy were also highly predictive (c-statistics = 0.88. The accuracy of the algorithms was not affected by age, gender, or ICD coding system, but the acetaminophen overdose algorithm varied between hospitals (c-statistics 0.84–0.98; P = 0.003. Conclusion Administrative databases can be used to identify patients with acetaminophen overdose and hepatic complications. If externally validated, these algorithms will facilitate investigations of the epidemiology and outcomes of acetaminophen overdose.

  17. Enhanced Physical Stability of Amorphous Drug Formulations via Dry Polymer Coating.

    Science.gov (United States)

    Capece, Maxx; Davé, Rajesh

    2015-06-01

    Although amorphous solid drug formulations may be advantageous for enhancing the bioavailability of poorly soluble active pharmaceutical ingredients, they exhibit poor physical stability and undergo recrystallization. To address this limitation, this study investigates stability issues associated with amorphous solids through analysis of the crystallization behavior for acetaminophen (APAP), known as a fast crystallizer, using a modified form of the Avrami equation that kinetically models both surface and bulk crystallization. It is found that surface-enhanced crystallization, occurring faster at the free surface than in the bulk, is the major impediment to the stability of amorphous APAP. It is hypothesized that a novel use of a dry-polymer-coating process referred to as mechanical-dry-polymer-coating may be used to inhibit surface crystallization and enhance stability. The proposed process, which is examined, simultaneously mills and coats amorphous solids with polymer, while avoiding solvents or solutions, which may otherwise cause stability or crystallization issues during coating. It is shown that solid dispersions of APAP (64% loading) with a small particle size (28 μm) could be prepared and coated with the polymer, carnauba wax, in a vibratory ball mill. The resulting amorphous solid was found to have excellent stability as a result of inhibition of surface crystallization.

  18. Short-term acetaminophen consumption enhances the exercise-induced increase in Achilles peritendinous IL-6 in humans

    DEFF Research Database (Denmark)

    Gump, Brian S; McMullan, David R; Cauthon, David J;

    2013-01-01

    Through an unknown mechanism the cyclooxygenase (COX) inhibitor acetaminophen (APAP) alters tendon mechanical properties in humans when consumed during exercise. Interleukin-6 (IL-6) is produced by tendon during exercise and is a potent stimulator of collagen synthesis. In non-tendon tissue, IL-6...

  19. Understanding the Solubility of Acetaminophen in 1-n-Alkyl-3-methylimidazolium-Based Ionic Liquids Using Molecular Simulation.

    Science.gov (United States)

    Paluch, Andrew S; Lourenço, Tuanan C; Han, Fenglin; Costa, Luciano T

    2016-04-07

    During the manufacturing of pharmaceutical compounds, solvent mixtures are commonly used, where the addition of a cosolvent allows for the tuning of the intermolecular interactions present in the system. Here we demonstrate how a similar effect can be accomplished using a room temperature ionic liquid. The pharmaceutical compound acetaminophen is studied in 21 common ionic liquids composed of a 1-n-alkyl-3-methylimidazolium cation with 1 of 7 anions. Using the acetate anion, we predict a large enhancement in solubility of acetaminophen relative to water. We show how this is caused by a synergistic effect of favorable interactions between the ionic liquid and the phenyl, hydroxyl and amide groups of acetaminophen, demonstrating how the ionic liquid cation and anion may be chosen to preferentially solvate different functional groups of complex pharmaceutical compounds. Additionally, while the use of charge scaling in ionic liquid force fields has previously been found to have a minute effect on ionic liquid structural properties, we find it appreciably affects the computed solvation free energy of acetaminophen, which in turn affects the predicted solubility.

  20. Acetaminophen-induced S-nitrosylation and S-sulfenylation signalling in 3D cultured hepatocarcinoma cell spheroids

    DEFF Research Database (Denmark)

    Wojdyla, Katarzyna; Wrzesinski, Krzysztof; Williamson, James;

    2016-01-01

    Acetaminophen (APAP) is possibly the most widely used medication globally and yet little is known of its molecular effects at therapeutic doses. Using a novel approach, we have analysed the redox proteome of the hepatocellular cell line HepG2/C3A treated with therapeutic doses of APAP...

