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Sample records for early hepatotoxicity incidence

  1. Leflunomide for the treatment of rheumatoid arthritis in clinical practice - Incidence and severity of hepatotoxicity

    NARCIS (Netherlands)

    van Roon, EN; Jansen, TLTA; Houtman, NM; Spoelstra, P; Brouwers, JRBJ

    2004-01-01

    Objective: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of hepatotoxici

  2. Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease.

    Science.gov (United States)

    Wong, D R; Coenen, M J H; Derijks, L J J; Vermeulen, S H; van Marrewijk, C J; Klungel, O H; Scheffer, H; Franke, B; Guchelaar, H-J; de Jong, D J; Engels, L G J B; Verbeek, A L M; Hooymans, P M

    2017-02-01

    Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 10(8) erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure. © 2016 John Wiley & Sons Ltd.

  3. Early Stage HIV Management and Reduction of Stavudine-Induced Hepatotoxicity in Rats by Experimentally Developed Biodegradable Nanoparticles.

    Science.gov (United States)

    Ghosh, Saikat; Mondal, Laboni; Chakraborty, Samrat; Mukherjee, Biswajit

    2017-04-01

    The objectives of this research work were to develop optimized nanoparticulate formulations of poly (d,l-lactic-co-glycolic acid) (PLGA) (85:15) with an anti-AIDS drug stavudine and to evaluate their in-vitro uptake by the macrophages and hepatotoxicity in-vivo. Nanoparticles were prepared by nanoprecipitation method based on a factorial design with varying parameters such as the amounts of polymer and stabilizer used. Physicochemical characterizations such as drug-excipient interaction, surface morphology, particle size, and zeta potential measurements were carried out. The best formulation was selected and tagged with fluorescein isothiocyanate (FITC) for cellular uptake study of the formulation. In-vitro uptake of nanoparticles by macrophages was carried out. Formulation-induced hepatotoxicity was assessed by analyzing some serum hepatotoxic parameters and hepatic histology following 10-day treatment in comparison with the free drug. Nanoparticles exhibited smooth surface with particle size 84-238 nm, high entrapment efficiency (approx 85%), and negative surface charge. Formulations showed a sustained drug release pattern over the study period. In-vitro uptake study by macrophages exhibited a time-dependent profile. In-vivo studies on rats showed improvement in the serum parameters and maintenance of the integrity of the hepatic architecture indicating decreased hepatotoxicity with the formulations as compared to the free drug. The experimental results showed a positive outcome in the development of antiretroviral drug carrier exhibiting sustained drug release, macrophage-targeted delivery characteristics, and having reduced hepatoxicity. This could be beneficial for the management of early stage of HIV infection besides reducing the drug load for effective treatment, thereby offering an attractive option in AIDS therapy.

  4. Early estimates of SEER cancer incidence, 2014.

    Science.gov (United States)

    Lewis, Denise Riedel; Chen, Huann-Sheng; Cockburn, Myles G; Wu, Xiao-Cheng; Stroup, Antoinette M; Midthune, Douglas N; Zou, Zhaohui; Krapcho, Martin F; Miller, Daniel G; Feuer, Eric J

    2017-07-01

    Cancer incidence rates and trends for cases diagnosed through 2014 using data reported to the Surveillance, Epidemiology, and End Results (SEER) program in February 2016 and a validation of rates and trends for cases diagnosed through 2013 and submitted in February 2015 using the November 2015 submission are reported. New cancer sites include the pancreas, kidney and renal pelvis, corpus and uterus, and childhood cancer sites for ages birth to 19 years inclusive. A new reporting delay model is presented for these estimates for more consistent results with the model used for the usual November SEER submissions, adjusting for the large case undercount in the February submission. Joinpoint regression methodology was used to assess trends. Delay-adjusted rates and trends were checked for validity between the February 2016 and November 2016 submissions. Validation revealed that the delay model provides similar estimates of eventual counts using either February or November submission data. Trends declined through 2014 for prostate and colon and rectum cancer for males and females, male and female lung cancer, and cervical cancer. Thyroid cancer and liver and intrahepatic bile duct cancer increased. Pancreas (male and female) and corpus and uterus cancer demonstrated a modest increase. Slight increases occurred for male kidney and renal pelvis, and for all childhood cancer sites for ages birth to 19 years. Evaluating early cancer data submissions, adjusted for reporting delay, produces timely and valid incidence rates and trends. The results of the current study support using delay-adjusted February submission data for valid incidence rate and trend estimates over several data cycles. Cancer 2017;123:2524-34. © 2017 American Cancer Society. © 2017 American Cancer Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

  5. Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy.

    Directory of Open Access Journals (Sweden)

    Rekha Gautam

    Full Text Available Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/- mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/- mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.

  6. Drug-induced hepatotoxicity: incidence of abnormal liver function tests consistent with volatile anaesthetic hepatitis in trauma patients.

    Science.gov (United States)

    Lin, Jonathan; Moore, David; Hockey, Brad; Di Lernia, Rachel; Gorelik, Alexandra; Liew, Danny; Nicoll, Amanda

    2014-04-01

    Volatile anaesthetic drug-induced liver injury can range from asymptomatic alanine transaminase elevations to fatal hepatic necrosis. There is very limited research regarding hepatotoxicity of modern volatile anaesthetic agents. The aim of this study was to determine how common liver injury consistent with volatile anaesthetic hepatitis is, following exposure to isoflurane, desflurane and sevoflurane; and to propose risk factors for its development. Following ethics approval, we conducted a retrospective audit of adult trauma patients with abnormal liver biochemistry following volatile anaesthesia during January 1 to December 31, 2009. The data collected included patient demographics, volatile anaesthetic administration, concurrent medication, perioperative liver biochemistry results and comorbidities. The Council for International Organisations of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system was used to group cases according to the likelihood of volatile anaesthetic being the causative agent of drug-induced hepatotoxicity. Forty-seven (3%) of 1556 patients had abnormal post-operative liver biochemistry potentially attributable to volatile anaesthetic. Of the 47, 12 patients (26%) had peak alanine transaminase levels greater than 200 U/L. No significant predictors of volatile anaesthetic drug-induced liver injury following isoflurane, desflurane or sevoflurane anaesthesia could be identified. Volatile anaesthetic drug-induced liver injury in adult trauma patients may be significantly more common than previously noted. This study suggests that about a quarter of patients with volatile anaesthetic drug-induced liver injury develop significant liver injury. Further prospective studies are required to define risk factors and clinical outcomes. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Early Risk Factors of Moderate/Severe Hepatotoxicity After Suicide Attempts With Acetaminophen in 11- to 15-Year-Old Children

    DEFF Research Database (Denmark)

    Hedeland, Rikke Lindgaard; Christensen, Vibeke Brix; Jørgensen, Marianne Hørby

    2014-01-01

    Objective. To characterize early risk factors of moderate/severe hepatotoxicity in a pediatric population with acetaminophen overdose, due to suicide attempt, admitted to a general secondary-level pediatric department. Methods. A retrospective case study of 107 patients, 11 to 15 years old. Results...... was significantly related to the elevation of several hepatologically relevant biochemical parameters (eg, maximum γ-glutamyl transferase; P = .0001). Patients suffering from illness prior to their suicide attempt had significantly greater elevations of their hepatologically relevant biochemical parameters...

  8. Incidence of early-onset dementia in Mar del Plata.

    Science.gov (United States)

    Sanchez Abraham, M; Scharovsky, D; Romano, L M; Ayala, M; Aleman, A; Sottano, E; Etchepareborda, I; Colla Machado, C; García, M I; Gonorazky, S E

    2015-03-01

    Early-onset dementia (EOD) is defined as dementia with onset before the age of 65 years. EOD is increasingly recognised as an important clinical and social problem with devastating consequences for patients and caregivers. Determine the annual crude incidence rate and the specific incidence rates by sex and age in patients with EOD, and the standardised rate using the last national census of the population of Argentina (NCPA), from 2010. Hospital Privado de Comunidad, Mar del Plata, Argentina, attends a closed population and is the sole healthcare provider for 17 614 people. Using the database pertaining to the Geriatric Care department, we identified all patients diagnosed with EOD between 1 January, 2005 and 31 December, 2011. EOD was defined as dementia diagnosed in patients younger than 65. The study period yielded 14 patients diagnosed with EOD out of a total of 287 patients evaluated for memory concerns. The crude annual incidence of EOD was 11 per 100 000/year (CI 95%: 6.25-19.1): 17 per 100 000 (CI 95%: 7.2-33.1) in men and 8 per 100 000 (CI 95%: 3.4-17.2) in women. We observed a statistically significant increase when comparing incidence rates between patients aged 21 to <55 years and ≥ 55 to <65 years (3 vs 22 per 100 000, P=.0014). The rate adjusted by NCPA census data was 5.8 cases of EOD habitants/year. This study, conducted in a closed population, yielded an EOD incidence rate of 11 per 100 000 inhabitants/year. To the best of our knowledge, this is the first prospective epidemiological study in Argentina and in Latin America. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  9. Incidence and prevention of early parturition in sows.

    Science.gov (United States)

    Vanderhaeghe, C; Dewulf, J; Jourquin, J; De Kruif, A; Maes, D

    2011-06-01

    A retrospective study, based on 60,990 farrowing records from 35 commercial herds, was performed to determine the incidence of early parturition (gestation length was 115.4 ± 1.62 d, and early parturition occurred in 10% of all farrowing records. Sows with early parturition had significantly more stillborn piglets and a larger litter size compared to sows with a normal gestation length (114-117 d). Sows with a gestation length gestation length of sows of the altrenogest group (T112 + T113) (115.3 ± 1.23 d) was significantly longer compared to gestation length of the non-treated sows (114.7 ± 1.69d) (p<0.01). Altrenogest treatment had no negative effect on the reproductive performances of the sows. In conclusion, the administration of altrenogest in late gestation is an effective and safe method to prevent early parturition and can counteract the reproductive losses because of premature farrowing, which may occur in a substantial part of the farrowing events.