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

    Science.gov (United States)

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

    2016-05-31

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

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

    Directory of Open Access Journals (Sweden)

    Robim M. Rodrigues

    2016-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Ndatsu Yakubu

    2016-01-01

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

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

    Science.gov (United States)

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

    2008-01-01

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

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

    Science.gov (United States)

    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…

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

    Directory of Open Access Journals (Sweden)

    Eskandar Moghimipour

    2013-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

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    Abolfazl Dadkhah

    2014-06-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2006-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  11. A comparison of the newer COX-2 drugs and older nonnarcotic oral analgesics.

    Science.gov (United States)

    Sunshine, A

    2000-09-01

    The newer COX-2 drugs are safer analgesics than the older NSAIDs. At the usual dose used in osteoarthritis, they have less analgesic effect than the older NSAIDs. The non-narcotic analgesics such as acetaminophen, salicylate, NSAIDs, and the newer COX-2 drugs seem to have distinctly different mechanisms of action. In limited clinical trials, some of these drugs in combination give additive analgesia. Consideration should be given to using these drugs in combination, after suitable clinical trials, to enhance the efficacy of this category of analgesics.

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

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    Howie Forbes

    2010-03-01

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

  13. Simultaneous Determination of Acetaminophen and Synthetic Color(s) by Derivative Spectroscopy in Syrup Formulations and Validation by HPLC: Exposure Risk of Colors to Children.

    Science.gov (United States)

    Rastogi, Shanya Das; Dixit, Sumita; Tripathi, Anurag; Das, Mukul

    2015-06-01

    Color additives are used in pediatric syrup formulations as an excipient; though not pre-requisite, but pediatric syrup formulations are normally colored. An attempt has been made to measure simultaneously the single drug, acetaminophen (AT), along with the colors, carmoisine (CA), erythrosine (ET), and sunset yellow FCF (SSY) added in it by three derivative spectroscopy methods namely, 1st order, ratio, and differential derivative methods. Moreover, evaluation has been made for the exposure assessment of the colors added as excipient because some colors have been reported to cause allergic reactions and hypersensitivity in children. The present methods provide simple, accurate, and reproducible quantitative determination of the drug, AT, along with the color in synthetic mixtures and commercial drug formulations without any interference. The limit of detection varied from 0.0001-0.31 μg/ml while limit of quantification ranged from 0.002-1.04 μg/ml in all the three methods. The calibration curve of all the three derivative methods exhibited good linear relationship with excellent regression coefficients (0.9986-1.000). Both intra-day and inter-day precisions showed %RSD value less than 2% while the percentage recovery was found between 96.8-103.8%. The sensitivity of the proposed methods is almost comparable to HPLC and thus, can be used for determination of drug AT, and color simultaneously in pharmaceutical formulation on routine basis. The present methods also showed that colors like SSY and ET are saturating more than 50% of acceptable daily intake (ADI) value which is alarming and needs to be considered for modification by regulatory authorities to safeguard the health of children.

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

    Science.gov (United States)

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

    2014-01-01

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

  15. Determination of Acetaminophen based on Poly(glutamic acid)/Multi-walled Carbon Nanotube Modified Glassy Carbon Electrode%聚谷氨酸/多壁碳纳米管修饰玻碳电极测定扑热息痛

    Institute of Scientific and Technical Information of China (English)

    陈东辉; 翟秋阁

    2014-01-01

    将聚谷氨酸和多壁碳纳米管修饰到玻碳电极表面制成了一种新型的电化学传感器,用于扑热息痛测定.研究了扑热息痛在修饰电极上的电化学行为.结果表明,在0.1 mol/L磷酸盐缓冲溶液中(pH7.0),修饰电极显著提高了扑热息痛电化学响应信号.在2.0×10-7~6.0×10-5 mol/L浓度范围内扑热息痛的浓度在该电极上与电化学响应信号呈良好的线性关系.信噪比为3时,检出限为2.0×10-8 mol/L.将该方法用于药品中扑热息痛的测定,回收率为92.4%~103.1%.%A novel electrochemical sensor was fabricated for acetaminophen determination based on poly( glutamic acid)/multi-walled carbon nanotube modified glassy carbon electrode. The electrochemical behaviors of acetaminophen on the modified electrode were investigated. The experimental results showed that the electrochemical respond of acet-aminophen at the modified electrode was significantly improved in phosphate buffer solutions (pH 7. 0). The concen-tration of acetaminophen showed good linear relationships with the peak current in the range of 2. 0 × 10 -7 ~6. 0 × 10 -5 mol/L. The limit of detection was 2. 0 × 10 -8 mol/L (RSN = 3). The method was used to detect acetaminophen in drugs with recoveries of 92. 4% ~103. 1%.

  16. A study of drug eruptions by provocative tests

    Directory of Open Access Journals (Sweden)

    Das J

    2001-09-01

    Full Text Available Sixty cases of drug eruptions were observed during the period of one year. The incidence of drug eruption was 0.47% amongst all Dermatology O.P.D. attendances. Male to female ratio was 7:3. The highest number of cases were seen in the age group of 21-30 years. Fixed drug eruptions were the most frequent (58.3%, followed by urticaria and angioedema (20%. The drug sulphonamides (including co-trimoxazole accounted for the highest number of eruptions (35%. The other drugs which were responsible for the eruptions, in order of frequency, were oxyphenbutazone, ampicillin, analgin, penicillin, tetracycline, ibuprofen, paracetamol, phenylbutazone, acetaminophen and phenobarbitone. The causative drug (s were confirmed by provocation tests in 42 (70% cases.

  17. Detection of Illegal Added Acetaminophen in Yinqiao Jiedu Preparation by HPLC%HPLC法检测银翘解毒制剂中非法添加的对乙酰氨基酚

    Institute of Scientific and Technical Information of China (English)

    邱国俊; 许亚玲; 田静; 何咏梅

    2013-01-01

    OBJECTIVE:To establish a method for determining whether there are illegal added acetaminophen in Yinqiao jiedu preparation.METHODS:HPLC method was adopted.The determination was performed on Waters C18(250 min×5.0 mm,4.6 μm)column with mobile phase consisted of methanol-glacial acetic acid (2∶98,V/V) at the flow rate of 1 ml/min.The detection wavelength was set at 249 nm,and column temperature was set at 30 ℃.The sample size was 5 μl.205 batches of samples from 73 factories were determined under the same condition.A positive control was made by adding appropriate amount of reference substance into samples in which acetaminophen was not detected.RESULTS:The linear range of acetaminophen was 0.050 7-1.010 4 μg(r=0.9999).The examination limits was 0.4 ng.Average recoveries of Yinqiao jiedu preparations (tablets,pills,particles) were 99.9%(RSD=0.7%,n=6),96.9% (RSD=0.6%,n=6) and 97.6% (RSD=0.4%,n=6),respectively.Acetaminophen were detected in positive reference substance and not detected in 205 batches of samples.CONCLUSIONS:The method is specific,sensitive and simple,and can be used to detect illegal added acetaminophen in Chinese patent medicine.%目的:建立检测银翘解毒制剂中是否非法添加解热镇痛药对乙酰氨基酚的方法.方法:采用高效液相色谱法.色谱柱为Waters C18(250 mm×5.0 mm,4.6μm),流动相为甲醇-0.5%冰醋酸溶液(2∶98,V/V),检测波长为249nm,柱温为30℃,流速为1 ml/min,进样量为5μl.在此条件下检测了73个厂家205批样品,并在未检出对乙酰氨基酚的样品中添加适量对照品作为阳性参比对照进行检测.结果:对乙酰氨基酚的进样量在0.0507~1.0104μg范围内与其峰面积积分值呈良好的线性关系(r=0.9999);检出限为0.4 ng.银翘解毒片、丸、颗粒的平均加样回收率分别为99.9%(RSD=0.7%,n=6)、96.9%(RSD=0.6%,n=6)、97.6%(RSD=0.4%,n=6).阳性参比对照均检出对乙酰氨基酚,205批样品均未检出.结论

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

    Directory of Open Access Journals (Sweden)

    Selvaraj Kunjiappan

    2015-04-01

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

  19. Particle Pollution

    Science.gov (United States)

    ... Your Health Particle Pollution Public Health Issues Particle Pollution Recommend on Facebook Tweet Share Compartir Particle pollution ... see them in the air. Where does particle pollution come from? Particle pollution can come from two ...