  10. EARLY COMPLICATIONS IN BARIATRIC SURGERY: incidence, diagnosis and treatment

    Directory of Open Access Journals (Sweden)

    Marco Aurelio SANTO

    2013-03-01

    Full Text Available Context Bariatric surgery has proven to be the most effective method of treating severe obesity. Nevertheless, the acceptance of bariatric surgery is still questioned. The surgical complications observed in the early postoperative period following surgeries performed to treat severe obesity are similar to those associated with other major surgeries of the gastrointestinal tract. However, given the more frequent occurrence of medical comorbidities, these patients require special attention in the early postoperative follow-up. Early diagnosis and appropriate treatment of these complications are directly associated with a greater probability of control. Method The medical records of 538 morbidly obese patients who underwent surgical treatment (Roux-en-Y gastric bypass surgery were reviewed. Ninety-three (17.2% patients were male and 445 (82.8% were female. The ages of the patients ranged from 18 to 70 years (average = 46, and their body mass indices ranged from 34.6 to 77 kg/m2. Results Early complications occurred in 9.6% and were distributed as follows: 2.6% presented bleeding, intestinal obstruction occurred in 1.1%, peritoneal infections occurred in 3.2%, and 2.2% developed abdominal wall infections that required hospitalization. Three (0.5% patients experienced pulmonary thromboembolism. The mortality rate was 0,55%. Conclusion The incidence of early complications was low. The diagnosis of these complications was mostly clinical, based on the presence of signs and symptoms. The value of the clinical signs and early treatment, specially in cases of sepsis, were essential to the favorable surgical outcome. The mortality was mainly related to thromboembolism and advanced age, over 65 years. Contexto A cirurgia bariátrica tem mostrado ser o método mais eficaz de tratamento da obesidade grave. No entanto, sua aceitação como terapia padrão-ouro ainda é questionada. As complicações cirúrgicas observadas no início do período p

  11. Proteomic investigation of signatures for geniposide-induced hepatotoxicity.

    Science.gov (United States)

    Wei, Junying; Zhang, Fangbo; Zhang, Yi; Cao, Chunyu; Li, Xianyu; Li, Defeng; Liu, Xin; Yang, Hongjun; Huang, Luqi

    2014-12-05

    Evaluating the safety of traditional medicinal herbs and their major active constituents is critical for their widespread usage. Geniposide, a major active constituent with a defined structure from the traditional medicinal herb Gardenia jasminoides ELLIS fruit, exhibits remarkable anti-inflammatory, antiapoptotic, and antifibrotic properties and has been used in a variety of medical fields, mainly for the treatment of liver diseases. However, geniposide-induced hepatotoxicity and methods for the early detection of hepatotoxicity have yet to be reported. In this study, geniposide-induced hepatotoxicity was investigated. In addition, candidate biomarkers for the earlier detection of geniposide-induced hepatotoxicity were identified using a label-free quantitative proteomics approach on a geniposide overdose-induced liver injury in a rat model. Using an accurate intensity-based, absolute quantification (iBAQ)-based, one-step discovery and verification approach, a candidate biomarker panel was easily obtained from individual samples in response to different conditions. To determine the biomarkers' early detection abilities, five candidate biomarkers were selected and tested using enzyme-linked immunosorbent assays (ELISAs). Two biomarkers, glycine N-methyltransferase (GNMT) and glycogen phosphorylase (PYGL), were found to indicate hepatic injuries significantly earlier than the current gold standard liver biomarker. This study provides a first insight into geniposide-induced hepatotoxicity in a rat model and describes a method for the earlier detection of this hepatotoxicity, facilitating the efficient monitoring of drug-induced hepatotoxicity.

  12. Hepatotoxicity related to agomelatine and other new antidepressants: a case/noncase approach with information from the Portuguese, French, Spanish, and Italian pharmacovigilance systems.

    Science.gov (United States)

    Montastruc, François; Scotto, Stefania; Vaz, Ines Ribeiro; Guerra, Leonor Nogueira; Escudero, Antonio; Sáinz, María; Falomir, Teresa; Bagheri, Haleh; Herdeiro, Maria Teresa; Venegoni, Mauro; Montastruc, Jean Louis; Carvajal, Alfonso

    2014-06-01

    Antidepressants have been associated with a low incidence of idiosyncratic hepatic injury. Some of them, nefazodone or amineptine, were observed to induce severe hepatic injury and withdrawn from the market. Recently, some cases of this severe condition have been reported in association with agomelatine use. Therefore, the objective of this study is to learn the risk of hepatic damage with agomelatine as compared with other new antidepressants. We took data from the Spanish, French, Italian, and Portuguese pharmacovigilance system databases. A case/noncase approach to assess the strength of the association between whichever antidepressant and hepatotoxicity was performed; cases were defined as reports of hepatotoxicity; noncases were reports of all reactions other than hepatotoxicity. Exposure was the recording of a new antidepressant in a report, whether or not it was suspected of causing the reaction. During the period surveyed, 3300 cases of hepatotoxicity were collected for the antidepressants assessed. They represent 10.3% of all cases collected for these drugs; the corresponding figure for all drugs was 6.0%. Meanwhile, 63 cases of hepatotoxicity associated with agomelatine were collected since its introduction until the end of the period studied; they account for a percentage of 14.6. Agomelatine was statistically associated with hepatotoxicity in Spain [reporting odds ratio (ROR), 4.9 (95% confidence interval [CI], 2.4-9.7)], France (ROR, 2.4 [95% CI, 1.5-3.7]), and Italy (ROR, 5.1 [95% CI, 1.7-14.0]). Current results support the idea of agomelatine to be related to a higher hepatotoxicity risk. Physicians should consider early discontinuation if the condition is suspected; health authorities should promptly explore the best regulatory actions to be taken.

  13. Early identification and management of critical incident stress.

    Science.gov (United States)

    Caine, Randy M; Ter-Bagdasarian, Levon

    2003-02-01

    Everyone experiences stress. That stress may be related to work (internal), community (external), or family; it may be cumulative or related to a particular critical incident. The cost related to treating acute stress is staggering, both to individuals and to organizations. Critical care nurses are well educated in the physiological responses to the stress of acute illness. Recognizing the emotional impact of stress and the techniques to manage it in themselves and in those with whom they work is equally as important. CISD is widely advocated as an intervention after critical incidents. Although debriefing in and of itself is effective, a single-session semistructured crisis intervention will not prevent posttraumatic stress; thus, the use of CISD as part of a comprehensive multifaceted approach to the management of acute stress related to a critical incident is recommended.

  14. Early course of schizophrenia in a representative Dutch incidence cohort

    NARCIS (Netherlands)

    Selten, Jean-Paul; Veen, Natalie D.; Hoek, Hans W.; Laan, Winfried; Schols, Diede; van der Tweel, Ingeborg; Feller, Wilma; Kahn, Rene S.

    2007-01-01

    Purpose: To describe the early course of psychotic disorders in general and to examine whether certain variables can predict the early course of schizophrenic disorders (DSM-IV: schizophrenia, schizophreniform or schizoaffective disorder), Subjects and method: Follow-up and re-diagnosis of a highly

  15. Proteomics Investigations of Drug-Induced Hepatotoxicity in HepG2 Cells

    OpenAIRE

    Van Summeren, Anke; Renes, Johan; Bouwman, Freek G.; Noben, Jean-Paul; van Delft, Joost H. M.; Kleinjans, Jos C.S.; Mariman, Edwin C. M.

    2011-01-01

    Unexpected hepatotoxicity is one of the major reasons of drugs failing in clinical trials. This emphasizes the need for new screening methods that address toxicological hazards early in the drug discovery process. Here, proteomics techniques were used to gain further insight into the mechanistic processes of the hepatotoxic compounds. Drug-induced hepatotoxicity is mainly divided in hepatic steatosis, cholestasis, or necrosis. For each class, a compound was selected, respectively amiodarone, ...

  16. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy

    National Research Council Canada - National Science Library

    Shinwell, E S; Karplus, M; Reich, D; Weintraub, Z; Blazer, S; Bader, D; Yurman, S; Dolfin, T; Kogan, A; Dollberg, S; Arbel, E; Goldberg, M; Gur, I; Naor, N; Sirota, L; Mogilner, S; Zaritsky, A; Barak, M; Gottfried, E

    2000-01-01

    To study the long term neurodevelopmental outcome of children who participated in a randomised, double blind, placebo controlled study of early postnatal dexamethasone treatment for prevention of chronic lung disease...

  17. Early Detection and Localization of Downhole Incidents in Managed Pressure Drilling

    DEFF Research Database (Denmark)

    Willersrud, Anders; Imsland, Lars; Blanke, Mogens

    2015-01-01

    , distributed pressure measurements from wired pipe, and statistical change detection methods. Using statistical change detection methods, it is possible to detect the incidents and their location at a very early stage when small changes in operating parameters are covered in measurement noise. The method has......Downhole incidents such as kick, lost circulation, pack-off, and hole cleaning issues are important contributors to downtime in drilling. In managed pressure drilling (MPD), operations margins are typically narrower, implying more frequent incidents and more severe consequences. Detection...... and handling of symptoms of downhole drilling contingencies at an early stage are therefore crucial for the reliability and safety of MPD operations. In this paper we describe a method for early detection and localization of such incidents, based on a fit for purpose model of the downhole pressure hydraulics...