  20. Particle Characterization for a Protein Drug Product Stored in Pre-Filled Syringes Using Micro-Flow Imaging, Archimedes, and Quartz Crystal Microbalance with Dissipation.

    Science.gov (United States)

    Zheng, Songyan; Puri, Aastha; Li, Jinjiang; Jaiswal, Archana; Adams, Monica

    2017-01-01

    Micro-flow imaging (MFI) has been used for formulation development for analyzing sub-visible particles. Archimedes, a novel technique for analyzing sub-micron particles, has been considered as an orthogonal method to currently existing techniques. This study utilized these two techniques to investigate the effectiveness of polysorbate (PS-80) in mitigating the particle formation of a therapeutic protein formulation stored in silicone oil-coated pre-filled syringes. The results indicated that PS-80 prevented the formation of both protein and silicone oil particles. In the case of protein particles, PS-80 might involve in the interactions with the hydrophobic patches of protein, air bubbles, and the stressed surfaces of silicone oil-coated pre-filled syringes. Such interactions played a role in mitigating the formation of protein particles. Subsequently, quartz crystal microbalance with dissipation (QCM-D) was utilized to characterize the interactions associated with silicone oil, protein, and PS-80 in the solutions. Based on QCM-D results, we proposed that PS-80 likely formed a layer on the interior surfaces of syringes. As a result, the adsorbed PS-80 might block the leakage of silicone oil from the surfaces to solution so that the silicone oil particles were mitigated at the presence of PS-80. Overall, this study demonstrated the necessary of utilizing these three techniques cooperatively in order to better understand the interfacial role of PS-80 in mitigating the formation of protein and silicone oil particles.

  1. LES of Laminar-to-Turbulent Particle-Fluid Dynamics in Human and Nonhuman Primate Airways: Applications to Aerosolized Drug Delivery Animal Testing

    Science.gov (United States)

    Geisler, Taylor; Padhy, Sourav; Shaqfeh, Eric; Iaccarino, Gianluca

    2016-11-01

    Both the human health benefit and risk from the inhalation of aerosolized medications is often predicted by extrapolating experimental data taken using nonhuman primates to human inhalation. In this study, we employ Large Eddy Simulation to simulate particle-fluid dynamics in realistic upper airway models of both humans and rhesus monkeys. We report laminar-to-turbulent flow transitions triggered by constrictions in the upper trachea and the persistence of unsteadiness into the low Reynolds number bifurcating lower airway. Micro-particle deposition fraction and locations are shown to depend significantly on particle size. In particular, particle filtration in the nasal airways is shown to approach unity for large aerosols (8 microns) or high-rate breathing. We validate the accuracy of LES mean flow predictions using MRV imaging results. Additionally, particle deposition fractions are validated against experiments in 3 model airways.

  2. Fenton-Like Catalysis and Oxidation/Adsorption Performances of Acetaminophen and Arsenic Pollutants in Water on a Multimetal Cu-Zn-Fe-LDH.

    Science.gov (United States)

    Lu, Hongtao; Zhu, Zhiliang; Zhang, Hua; Zhu, Jianyao; Qiu, Yanling; Zhu, Linyan; Küppers, Stephan

    2016-09-28

    Acetaminophen can increase the risk of arsenic-mediated hepatic oxidative damage; therefore, the decontamination of water polluted with coexisting acetaminophen and arsenic gives rise to new challenges for the purification of drinking water. In this work, a three-metal layered double hydroxide, namely, Cu-Zn-Fe-LDH, was synthesized and applied as a heterogeneous Fenton-like oxidation catalyst and adsorbent to simultaneously remove acetaminophen (Paracetamol, PR) and arsenic. The results showed that the degradation of acetaminophen was accelerated with decreasing pH or increasing H2O2 concentrations. Under the conditions of a catalyst dosage of 0.5 g·L(-1) and a H2O2 concentration of 30 mmol·L(-1), the acetaminophen in a water sample was completely degraded within 24 h by a Fenton-like reaction. The synthesized Cu-Zn-Fe-LDH also exhibited a high efficiency for arsenate removal from aqueous solutions, with a calculated maximum adsorption capacity of 126.13 mg·g(-1). In the presence of hydrogen peroxide, the more toxic arsenite can be gradually oxidized into arsenate and adsorbed at the same time by Cu-Zn-Fe-LDH. For simulated water samples with coexisting arsenic and acetaminophen pollutants, after treatment with Cu-Zn-Fe-LDH and H2O2, the residual arsenic concentration in water was less than 10 μg·L(-1), and acetaminophen was not detected in the solution. These results indicate that the obtained Cu-Zn-Fe-LDH is an efficient material for the decontamination of combined acetaminophen and arsenic pollution.