  18. Early Detection and Localization of Downhole Incidents in Managed Pressure Drilling

    DEFF Research Database (Denmark)

    Willersrud, Anders; Imsland, Lars; Blanke, Mogens

    2015-01-01

    Downhole incidents such as kick, lost circulation, pack-off, and hole cleaning issues are important contributors to downtime in drilling. In managed pressure drilling (MPD), operations margins are typically narrower, implying more frequent incidents and more severe consequences. Detection...... and handling of symptoms of downhole drilling contingencies at an early stage are therefore crucial for the reliability and safety of MPD operations. In this paper we describe a method for early detection and localization of such incidents, based on a fit for purpose model of the downhole pressure hydraulics......, distributed pressure measurements from wired pipe, and statistical change detection methods. Using statistical change detection methods, it is possible to detect the incidents and their location at a very early stage when small changes in operating parameters are covered in measurement noise. The method has...

  19. Incidence of prostate cancer in Lithuania after introduction of the Early Prostate Cancer Detection Programme.

    Science.gov (United States)

    Smailyte, G; Aleknaviciene, B

    2012-12-01

    In Lithuania, prostate-specific antigen (PSA) testing is offered to healthy asymptomatic men as a screening test in the population-based Early Prostate Cancer Detection Programme (EPCDP). The aim of this study was to analyse the incidence of prostate cancer before and after introduction of the EPCDP in Lithuania. Prostate cancer incidence and mortality data from the Lithuanian Cancer Registry were analysed for the period 1990-2008. Age-specific incidence and mortality data were adjusted to the European Standard Population. There have been extraordinary changes in the incidence of prostate cancer in Lithuania following introduction of the EPCDP, and there is strong evidence that these changes are the result of increased detection rates, especially in men of screening age. Further observation of changes in prostate cancer incidence and mortality in Lithuania may help to determine the extent to which PSA testing at the population level influences incidence and mortality in the general population.

  20. Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS

    Science.gov (United States)

    Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Acioli-Santos, Bartolomeu; Maruza, Magda; Montarroyos, Ulisses Ramos; Ximenes, Ricardo Arraes de Alencar; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito de Barros; de Albuquerque, Maria de Fátima P. Militão

    2016-01-01

    Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA. PMID:27332812

  1. Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS.

    Science.gov (United States)

    Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Acioli-Santos, Bartolomeu; Maruza, Magda; Montarroyos, Ulisses Ramos; Ximenes, Ricardo Arraes de Alencar; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito de Barros; Albuquerque, Maria de Fátima P Militão de

    2016-01-01

    Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA.

  2. Age Related Incidence and Early Outcomes of Hip Fractures: A Prospective Cohort Study of 1177 patients

    OpenAIRE

    Shenoy Ravikiran; Eranki Vivek; Pillai Anand; Hadidi Mahar

    2011-01-01

    Abstract Introduction Associated with the increase in the aging population, there is an increase in the incidence of hip fractures worldwide. Outcome following such fractures is affected by age of the patient. This study aims to assess the incidence and early outcome of hip fractures, comparing between different age groups. Methods Data of hip fractures collected over a period of five years was analysed. Patients were divided into three groups, group A (patients under the age of 64), group B ...

  3. High incidence of bacteriuria in early post-kidney transplantation; results from a randomized controlled study.

    Science.gov (United States)

    Parapiboon, W; Ingsathit, A; Jirasiritham, S; Sumethkul, V

    2012-04-01

    Since the incidence of bacteriuria in kidney transplant recipients varyes according to the study, we examined it among our cases. Our post hoc analysis of data from a single-center, parallel, randomized, controlled, open label study included 90 patients who underwent kidney transplantation at our hospital from April 2010 to January 2011. Patients were randomized to early ureteric stent removal at 8 days versus routine ureteric stent removal at 15 days after kidney transplantation. We identified the incidence of and causative organism for bacteriuria in the early posttransplant period. Seventy-Four patients (58% living donors) participated in this study. The overall incidence of bacteriuria was 56.7% during the first month after kidney transplantation. In patients who had bacteriuria, 48% showed symptomatic urinary tract infection, 40% asymptomatic bacteriuria and 12% urosepsis. The most common organism was Escherichia coli (40%) follow by Klebsiella pneumoniae (19%). The incidence of an ESBL producing organism was 34%. The incidence of bacteriuria was high during the early post-kidney transplant period, requiring increased awareness and surveillance. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. [Decrease of the incidence of sepsis syndrome after early enteral nutrition of patients with severe burns].

    Science.gov (United States)

    Pereira, J L; Gómez-Cia, T; Garrido, M; Parejo, J; Jódar, E; Serrano, P; Romero, H; Fraile, J; Franco, A; García-Luna, P P

    1996-01-01

    The objective of this study was to evaluate the effect of early enteral nutrition on the incidence of the septic syndrome as well as its tolerance, in patients with severe burns. We retrospectively studied 64 patients older than 15 years of age, with a greater than 20% burned body surface area. They were divided into 2 groups as a function of the time elapsed between the beginning of Enteral Nutrition and the time of the burning: 23 patients were given Enteral Nutrition within 24 hours after the burn, and in 41 patients the enteral nutrition was started later than 24 hours after sustaining the thermal injury. Both groups were similar with respect to age, sex, percentage of 2nd and 3rd degree burns, incidence of inhalation, and deaths. All patients received the Enteral Nutrition through a nasogastric tube, with administration of a polymeric, hyperprotein and hypocaloric formula through a continuous infusion pump. In our study we saw a reduction of the incidence of the septic syndrome in the patients who received early enteral Nutrition (26%; 6 patients of a total of 23), with respect to those who did non receive early Enteral Nutrition (54%; 22 patients of a total of 41), with a statistical significance of p > 0.05. There were no differences between both groups with respect to the digestive tolerance to Enteral Nutrition. From our study we can deduce that early Enteral Nutrition reduces the incidence of septic complications, without this increasing the digestive intolerance to the same.

  5. 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.

  6. Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study

    OpenAIRE

    Farvid, Maryam S; Cho, Eunyoung; Chen, Wendy Y.; Eliassen, A Heather; Willett, Walter C.

    2014-01-01

    Objective: To investigate the association between dietary protein sources in early adulthood and risk of breast cancer. Design: Prospective cohort study. Setting: Health professionals in the United States. Participants: 88 803 premenopausal women from the Nurses’ Health Study II who completed a questionnaire on diet in 1991. Main outcome measure Incident cases of invasive breast carcinoma, identified through self report and confirmed by pathology report. Results: We documented 2830 cases of b...

  7. Dietary protein sources in early adulthood and breast cancer incidence: prospective cohort study

    OpenAIRE

    Farvid, Maryam S; Cho, Eunyoung; Chen, Wendy Y.; Eliassen, A Heather; Willett, Walter C.

    2014-01-01

    Objective To investigate the association between dietary protein sources in early adulthood and risk of breast cancer. Design Prospective cohort study. Setting Health professionals in the United States. Participants 88 803 premenopausal women from the Nurses’ Health Study II who completed a questionnaire on diet in 1991. Main outcome measure Incident cases of invasive breast carcinoma, identified through self report and confirmed by pathology report. Results We documented 2830 cases of breast...

  8. Early life treatment with vancomycin reduces diabetes incidence in NOD mice

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis

    immune response and a fine-tuned balance between these immunological components is crucial for characteristics of the disease, such as severity, onset time and recovery. The balance between the regulatory and the adaptive immune response is heavily influenced by early life bacterial stimulation......Type 1 diabetes (T1D) results from an uncontrolled T cell mediated destruction of the insulin-producing beta-cells in the pancreas. Causal factors include a combination of genetics, early life incidents and the food we eat. The involved adaptive immune response can be down regulated by a regulatory....... An interplay that is likely to represent a critical environmental component to diabetes induction. In a period after birth alterations of the early microbial colonization of the gut therefore can be expected to have an immense impact on diabetes progression later in life. In this study neonate NOD mice were...

  9. Early life treatment with vancomycin reduces diabetes incidence in NOD mice

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis; Nielsen, Dennis Sandris; Vogensen, Finn Kvist;

    immune response and a fine-tuned balance between these immunological components is crucial for characteristics of the disease, such as severity, onset time and recovery. The balance between the regulatory and the adaptive immune response is heavily influenced by early life bacterial stimulation......Type 1 diabetes (T1D) results from an uncontrolled T cell mediated destruction of the insulin-producing beta-cells in the pancreas. Causal factors include a combination of genetics, early life incidents and the food we eat. The involved adaptive immune response can be down regulated by a regulatory....... An interplay that is likely to represent a critical environmental component to diabetes induction. In a period after birth alterations of the early microbial colonization of the gut therefore can be expected to have an immense impact on diabetes progression later in life. In this study neonate NOD mice were...

  10. Early Prediction of Sepsis Incidence in Critically Ill Patients Using Specific Genetic Polymorphisms.

    Science.gov (United States)

    David, Vlad Laurentiu; Ercisli, Muhammed Furkan; Rogobete, Alexandru Florin; Boia, Eugen S; Horhat, Razvan; Nitu, Razvan; Diaconu, Mircea M; Pirtea, Laurentiu; Ciuca, Ioana; Horhat, Delia; Horhat, Florin George; Licker, Monica; Popovici, Sonia Elena; Tanasescu, Sonia; Tataru, Calin

    2017-06-01

    Several diagnostic methods for the evaluation and monitoring were used to find out the pro-inflammatory status, as well as incidence of sepsis in critically ill patients. One such recent method is based on investigating the genetic polymorphisms and determining the molecular and genetic links between them, as well as other sepsis-associated pathophysiologies. Identification of genetic polymorphisms in critical patients with sepsis can become a revolutionary method for evaluating and monitoring these patients. Similarly, the complications, as well as the high costs associated with the management of patients with sepsis, can be significantly reduced by early initiation of intensive care.

  11. The Incidence of Infection After Early Closure of Evulsive Facial Wounds

    Directory of Open Access Journals (Sweden)

    Hosseini-e- Todashki H

    2000-06-01

    Full Text Available The aim of this study was to evaluate the incidence of postoperative wound dehiscence and"ninfection after early closure of evulsive facial wounds. This treatment was conducted on 28 male patients"nwith evulsive facial wounds. The formation of these evulsive wounds was due to the rupture of"ntemporary cavitation caused by high and extra high velocity messiles. All patients with average age of 18"nyears old were treated 24-48 hrs afire accidents at base hospitals (1988-1990."nPrimary healing was achieved in 24 subjects from 7 tO 15 days after the standard operation. Wound"ndehiscences and bacterial infections were observed in 4 subjects."nThe conclusion can be made from the results is that the early closure of evulsive facial wounds may"nreduce the rate of wound dehiscence and infection because of high vascularity in this area.

  12. Age Related Incidence and Early Outcomes of Hip Fractures: A Prospective Cohort Study of 1177 patients

    Directory of Open Access Journals (Sweden)

    Shenoy Ravikiran

    2011-01-01

    Full Text Available Abstract Introduction Associated with the increase in the aging population, there is an increase in the incidence of hip fractures worldwide. Outcome following such fractures is affected by age of the patient. This study aims to assess the incidence and early outcome of hip fractures, comparing between different age groups. Methods Data of hip fractures collected over a period of five years was analysed. Patients were divided into three groups, group A (patients under the age of 64, group B (patients between 65 and 84 years of age, and group C (patients over the age of 85. Results Of the 1177 patients included in the study, there were 90 patients in group A, 702 patients in group B and 385 patients in group C. There was a female preponderance across all age groups, and this increased as age advanced (p Conclusions Hip fractures are more common among females irrespective of age group. Older patients have a higher mortality and a greater deterioration of walking ability after such injuries. Internal fixation of intracapsular fractures have demonstrated satisfactory early outcome in the immediate period. This could be attributed to retention of native bone, better propioception and shorter operation time.

  13. Association of Kidney Function and Early Kidney Injury With Incident Hypertension in HIV-Infected Women.

    Science.gov (United States)

    Ascher, Simon B; Scherzer, Rebecca; Peralta, Carmen A; Tien, Phyllis C; Grunfeld, Carl; Estrella, Michelle M; Abraham, Alison; Gustafson, Deborah R; Nowicki, Marek; Sharma, Anjali; Cohen, Mardge H; Butch, Anthony W; Young, Mary A; Bennett, Michael R; Shlipak, Michael G

    2017-02-01

    Subclinical kidney disease is associated with developing hypertension in the general population, but data are lacking among HIV-infected people. We examined associations of kidney function and injury with incident hypertension in 823 HIV-infected and 267 HIV-uninfected women in the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected and uninfected women in the United States. Baseline kidney biomarkers included estimated glomerular filtration rate using cystatin C, urine albumin-to-creatinine ratio, and 7 urine biomarkers of tubular injury: α-1-microglobulin, interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, N-acetyl-β-d-glucosaminidase, and α1-acid-glycoprotein. We used multivariable Poisson regression to evaluate associations of kidney biomarkers with incident hypertension, defined as 2 consecutive visits of antihypertensive medication use. During a median follow-up of 9.6 years, 288 HIV-infected women (35%) developed hypertension. Among the HIV-infected women, higher urine albumin-to-creatinine ratio was independently associated with incident hypertension (relative risk =1.13 per urine albumin-to-creatinine ratio doubling, 95% confidence interval, 1.07-1.20), as was lower estimated glomerular filtration rate (relative risk =1.10 per 10 mL/min/1.73 m(2) lower estimated glomerular filtration rate; 95% confidence interval, 1.04-1.17). No tubular injury and dysfunction biomarkers were independently associated with incident hypertension in HIV-infected women. In contrast, among the HIV-uninfected women, urine albumin-to-creatinine ratio was not associated with incident hypertension, whereas higher urine interleukin-18, α1-acid-glycoprotein, and N-acetyl-β-d-glucosaminidase levels were significantly associated with incident hypertension. These findings suggest that early glomerular injury and kidney dysfunction may be involved in the pathogenesis of hypertension in

  14. Herbal and dietary supplement hepatotoxicity.

    Science.gov (United States)

    Navarro, Victor J

    2009-11-01

    Herbal and dietary supplements (HDS) are commonly used in the United States and throughout the world. The Dietary Supplement Health and Education Act and public standards set through the U.S. Pharmacopeia provide regulatory framework for these products. These regulations help to ensure the safety of grandfathered and new HDS coming onto the market, and the opportunity to identify and take action against unsafe products that have been distributed. The clinical patterns of presentation and severity of HDS-associated hepatotoxicity can be highly variable, even for the same product. In addition, accurate causality assessment in cases of suspected HDS hepatotoxicity is confounded by infrequent ascertainment of product intake by healthcare providers, under-reporting of HDS use by patients, the ubiquity of HDS and the complexity of their components, and the possibility for product adulteration. Additional measures to prevent HDS-induced hepatotoxicity include greater consumer and provider awareness, increased spontaneous reporting, and reassessment of regulations regarding the manufacturing, distribution, and marketing of these products.

  15. Effect of Lagenaria siceraria fruit extract (Bottle gourd) on hepatotoxicity induced by antitubercular drugs in albino rats

    OpenAIRE

    Satyajeet K. Funde; Jugalkishore B. Jaju; Shrikant C. Dharmadhikari; Ganesh R. Pawar

    2013-01-01

    Background: Anti TB drug induced hepatotoxicity has higher incidence in Indian population [11.5%] than western population [4.5%]. Antitubercular drug induced hepatotoxicity is mediated through oxidative and free radical damage to hepatocytes. Lagenaria siceraria [Bottle Gourd] is reported to have antioxidant and hepatoprotective activity. Hence in the present study we tested hepatoprotective and antioxidant activity of fruit extract of L. Siceraria in anti tubercular drug induced hepatotoxici...

  16. Early diagnostics and incidence of diabetic nephropathy depending on type 1 diabetes mellitus duration

    Directory of Open Access Journals (Sweden)

    V.A. Maslianko

    2017-05-01

    Full Text Available The objective — to establish the incidence of diabetic nephropathy (DN depending on duration of type 1 diabetes mellitus (DM, and also the content of cystatin С as a marker of early kidney damage. Materials and methods. Twenty eight patients with type 1 DM were enrolled in prospective study (11 men and 17 women aged 34.8 ± 7.2 years. Clinical and functional examination included the standard evaluation of renal function, and also the study of serum level of cystatin С. Results. In 17 out of 28 patients, the indexes of glomerular filtration rate calculated using the formulas of CKD-ЕРIcreat and CKD-ЕРIcys, indicated the different stages of chronic kidneys disease. Conclusions. Determination of cystatin C level and calculation of glomerular filtration rate using this index allows diagnosing the preclinical stages of kidney dysfunction in patients with type 1 DM in the normal creatinine level in the blood and without decline in glomerular filtration rate calculated using creatinine value. According to a retrospective study, the incidence and severity of DN in patients with type 1 DM increases with disease duration of more than 10 years.

  17. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Andreas Buness

    Full Text Available Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI using transcriptomics, metabolite profiling (metabolomics and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine, classical clinical chemistry markers like AST (aspartate aminotransferase, ALT (alanine aminotransferase, and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1 and Egr1 (early growth response protein 1. The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  18. Early changes in body weight and blood pressure are associated with mortality in incident dialysis patients.

    Science.gov (United States)

    Duranton, Flore; Duny, Yohan; Szwarc, Ilan; Deleuze, Sébastien; Rouanet, Catherine; Selcer, Isabelle; Maurice, François; Rivory, Jean-Pierre; Servel, Marie-Françoise; Jover, Bernard; Brunet, Philippe; Daurès, Jean-Pierre; Argilés, Àngel

    2016-04-01

    While much research is devoted to identifying novel biomarkers, addressing the prognostic value of routinely measured clinical parameters is of great interest. We studied early blood pressure (BP) and body weight (BW) trajectories in incident haemodialysis patients and their association with all-cause mortality. In a cohort of 357 incident patients, we obtained all records of BP and BW during the first 90 days on dialysis (over 12 800 observations) and analysed trajectories using penalized B-splines and mixed linear regression models. Baseline comorbidities and all-cause mortality (median follow-up: 2.2 years) were obtained from the French Renal Epidemiology and Information Network (REIN) registry, and the association with mortality was assessed by Cox models adjusting for baseline comorbidities. During the initial 90 days on dialysis, there were non-linear decreases in BP and BW, with milder slopes after 15 days [systolic BP (SBP)] or 30 days [diastolic BP (DBP) and BW]. SBP or DBP levels at dialysis initiation and changes in BW occurring in the first month or during the following 2 months were significantly associated with survival. In multivariate models adjusting for baseline comorbidities and prescriptions, higher SBP value and BW slopes were independently associated with a lower risk of mortality. Hazard ratios of mortality and 95% confidence intervals were 0.92 (0.85-0.99) for a 10 mmHg higher SBP and 0.76 (0.66-0.88) for a 1 kg/month higher BW change on Days 30-90. BW loss in the first weeks on dialysis is a strong and independent predictor of mortality. Low BP is also associated with mortality and is probably the consequence of underlying cardiovascular diseases. These early markers appear to be valuable prognostic factors.