  3. Determination of residues of acetaminophen, caffeine, and drotaverine hydrochloride on swabs collected from pharmaceutical manufacturing equipment using HPLC in support of cleaning validation.

    Science.gov (United States)

    Hassouna, Mohamed E M; Issa, Yousry M; Zayed, Ashraf G

    2014-01-01

    An HPLC method was developed for the simultaneous determination of residues of acetaminophen (paracetamol, PA), caffeine (CA), and drotaverine HCl (DH) on swabs collected from pharmaceutical manufacturing equipment surfaces. The challenge in cleaning validation is to develop analytical methods that are sensitive enough to detect traces of the active compounds remaining on the surface of pharmaceutical manufacturing equipment after cleaning. Chromatography was performed in the isocratic mode on a Hypersil C18 BDS column using the mobile phase 0.02 M tetrabutylammonium bisulfate-methanol (100 + 45, v/v) at 50°C with UV detection at 210 nm. The method was tested for specificity, linearity, LOD, LOQ, accuracy, and precision for determination of traces of the above-mentioned drugs. The time required for a single analysis was 12 min. The response was linear in the ranges of 6.900-52.100, 1.040-7.800, and 0.694-5.210 μg/mL for PA, CA, and DH, respectively.

  4. 扑热息痛肝损伤机制研究进展%Advances on mechanisms of acetaminophen-induced hepatic injury

    Institute of Scientific and Technical Information of China (English)

    顾兴丽; 孙继红; 季晖

    2009-01-01

    Acetaminophen(AAP) -induced hepatic injury is one of the common causes of drug-induced hepatic injury. Up to date, the mechanisms of AAP-induced hepatic injury are still incompletely understood. Recent advances suggest that reactive metabolite formation, glutathione depletion, alkylation of proteins, especially mitochondrial proteins and peroxynitrite formation are critical initiating events for the toxicity. This review will focus on more recent advances in mitochon- drial dysfunction after AAP overdose. Additional, oxi-dative stress and inflammatory mediators are also important for the overall outcome.%扑热息痛(AAP)肝损伤是药物性肝损伤的常见原因之一.但迄今为止,其肝损伤机制仍不完全清楚.最新研究进展指出活性代谢产物的形成、谷胱甘肽的耗竭、线粒体蛋白的烷化和过氧化亚硝酸盐的形成是主要原因.本文主要描述了AAP过量所致的线粒体功能异常的研究进展,另外也综述了氧化应激和炎症介质在扑热息痛肝损伤机制中的作用.

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

    Directory of Open Access Journals (Sweden)

    Yu Ri Kim

    2013-01-01

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

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

    Science.gov (United States)

    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.

  7. Modulation of trichloroethylene in vitro metabolism by different drugs in human.

    Science.gov (United States)