  19. Identification of key performance indicators for on-farm animal welfare incidents: possible tools for early warning and prevention

    Directory of Open Access Journals (Sweden)

    Kelly Patricia C

    2011-10-01

    Full Text Available Abstract Background The objective of this study was to describe aspects of case study herds investigated by the Department of Agriculture, Fisheries and Food (DAFF in which animal welfare incidents occurred and to identify key performance indicators (KPIs that can be monitored to enhance the Early Warning System (EWS. Despite an EWS being in place for a number of years, animal welfare incidents continue to occur. Questionnaires regarding welfare incidents were sent to Superintending Veterinary Inspectors (SVIs, resulting in 18 herds being chosen as case study herds, 12 of which had a clearly defined welfare incident date. For each study herd, data on six potential KPIs were extracted from DAFF databases. The KPIs for those herds with a clearly defined welfare incident date were studied for a consecutive four year window, with the fourth year being the 'incident year', when the welfare incident was disclosed. For study herds without a clearly defined welfare incident date, the KPIs were determined on a yearly basis between 2001 and 2009. Results We found that the late registration of calves, the use of on-farm burial as a method of carcase disposal, an increasing number of moves to knackeries over time and records of animals moved to 'herd unknown' were notable on the case farms. Conclusion Four KPIs were prominent on the case study farms and warrant further investigation in control herds to determine their potential to provide a framework for refining current systems of early warning and prevention.

  20. A Topology Visualization Early Warning Distribution Algorithm for Large-Scale Network Security Incidents

    Directory of Open Access Journals (Sweden)

    Hui He

    2013-01-01

    Full Text Available It is of great significance to research the early warning system for large-scale network security incidents. It can improve the network system’s emergency response capabilities, alleviate the cyber attacks’ damage, and strengthen the system’s counterattack ability. A comprehensive early warning system is presented in this paper, which combines active measurement and anomaly detection. The key visualization algorithm and technology of the system are mainly discussed. The large-scale network system’s plane visualization is realized based on the divide and conquer thought. First, the topology of the large-scale network is divided into some small-scale networks by the MLkP/CR algorithm. Second, the sub graph plane visualization algorithm is applied to each small-scale network. Finally, the small-scale networks’ topologies are combined into a topology based on the automatic distribution algorithm of force analysis. As the algorithm transforms the large-scale network topology plane visualization problem into a series of small-scale network topology plane visualization and distribution problems, it has higher parallelism and is able to handle the display of ultra-large-scale network topology.

  1. A topology visualization early warning distribution algorithm for large-scale network security incidents.

    Science.gov (United States)

    He, Hui; Fan, Guotao; Ye, Jianwei; Zhang, Weizhe

    2013-01-01

    It is of great significance to research the early warning system for large-scale network security incidents. It can improve the network system's emergency response capabilities, alleviate the cyber attacks' damage, and strengthen the system's counterattack ability. A comprehensive early warning system is presented in this paper, which combines active measurement and anomaly detection. The key visualization algorithm and technology of the system are mainly discussed. The large-scale network system's plane visualization is realized based on the divide and conquer thought. First, the topology of the large-scale network is divided into some small-scale networks by the MLkP/CR algorithm. Second, the sub graph plane visualization algorithm is applied to each small-scale network. Finally, the small-scale networks' topologies are combined into a topology based on the automatic distribution algorithm of force analysis. As the algorithm transforms the large-scale network topology plane visualization problem into a series of small-scale network topology plane visualization and distribution problems, it has higher parallelism and is able to handle the display of ultra-large-scale network topology.

  2. REDUCTION IN INCIDENCE OF HOSPITALIZATIONS FOR PSYCHOTIC EPISODES THROUGH EARLY IDENTIFICATION AND INTERVENTION

    Science.gov (United States)

    McFarlane, William R.; SUSSER, EZRA; McCleary, Richard; Verdi, Mary; Lynch, Sarah; Williams, Deanna; McKeague, Ian W

    2014-01-01

    Objective This study tested whether the incidence of hospitalization for psychosis was reduced by a community-wide system of early identification and intervention to prevent onset of psychosis. Method The Portland Identification and Early Referral (PIER) program was initiated in 2001. Youth and young adults ages 12-35 were identified by professionals in a wide variety of educational, health and mental health settings. PIER staff assessed, confirmed risk for psychosis and provided treatment for 24 months to eligible and consenting young people (N=148). The monthly rate of hospital admissions for first episode psychosis was the outcome measure for efficacy of identification and intervention. Admission rates before and after the program began accepting referrals were compared, both in the experimental area and in aggregated urban areas of Maine. ARIMA models were used to assess the effect. Results Based on ARIMA models, the rate of hospitalized psychosis decreased significantly by 26% (95% C.I., -64% to -11%) in the Greater Portland area. Conversely, it increased by 8% (95% C.I. -5% to +36%) in the Urban Control area. Including increases in the control area, the actual vs. expected difference (-26% -8%) was -34%. The change was largest for non-affective-non-schizophrenic Disorders. Conclusions PIER demonstrated that population-wide early identification is feasible. Preventive intervention can reduce rates of initial hospitalizations for psychosis in a mid-sized city. Clinical trial registration The study was reviewed and approved by the Maine Medical Center Institutional Review Board and registered at ClinicalTrials.gov (NCT01597141). All research subjects gave informed consent prior to participating. PMID:24632857

  3. Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study

    Science.gov (United States)

    Jaeger, Veronika K.; Allanore, Yannick; Rossbach, Philipp; Riemekasten, Gabriela; Hachulla, Eric; Distler, Oliver; Airò, Paolo; Carreira, Patricia E.; Balbir Gurman, Alexandra; Vettori, Serena; Damjanov, Nemanja; Müller-Ladner, Ulf; Distler, Jörg H. W.; Li, Mangtao; Walker, Ulrich A.

    2016-01-01

    Objective Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc. Methods In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis. Results Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis. Conclusion In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to ‘widen' the still very narrow ‘window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately. PMID:27706206

  4. Greater Celandine hepatotoxicity: a clinical review.

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian; Glass, Xaver; Schulze, Johannes; Eickhoff, Axel

    2012-01-01

    Herbal hepatotoxicity is a rare and poorly described disease because reported cases are mostly scattered and lack an appropriate causality assessment. We now describe in detail the clinical picture of herbal hepatotoxicity by extracts of Greater Celandine (GC), syn. Chelidonium majus L. from the Papaveraceae family, which contain more than 20 ingredients including various biologically active isoquinoline alkaloids. For this purpose, we analyzed and reviewed published cases of 16 patients from various European countries. In all patients, herbal hepatotoxicity was of probable and highly probable causality for GC, using the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences). GC associated hepatotoxicity usually has an acute clinical course exhibiting a hepatocellular pattern of injury and is correlated to an idiosyncratic reaction with its metabolic subtype. Jaundice combined with high values of serum aminotransferases was present in virtually all cases with favourable outcome despite severe clinical course. In conclusion, GC hepatotoxicity is a typical herbal hepatotoxicity with a sound causality track for GC, but there is uncertainty regarding the respective causative compound(s). The present detailed review of GC hepatotoxicity may serve as an example for clinical causality assessments of future cases of liver injury due to other herbs.

  5. Early life instruction in foreign language and music and incidence of mild cognitive impairment.

    Science.gov (United States)

    Wilson, Robert S; Boyle, Patricia A; Yang, Jingyun; James, Bryan D; Bennett, David A

    2015-03-01

    To test the hypothesis that foreign language and music instruction in early life are associated with lower incidence of mild cognitive impairment (MCI) and slower rate of cognitive decline in old age. At enrollment in a longitudinal cohort study, 964 older persons without cognitive impairment estimated years of foreign language and music instruction by age 18. Annually thereafter they completed clinical evaluations that included cognitive testing and clinical classification of MCI. There were 264 persons with no foreign language instruction, 576 with 1-4 years, and 124 with > 4 years; 346 persons with no music instruction, 360 with 1-4 years, and 258 with > 4 years. During a mean of 5.8 years of observation, 396 participants (41.1%) developed MCI. In a proportional hazards model adjusted for age, sex, and education, higher levels (> 4 years) of foreign language (hazard ratio [HR] = 0.687, 95% confidence interval [CI] [0.482, 0.961]) and music (HR = 0.708, 95% CI [0.539, 0.930]) instruction by the age of 18 were each associated with reduced risk of MCI. The association persisted after adjustment for other early life indicators of an enriched cognitive environment, and it was stronger for nonamnestic than amnestic MCI. Both foreign language and music instruction were associated with higher initial level of cognitive function, but neither instruction measure was associated with cognitive decline. Higher levels of foreign language and music instruction during childhood and adolescence are associated in old age with lower risk of developing MCI but not with rate of cognitive decline. PsycINFO Database Record (c) 2015 APA, all rights reserved.

  6. High incidence and spontaneous resolution of mastoid effusion after craniotomy on early postoperative magnetic resonance images

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, T.; Saito, N.; Takahashi, A.; Fujimaki, H.; Tosaka, M.; Sasaki, T. [Department of Neurosurgery, Gunma University School of Medicine, 3-39-22 Showa-machi, 371-8511, Maebashi, Gunma (Japan); Sato, N. [Department of Diagnostic Radiology, Gunma University School of Medicine, Maebashi, Gunma (Japan)

    2003-07-01

    Mastoid effusion is a poorly understood complication after craniotomy. The incidence and severity of postoperative mastoid effusion were retrospectively examined on postoperative magnetic resonance (MR) images to assess any association with craniotomy procedures, time course, and neuro-otological complications. We evaluated the early postoperative MR images (within 4 days of craniotomy) and medical records of 74 patients who underwent 77 operations for the treatment of various intracranial diseases from January 2000 to December 2001. Mastoid effusion was classified into four grades: none, partial, moderate, and severe diffuse effusion in the mastoid air cells. Thirty-three follow-up MR images from 26 patients were also reviewed. Postoperative mastoid effusion occurred ipsilateral to the craniotomy site in 62 cases and contralateral in 56 cases. Mastoid effusion was significantly more severe ipsilateral than contralateral to craniotomy with exposure of the mastoid air cells (P<0.0001). There was no significant difference in severity between the contralateral and ipsilateral sides after craniotomy without mastoid air cell opening (P=0.437). Mastoid effusion following craniotomy without exposure of mastoid air cells resolved within 3 months. However, otitis media with effusion developed in six patients with severe mastoid effusion ipsilateral to craniotomy with exposure of the mastoid air cells. Mastoid effusion frequently developed on both sides. Any grade of mastoid effusion on the ipsilateral side to craniotomy without exposure of mastoid air cells, or on the contralateral side, was asymptomatic or had a benign course, and disappeared within 3 months. (orig.)