    Cheikh Rouhou, Mouna; Haddad, Sami

    2014-08-01

    Toxicological interactions with drugs have the potential to modulate the toxicity of trichloroethylene (TCE). Our objective is to identify metabolic interactions between TCE and 14 widely used drugs in human suspended hepatocytes and characterize the strongest using microsomal assays. Changes in concentrations of TCE and its metabolites were measured by headspace GC-MS. Results with hepatocytes show that amoxicillin, cimetidine, ibuprofen, mefenamic acid and ranitidine caused no significant interactions. Naproxen and salicylic acid showed to increase both TCE metabolites levels, whereas acetaminophen, carbamazepine and erythromycin rather decreased them. Finally, diclofenac, gliclazide, sulphasalazine and valproic acid had an impact on the levels of only one metabolite. Among the 14 tested drugs, 5 presented the most potent interactions and were selected for confirmation with microsomes, namely naproxen, salicylic acid, acetaminophen, carbamazepine and valproic acid. Characterization in human microsomes confirmed interaction with naproxen by competitively inhibiting trichloroethanol (TCOH) glucuronidation (Ki=2.329 mM). Inhibition of TCOH formation was also confirmed for carbamazepine (partial non-competitive with Ki=70 μM). Interactions with human microsomes were not observed with salicylic acid and acetaminophen, similar to prior results in rat material. For valproic acid, interactions with microsomes were observed in rat but not in human. Inhibition patterns were shown to be similar in human and rat hepatocytes, but some differences in mechanisms were noted in microsomal material between species. Next research efforts will focus on determining the adequacy between in vitro observations and the in vivo situation.

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

    Institute of Scientific and Technical Information of China (English)

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

    2004-01-01

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

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

    Science.gov (United States)

    Sharma, Chandra Kant; Sharma, Vinay

    2012-01-01

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

  10. The role of para-aminophenol in acetaminophen-induced methemoglobinemia in dogs and cats.

    Science.gov (United States)

    McConkey, S E; Grant, D M; Cribb, A E

    2009-12-01

    Acetaminophen (APAP) overdose in most species is associated with hepatotoxicity because of the metabolite N-acetyl-p-benzoquinoneimine (NAPQI). In dogs and cats, APAP overdose primarily causes methemoglobinemia and hemolysis. Although NAPQI has been proposed as the responsible intermediate in dogs and cats, it lacks chemical or pharmacokinetic characteristics that favor methemoglobin formation. We hypothesized that para-aminophenol (PAP) rather than NAPQI induces methemoglobinemia and that deficient arylamine N-acetyltransferase (NAT) activity in dogs and cats contributes to this species-dependent methemoglobinemia. Erythrocytes from dogs, cats, mice, and rats were exposed in vitro to APAP, NAPQI, and PAP. Only PAP induced methemoglobin and it induced more methemoglobin formation in dog and cat than rat and mouse erythrocytes. PAP also induced more methemoglobin in erythrocytes from Nat1/Nat2 knockout mice than wildtype (WT) mouse erythrocytes (P dog and cat erythrocytes (P dogs and cats contributes to this species-dependent toxicity.

  11. Quantitative determination of acetaminophen, phenylephrine and carbinoxamine in tablets by high-performance liquid chromatography

    Directory of Open Access Journals (Sweden)

    Carina de A. Bastos

    2009-01-01

    Full Text Available An alternative methodology for analysis of acetaminophen (Ace, phenylephrine (Phe and carbinoxamine (Car in tablets by ion-pair reversed phase high performance liquid chromatography was validated. The pharmaceutical preparations were analyzed by using a C18 column (5 μm, 300 mm, 3.9 mm and mobile phase consisting of 60% methanol and 40% potassium monobasic phosphate aqueous solution (62.46 mmol L-1 added with 1 mL phosphoric acid, 0.50 mL triethylamine and 0.25 g sodium lauryl sulfate. Isocratic analysis was performed under direct UV detection at 220 nm for Phe and Car and at 300 nm for Ace within 5 min.

  12. Novel nanostructure-based electrochemical sensor for simultaneous determination of dopamine and acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Beitollahi, Hadi, E-mail: h.beitollahi@yahoo.com [Environment Department, Research Institute of Environmental Sciences, International Center for Science, High Technology and Environmental Sciences, Kerman (Iran, Islamic Republic of); Sheikhshoaie, Iran [Department of Chemistry, Faculty of Science, Shahid Bahonar University of Kerman, Kerman 76175-133 (Iran, Islamic Republic of)