  7. Etiopathogenesis of Nonalcoholic Steatohepatitis: Role of Obesity, Insulin Resistance and Mechanisms of Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Praveen Guturu

    2012-01-01

    Full Text Available Incidence of nonalcoholic fatty liver disease is increasing with an estimated prevalence of 20–30% in developed nations. This is leading to increased incidence of chronic liver disease, cirrhosis, and hepatocellular cancer. It is critical to understand the etiology and pathogenesis of any disease to create therapeutic targets and develop new treatments. In this paper we discuss the etiology and pathogenesis of nonalcoholic steatohepatitis with special focus on obesity, role of insulin resistance, and molecular mechanisms of hepatotoxicity.

  8. Utilisation of helicopter emergency medical services in the early medical response to major incidents: a systematic literature review.

    Science.gov (United States)

    Johnsen, Anne Siri; Fattah, Sabina; Sollid, Stephen J M; Rehn, Marius

    2016-02-09

    This systematic review identifies, describes and appraises the literature describing the utilisation of helicopter emergency medical services (HEMS) in the early medical response to major incidents. Early prehospital phase of a major incident. Systematic literature review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Web of Science, PsycINFO, Scopus, Cinahl, Bibsys Ask, Norart, Svemed and UpToDate were searched using phrases that combined HEMS and 'major incidents' to identify when and how HEMS was utilised. The identified studies were subjected to data extraction and appraisal. The database search identified 4948 articles. Based on the title and abstract, the full text of 96 articles was obtained; of these, 37 articles were included in the review, and an additional five were identified by searching the reference lists of the 37 articles. HEMS was used to transport medical and rescue personnel to the incident and to transport patients to the hospital, especially when the infrastructure was damaged. Insufficient air traffic control, weather conditions, inadequate landing sites and failing communication were described as challenging in some incidents. HEMS was used mainly for patient treatment and to transport patients, personnel and equipment in the early medical management of major incidents, but the optimal utilisation of this specialised resource remains unclear. This review identified operational areas with improvement potential. A lack of systematic indexing, heterogeneous data reporting and weak methodological design, complicated the identification and comparison of incidents, and more systematic reporting is needed. CRD42013004473. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. An evaluation of early countermeasures to reduce the risk of internal radiation exposure after the Fukushima nuclear incident in Japan.

    Science.gov (United States)

    Nomura, Shuhei; Tsubokura, Masaharu; Gilmour, Stuart; Hayano, Ryugo S; Watanabe, Yuni N; Kami, Masahiro; Kanazawa, Yukio; Oikawa, Tomoyoshi

    2016-05-01

    After a radiation-release incident, intake of radionuclides in the initial stage immediately following the incident may be the major contributor to total internal radiation exposure for individuals in affected areas. However, evaluation of early internal contamination risk is greatly lacking. This study assessed the relationship between initial stage evacuation/indoor sheltering and internal radiation contamination levels 4 months after the 2011 Fukushima nuclear incident in Japan and estimated potential pathways of the contamination. The study population comprised 525 participants in the internal radiation screening program at Minamisoma Municipal General Hospital, 23 km north of the Fukushima nuclear plant. The analysed dataset included the results of a screening performed in July 2011, 4 months after the incident, and of a questionnaire on early-incident response behaviours, such as sheltering indoors and evacuations, completed by participants. Association between such early countermeasures and internal contamination levels of cesium-134 were assessed using Tobit multiple regression analyses. Our study shows that individuals who evacuated to areas outside Fukushima Prefecture had similar contamination levels of cesium-134 to individuals who stayed in Fukushima (relative risk: 0.86; 95% confidence interval: 0.74-0.99). Time spent outdoors had no significant relationship with contamination levels. The effects of inhalation from radiological plumes released from the nuclear plant on total internal radiation contamination might be so low as to be undetectable by the whole-body counting unit used to examine participants. Given the apparent limited effectiveness of evacuation and indoor sheltering on internal contamination, the decision to implement such early responses to a radiation-release incident should be made by carefully balancing their potential benefits and health risks.

  10. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor.

  11. A review of methotrexate-associated hepatotoxicity.

    Science.gov (United States)

    Bath, Roopjeet K; Brar, Navkiran K; Forouhar, Faripour A; Wu, George Y

    2014-10-01

    Methotrexate is effective not only in treating psoriasis and rheumatoid arthritis but also various other disorders. The use of methotrexate has been somewhat limited by concerns regarding its adverse effects, including its potential for hepatotoxicity. The purpose of this article is to provide an overview of methotrexate-associated hepatotoxicity, including risk factors, pathogenesis and recommendations for monitoring it by US, UK and European guidelines, as well as providing a brief overview of its mechanism of action and of high-dose methotrexate.

  12. The Influence of Pharmacological Preconditioning with Sevoflurane on Incidence of Early Allograft Dysfunction in Liver Transplant Recipients

    Directory of Open Access Journals (Sweden)

    Andrei F. Minou

    2012-01-01

    Full Text Available Background. Pharmacological preconditioning is one of the tools used to diminish preservation injury. We investigated the influence of sevoflurane preconditioning of liver grafts on postoperative graft function. Methods. Consecutive 60 deceased brain donors were randomized into sevoflurane group or control group. In sevoflurane group donors were treated with endexpiratory 2,0 volume% of sevoflurane during procurement. Primary endpoint was postoperative liver injury. Secondary endpoint was incidence of early allograft dysfunction (EAD. Results. The groups were not different in median DRI, donor age, graft steatosis, and MELD score. Peak AST and ALT levels were lower in sevoflurane group than in control group: 792 and 1861 (=0,038 for AST and 606 and 1191 for ALT (=0,117. Incidence of EAD was 16,7% in sevoflurane group and 50% in control group (Fisher test, =0,013. In subgroups without steatosis preconditioning with sevoflurane did not have influence on incidence of EAD. In subgroups with mild and moderate steatosis incidence of EAD was lower in recipients of liver grafts treated with sevoflurane. Conclusions. Preconditioning with sevoflurane during organ procurement improves graft function by lowering incidence of early allograft dysfunction, particularly in recipients of steatotic liver grafts.

  13. Analysis of light incident location and detector position in early diagnosis of knee osteoarthritis by Monte Carlo simulation

    Science.gov (United States)

    Chen, Yanping; Chen, Yisha; Yan, Huangping; Wang, Xiaoling

    2017-01-01

    Early detection of knee osteoarthritis (KOA) is meaningful to delay or prevent the onset of osteoarthritis. In consideration of structural complexity of knee joint, position of light incidence and detector appears to be extremely important in optical inspection. In this paper, the propagation of 780-nm near infrared photons in three-dimensional knee joint model is simulated by Monte Carlo (MC) method. Six light incident locations are chosen in total to analyze the influence of incident and detecting location on the number of detected signal photons and signal to noise ratio (SNR). Firstly, a three-dimensional photon propagation model of knee joint is reconstructed based on CT images. Then, MC simulation is performed to study the propagation of photons in three-dimensional knee joint model. Photons which finally migrate out of knee joint surface are numerically analyzed. By analyzing the number of signal photons and SNR from the six given incident locations, the optimal incident and detecting location is defined. Finally, a series of phantom experiments are conducted to verify the simulation results. According to the simulation and phantom experiments results, the best incident location is near the right side of meniscus at the rear end of left knee joint and the detector is supposed to be set near patella, correspondingly.

  14. Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

    Science.gov (United States)

    Hassan, Hozeifa M.; Guo, Hongli; Yousef, Bashir A.; Ping-Ping, Ding; Zhang, Luyong; Jiang, Zhenzhou

    2017-01-01

    Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity.

  15. Estimating the incidence reporting rates of new influenza pandemics at an early stage using travel data from the source country.

    Science.gov (United States)

    Chong, K C; Fong, H F; Zee, C Y

    2014-05-01

    During the surveillance of influenza pandemics, underreported data are a public health challenge that complicates the understanding of pandemic threats and can undermine mitigation efforts. We propose a method to estimate incidence reporting rates at early stages of new influenza pandemics using 2009 pandemic H1N1 as an example. Routine surveillance data and statistics of travellers arriving from Mexico were used. Our method incorporates changes in reporting rates such as linearly increasing trends due to the enhanced surveillance. From our results, the reporting rate was estimated at 0·46% during early stages of the pandemic in Mexico. We estimated cumulative incidence in the Mexican population to be 0·7% compared to 0·003% reported by officials in Mexico at the end of April. This method could be useful in estimation of actual cases during new influenza pandemics for policy makers to better determine appropriate control measures.

  16. Estimating the incidence reporting rates of new influenza pandemics at an early stage using travel data from the source country

    OpenAIRE

    CHONG, K. C.; Fong, H. F.; ZEE, C. Y.

    2013-01-01

    SUMMARY During the surveillance of influenza pandemics, underreported data are a public health challenge that complicates the understanding of pandemic threats and can undermine mitigation efforts. We propose a method to estimate incidence reporting rates at early stages of new influenza pandemics using 2009 pandemic H1N1 as an example. Routine surveillance data and statistics of travellers arriving from Mexico were used. Our method incorporates changes in reporting rates such as linearly inc...

  17. Early adolescent pregnancy increases risk of incident HIV infection in the Eastern Cape, South Africa: a longitudinal study

    Directory of Open Access Journals (Sweden)

    Nicola J Christofides

    2014-03-01

    Full Text Available Introduction: Adolescents having unprotected heterosexual intercourse are at risk of HIV infection and unwanted pregnancy. However, there is little evidence to indicate whether pregnancy in early adolescence increases the risk of subsequent HIV infection. In this paper, we tested the hypothesis that adolescent pregnancy (aged 15 or younger increases the risk of incident HIV infection in young South African women. Methods: We assessed 1099 HIV-negative women, aged 15–26 years, who were volunteer participants in a cluster-randomized, controlled HIV prevention trial in the predominantly rural Eastern Cape province of South Africa. All of these young women had at least one additional HIV test over two years of follow-up. Outcomes were HIV incidence rates per 100 person years and HIV incidence rate ratios (IRRs estimated by Poisson multivariate models. Three pregnancy categories were created for the Poisson model: early adolescent pregnancy (a first pregnancy at age 15 years or younger; later adolescent pregnancy (a first pregnancy at age 16 to 19 years; and women who did not report an adolescent pregnancy. Models were adjusted for study design, age, education, time since first sexual experience, socio-economic status, childhood trauma and herpes simplex virus type 2 infection. Results: HIV incidence rates were 6.0 per 100 person years over two years of follow-up. The adjusted IRR was 3.02 (95% CI 1.50–6.09 for a pregnancy occurring at age 15 or younger. Women with pregnancies occurring between 16 and 19 years of age did not have a higher incidence of HIV (IRR 1.08; 95% CI 0.64–1.84. Early adolescent pregnancies were associated with higher partner numbers and a greater age difference with partners. Conclusions: Early adolescent pregnancies increase the incidence of HIV among South African women. The higher risk is associated with sexual risk behaviours such as higher partner numbers and a greater age difference with partners rather than a

  18. Hepatotoxicity and the present herbal hepatoprotective scenario

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    Priyankar Dey

    2013-01-01

    Full Text Available Most of the metabolic and physiological processes of our body as well as the detoxification of various drugs and xenobiotic chemicals occur in the liver. During this detoxification process, the reactive chemical intermediates damage the liver severely. There are several commercially available drugs, consumption of which results in idiosyncratic drug reaction mediated hepatotoxicity. Drug induced hepatotoxicity is a burning problem in this regard and several drugs are withdrawn from the market due to their hepatotoxic nature. Today, worldwide search of non-hepatotoxic drugs, especially potent hepatoprotective drugs have led towards the screening of numerous herbal products. Pharmaceutical companies and scientific communities have started to consider the therapeutic efficiency of the plant-based hepatoprotective remedies. Different herbs are mentioned in various ethnopharmacological practices possessing hepatoprotective capacities and around the globe, such herbs are still used by people to cure certain liver diseases. Therefore, we have documented the various aspects of hepatotoxicity and an overview on the current scenario of the hepatoprotective herbal remedies.

  19. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

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    Miren García-Cortés

    2016-04-01

    Full Text Available Dietary supplements (DS are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™ while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang. Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  20. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J

    2016-04-09

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  1. Contemporary, age-based trends in the incidence and management of patients with early-stage kidney cancer.

    Science.gov (United States)

    Tan, Hung-Jui; Filson, Christopher P; Litwin, Mark S

    2015-01-01

    Although kidney cancer incidence and nephrectomy rates have risen in tandem, clinical advances have generated new uncertainty regarding the optimal management of patients with small renal tumors, especially the elderly. To clarify existing practice patterns, we assessed contemporary trends in the incidence and management of patients with early-stage kidney cancer. Using Surveillance, Epidemiology, and End Results data, we identified adult patients diagnosed with T1aN0M0 kidney cancer from 2000 to 2010. We determined age-adjusted and age-specific incidence and management rates (i.e., nonoperative, ablation, partial nephrectomy [PN], and radical nephrectomy) per 100,000 adults and determined the average annual percent change (AAPC). Finally, we compared management groups using multinomial logistic regression accounting for patient characteristics, cancer information, and county-level measures for health. From 2000 to 2010, we identified 41,645 adults diagnosed with T1aN0M0 kidney cancer. Overall incidence increased from 3.7 to 7.0 per 100,000 adults (AAPC = 7.0%, Pmanagement and ablation approached nephrectomy rates for those aged 75 to 84 years and became the predominant strategy for patients older than 84 years. Adjusting for clinical, oncological, and environmental factors, older patients less frequently underwent PN and more often received ablative or nonoperative management (P<0.001). As the incidence of early-stage kidney cancer rises, patients are increasingly treated with nonoperative and nephron-sparing strategies, especially among the most elderly. The broader array of treatment options suggests opportunities to better personalize kidney cancer care for seniors. Published by Elsevier Inc.

  2. Mechanisms underlying the hepatotoxic effects of ecstasy.

    Science.gov (United States)

    Carvalho, Márcia; Pontes, Helena; Remião, Fernando; Bastos, Maria L; Carvalho, Félix

    2010-08-01

    3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a worldwide illegally used amphetamine-derived designer drug known to be hepatotoxic to humans. Jaundice, hepatomegaly, centrilobular necrosis, hepatitis and fibrosis represent some of the adverse effects caused by MDMA in the liver. Although there is irrefutable evidence of MDMA-induced hepatocellular damage, the mechanisms responsible for that toxicity remain to be thoroughly clarified. One well thought-of mechanism imply MDMA metabolism in the liver into reactive metabolites as responsible for the MDMA-elicited hepatotoxicity. However, other factors, including MDMA-induced hyperthermia, the increase in neurotransmitters efflux, the oxidation of biogenic amines, polydrug abuse pattern, and environmental features accompanying illicit MDMA use, may increase the risk for liver complications. Liver damage patterns of MDMA in animals and humans and current research on the mechanisms underlying the hepatotoxic effects of MDMA will be highlighted in this review.

  3. Sunlight and the 5-year incidence of early age-related maculopathy: the beaver dam eye study.

    Science.gov (United States)

    Cruickshanks, K J; Klein, R; Klein, B E; Nondahl, D M

    2001-02-01

    To investigate the relation of sunlight exposure and indicators of sun sensitivity with the 5-year incidence of early age-related maculopathy (ARM). Longitudinal, population-based study. Participants (aged 43-86 years at baseline) in the Beaver Dam Eye Study were reexamined from 1993 to 1995, 5 years after the baseline examination. Questionnaire data about sunlight exposure and sun sensitivity were obtained at baseline. Additional information about earlier life patterns of exposure was ascertained at follow-up. Stereoscopic color fundus photographs were graded to determine the presence of ARM at the 5-year follow-up in eyes free from signs of early ARM at the baseline examination. Leisure time spent outdoors while persons were teenagers (aged 13-19 years) and in their 30s (aged 30-39 years) was significantly associated with the risk of early ARM (odds ratio, 2.09; 95% confidence interval, 1.19-3.65). There was a slight, but nonsignificant, protective effect associated with use of hats and sunglasses while persons were teenagers and in their 30s (odds ratio, 0.72; 95% confidence interval, 0.50-1.03). People with red or blond hair were slightly more likely to develop early ARM than people with darker hair (odds ratio, 1.33; 95% confidence interval, 0.97-1.83). There were no associations between estimated ambient UV-B exposure or markers of sun sensitivity and the incidence of early ARM. Exposure to sunlight may be associated with the development of early ARM.

  4. The incidence of deep venous thrombosis in high-risk Indian neurosurgical patients: Need for early chemoprophylaxis?

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    Ajith John George

    2016-01-01

    Full Text Available Introduction: Deep venous thrombosis (DVT is thought to be less common in Asians than in Caucasian population. The incidence of DVT in high-risk groups, especially the neurosurgical (NS patients, has not been well studied. This leaves no firm basis for the start of early prophylactic anticoagulation within first 5 postoperative days in Indian NS patients. This is a prospective observational study to determine the early occurrence of DVT in the NS patients. Patients and Methods: We screened 137 consecutive high-risk NS patients based on inclusion and exclusion criteria. The femoral veins were screened using Doppler ultrasound on day 1, 3, and 5 of admission into the NS Intensive Care Unit (ICU at tertiary center from South India. Results: Among 2887 admissions to NICU 147 patients met inclusion criteria. One hundred thirty seven were screened for DVT. There was a 4.3% (6/137 incidence of DVT with none of the six patients having signs or symptoms of pulmonary embolism. Among the risk factors studied, there was a significant association with femoral catheterization and a probable association with weakness/paraparesis/paraplegia. The mortality in the study group was 10.8% with none attributable to DVT or pulmonary embolism. Conclusion: There is a low incidence of DVT among the high risk neurosurgical population evaluated within the first 5 days of admission to NICU, limiting the need for early chemical thrombo-prophylaxis in these patients. With strict protocols for mechanical prophylaxis with passive leg exercise, early mobilization and serial femoral Doppler screening, heparin anticoagulation can be restricted within the first 5 days of ICU admission in high risk patients.

  5. Training Early Interventionists in Low Incidence Disabilities (September 1996-August 2000). Final Report.

    Science.gov (United States)

    Kaczmarek, Louise A.