    2012-02-01

    A carbon-paste electrode modified with a novel molybdenum (VI) complex and carbon nanotubes have been applied to the electrocatalytic oxidation of dopamine (DA) which reduced the overpotential by about 125 mV with obviously increase the current response. Due to its strong electrocatalytic activity towards DA, the modified carbon-paste electrode can resolve the overlapped voltammetric waves of DA and acetaminophen (AC) into two well-defined voltammetric peaks with peak-to-peak separation in potentials of about 230 mV. This property allows to selective determination of DA in the presence of AC. The transfer coefficient (a) for the electrocatalytic oxidation of DA and diffusion coefficient of this substance under the experimental conditions were also investigated. In phosphate buffer solution of pH 7.0, the oxidation current increased linearly with two concentration intervals of DA, one is 0.1 to 40.0 {mu}M and, the other is 40.0 to 800.0 {mu}M. The detection limit (3{sigma}) obtained by DPV was 76.0 nM. The proposed method was successfully applied to the determination of DA, and AC in some commercial pharmaceutical samples. - Highlights: Black-Right-Pointing-Pointer A carbon paste electrode modified with a molybdenum (VI) complex and CNTs have been fabricated. Black-Right-Pointing-Pointer The electrode reduced the overpotential for electrocatalytic oxidation of dopamine by about 125 mV. Black-Right-Pointing-Pointer The electrode resolved overlapped voltammetric waves of dopamine and acetaminophen.

  13. Hepatotoxicity of anti-inflammatory and analgesic drugs:ultrastructural aspects

    Institute of Scientific and Technical Information of China (English)

    Irena MANOV; Helen MOTANIS; Idan FRUMIN; Theodore C IANCU

    2006-01-01

    With the increasing incidence of drug-induced liver disease,attempts are being made to better understand the mechanisms behind these frequently life-endangering reactions.Analgesics and anti-inflammatory drugs are a major group exhibiting hepatotoxicity.We review research relating to these reactions,focusing on ultrastructural findings,which may contribute to the comprehension and possible avoidance of drug-induced liver disease.We also present some original observations on clinical material and cultured cells exposed to acetaminophen alone or in combination with the antioxidant N-acetylcysteine or the P-glycoprotein inhibitor verapamil.

  14. Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients.

    Science.gov (United States)

    Kondo, Kazuma; Yamada, Naohito; Suzuki, Yusuke; Toyoda, Kaoru; Hashimoto, Tatsuji; Takahashi, Akemi; Kobayashi, Akio; Shoda, Toshiyuki; Kuno, Hideyuki; Sugai, Shoichiro

    2012-01-01

    Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500mg/kg and hepatic function parameters were increased at 300 and 500mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

  15. High-frequency ultrasonic atomization for drug delivery to rodent animal models - optimal particle size for lung inhalation of difluoromethyl ornithine.

    Science.gov (United States)

    Zhang, Guifang; Fandrey, Chris; Naqwi, Amir; Wiedmann, Timothy Scott

    2008-06-01

    A high-(8-MHz) and a low-(1.7-MHz) frequency ultrasonic transducer were compared for delivering aerosols to mouse lung. The aerosol concentration (mass of dry particles/volume of air) rose nonlinearly with solution concentration of difluoromethyl ornithine for both transducers. The particle size was linear with the cube root of the solution concentration, and the slope of the low-frequency transducer was 8 times greater than that of the high-frequency transducer. The deposition fraction assessed by the assayed mass in the lung relative to the calculated inhaled mass was found to decline exponentially with particle size. The lower-frequency transducer provided a higher dose despite a lower deposition fraction, but the high-frequency transducer was more efficient and provides a more selective deposition in the lower respiratory tract while operating with significantly less demands on aerosol drying.

  16. Synthesis and drug-loading properties of folic acid-modified superparamagnetic Fe3O4 hollow microsphere core/mesoporous SiO2 shell composite particles

    Science.gov (United States)

    Yang, Yong; Guo, Xue; Wei, Kaiwei; Wang, Lijuan; Yang, Dandan; Lai, Lifang; Cheng, Meiling; Liu, Qi

    2014-01-01

    A drug delivery system, which not only has superparamagnetic property, higher surface area but also has targeting function, has been developed. The core/shell structural magnetic magnetite mesoporous silica microspheres with amine groups (Fe3O4-SiO2-NH2) were first fabricated by a one-pot direct co-condensation method, then folic acid-modified magnetic mesoporous silica composite microspheres (Fe3O4-SiO2-NHFA) were obtained by the bonding of the Fe3O4-SiO2-NH2 with folic acid as targeted molecule. The resultant composite microspheres were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, scanning electron microscopy, low temperature nitrogen adsorption-desorption, and vibrat