    This final report summarizes the objectives, activities and outcomes of a federally-funded project that was designed to add an interdisciplinary specialization in multiple disabilities for infants and toddlers to an existing Early Intervention Master of Education/Early Childhood Education Certificate Program at the University of Pittsburgh. Seven…

  6. Unwanted Sexual Activity among Peers during Early and Middle Adolescence: Incidence and Risk Factors.

    Science.gov (United States)

    Small, Stephen A.; Kerns, Donell

    1993-01-01

    Assessed incidence and risk factors of unwanted sexual activity initiated by peers for 1,149 adolescent females. Twenty percent of sample reported some type of unwanted sexual contact in past year. Over one-third of this group reported having been forced to have sexual intercourse. Boyfriends were most commonly reported perpetrators followed by…

  7. Psychological factors and the incidence of temporomandibular disorders in early adolescence

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    Luciano José Pereira

    2009-06-01

    Full Text Available The purpose of the present study was to evaluate the relationship between psychological variables and the clinical diagnosis of temporomandbular disorders (TMD in 12-year-old adolescents. TMD pain was assessed by RDC/TMD examination (Research Diagnostic Criteria for Temporomandibular Disorders (Axis I and II. Five-hundred and fifty-eight subjects (330 girls and 228 boys were examined. Bivariate analyses were performed using the Chi-square test (χ2. The logistic regression models were adjusted estimating the Odds Ratios (OR, their 95% confidence intervals (CI, and significance levels. Only 2.19% of the boys and 8.18% of the girls presented one of the Axis I categories. All variables from axis II were related to TMD diagnosis (p < 0.001. Gender was significantly related to TMD diagnosis (p = 0.0028. The risk of TMD incidence for girls was 3.5 times higher than that for boys (Odds Ratio = 3.52, Confidence Interval 1.31-9.43. The individuals who presented the variable "characteristics of pain intensity" (CPI higher than 0 had 31 times more risk of TMD incidence (Odds Ratio = 31.361, Confidence interval 6.01-163.5. We concluded that psychological variables and female gender are important risk indicators related to TMD incidence, even in adolescents.

  8. Current and emerging biomarkers of hepatotoxicity

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    Yang X

    2012-08-01

    Full Text Available Xi Yang, William F Salminen, Laura K SchnackenbergDivision of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USAAbstract: Drug-induced liver injury (DILI is of great concern to human health. Generally, liver function and injury is evaluated based upon clinical signs, a select group of serum clinical biomarkers, and occasionally liver biopsies. While alanine aminotransferase, the most commonly used biomarker of hepatocellular injury, is a sensitive marker of liver injury, it is not necessarily specific for liver injury. Furthermore, alanine aminotransferase levels may not always correlate with the extent of injury. Therefore, new hepatotoxicity biomarkers are needed that are more predictive and specific indicators of liver injury and altered function. In addition, no current biomarker provides prognostic information about ultimate outcome once injury occurs, and any new biomarker filling this need is desperately needed. The omics technologies, including genomics, proteomics, and metabolomics, are being used in preclinical animal studies as well as clinical studies to evaluate markers of hepatotoxicity in easily obtained biofluids, such as urine and serum. Recently, the evaluation of circulating microRNAs in urine and blood has also shown promise for the identification of novel, sensitive markers of liver injury. This review evaluates the current status of proposed biomarkers of hepatotoxicity from the omics platforms, as well as from analysis of microRNAs. A brief description of the qualification of proposed biomarkers is also given.Keywords: biomarkers, hepatotoxicity, metabolomics, microRNA, proteomics, transcriptomics

  9. Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis

    DEFF Research Database (Denmark)

    Jaeger, Veronika K; Wirz, Elina G; Allanore, Yannick

    2016-01-01

    OBJECTIVE: Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed...... and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis. RESULTS: Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity...

  10. Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis

    DEFF Research Database (Denmark)

    Wirz, Elina G; Jaeger, Veronika K; Allanore, Yannick

    2016-01-01

    OBJECTIVES: To longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset of Raynaud's phenomenon (RP) in the European Scleroderma Trials and Research (EUSTAR) cohort. METHODS...

  11. Low Incidence of Early Postoperative Cerebral Edema After Coronary Artery Bypass Grafting

    NARCIS (Netherlands)

    Ottens, Thomas H.; Hendrikse, J; Slooter, Arjen J. C.; van Herwerden, LA; Dieleman, Stefan; van Dijk, Diederik

    2015-01-01

    Objective: Using magnetic resonance imaging, the authors studied the influence of a single high dose of intraoperative dexamethasone on the severity of cerebral edema that can occur early after coronary artery bypass grafting (CABG). It was hypothesized that high-dose intraoperative dexamethasone re

  12. Low Incidence of Synchronous or Metachronous Tumors after Endoscopic Submucosal Dissection for Early Gastric Cancer with Undifferentiated Histology.

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    Chan Hyuk Park

    Full Text Available Gastric cancer with undifferentiated histology has different clinicopathologic characteristics compared to differentiated type gastric cancer. We aimed to compare the risk of synchronous or metachronous tumors after curative resection of early gastric cancer (EGC via endoscopic submucosal dissection (ESD, according to the histologic differentiation of the primary lesion.Clinicopathological data of patients with initial-onset EGC curatively resected via ESD between January 2007 and November 2014 in a single institution were reviewed. We analyzed the incidence of synchronous or metachronous tumors after ESD with special reference to the differentiation status of the primary lesion.Of 1,560 patients with EGC who underwent curative resection via ESD, 1,447 had differentiated type cancers, and 113 had undifferentiated type cancers. The cumulative incidence of metachronous or synchronous tumor after ESD was higher in the differentiated cancer group than in the undifferentiated cancer group (P = 0.008. Incidence of metachronous or synchronous tumor was 4.8% and 1.2% per person-year in the differentiated and undifferentiated cancer groups, respectively. The Cox proportional hazard model revealed that undifferentiated cancers were associated with a low risk of synchronous or metachronous tumors after adjusting for confounding variables (hazard ratio [95% confidence interval] = 0.287 [0.090-0.918].The rate of synchronous or metachronous tumors after curative ESD was significantly lower for undifferentiated cancers compare to differentiated cancers. These findings suggest that ESD should be actively considered as a possible treatment for undifferentiated type EGCs.

  13. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs

    Science.gov (United States)

    Sewing, Sabine; Boess, Franziska; Moisan, Annie; Bertinetti-Lapatki, Cristina; Minz, Tanja; Hedtjaern, Maj; Tessier, Yann; Schuler, Franz; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Single stranded oligonucleotides (SSO) represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH) levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development. PMID:27442522

  14. Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs.

    Directory of Open Access Journals (Sweden)

    Sabine Sewing

    Full Text Available Single stranded oligonucleotides (SSO represent a novel therapeutic modality that opens new space to address previously undruggable targets. In spite of their proven efficacy, the development of promising SSO drug candidates has been limited by reported cases of SSO-associated hepatotoxicity. The mechanisms of SSO induced liver toxicity are poorly understood, and up to now no preclinical in vitro model has been established that allows prediction of the hepatotoxicity risk of a given SSO. Therefore, preclinical assessment of hepatic liability currently relies on rodent studies that require large cohorts of animals and lengthy protocols. Here, we describe the establishment and validation of an in vitro assay using primary hepatocytes that recapitulates the hepatotoxic profile of SSOs previously observed in rodents. In vitro cytotoxicity upon unassisted delivery was measured as an increase in extracellular lactate dehydrogenase (LDH levels and concomitant reduction in intracellular glutathione and ATP levels after 3 days of treatment. Furthermore, toxic, but not safe, SSOs led to an increase in miR-122 in cell culture supernatants after 2 days of exposure, revealing the potential use of miR122 as a selective translational biomarker for detection of SSO-induced hepatotoxicity. Overall, we have developed and validated for the first time a robust in vitro screening assay for SSO liver safety profiling which allows rapid prioritization of candidate molecules early on in development.

  15. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis; Krych, Lukasz; Nielsen, Dennis Sandris;

    2012-01-01

    Aims/hypothesis: Increasing evidence suggests that environmental factors changing the normal colonisation pattern in the gut strongly influence the risk of developing autoimmune diabetes. The aim of this study was to investigate, both during infancy and adulthood, whether treatment with vancomycin...... received vancomycin from 8 weeks of age until onset of diabetes. Pyrosequencing of the gut microbiota and flow cytometry of intestinal immune cells was used to investigate the effect of vancomycin treatment. Results: At the end of the study, the cumulative diabetes incidence was found to be significantly...... lower for the neonatally treated group compared with the untreated group, whereas the insulitis score and blood glucose levels were significantly lower for the mice treated as adults compared with the other groups. Mucosal inflammation was investigated by intracellular cytokine staining of the small...

  16. Diet, occupational exposure and early asthma incidence among bakers, pastry makers and hairdressers

    Directory of Open Access Journals (Sweden)

    Rémen Thomas

    2012-05-01

    Full Text Available Abstract Background The natural history of occupational asthma (OA is influenced by many determinants. This study aims to assess the combined roles of personal characteristics, including occupational exposure and nutritional habits, on the incidence of OA during the first years at work. Methods A nested case–control study was conducted within a retrospective cohort of young workers in the bakery, pastry-making and hairdressing sectors. Cases were subjects diagnosed as ‘confirmed’ or ‘probable’ OA consecutively to a medical visit (N = 31. Controls were subjects without OA (N = 196. Atopy was defined after blood specific IgE analysis, based on the PhadiatopTM test. Occupational exposure was characterized by standardized questionnaires and diet patterns by a food frequency questionnaire. Results Among bakers and pastry-makers, only atopy is an independent risk factor of OA (OR = 10.07 95%CI [2.76 – 36.65]. Among hairdressers, several variables are associated with OA. Body mass index (unit OR = 1.24 [1.03 – 1.48] and the score of exposure intensity (unit OR = 1.79 [1.05 – 3.05] are independent predictors of OA, but the role of atopy is weak (OR = 4.94 [0.66 – 36.75]. Intake of vitamin A is higher among hairdressers cases (crude p = 0.002, adjusted p = 0.01 after control for body mass index and atopy; the same observation is made for vitamin D (crude p = 0.004, adjusted p = 0.01. Conclusion This study suggests that the influence of several factors on the incidence of OA, including dietary vitamins, might vary across exposure settings.

  17. FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?

    Science.gov (United States)

    Graham, Garry G; Day, Richard O; Graudins, Andis; Mohamudally, Anthoulla

    2010-04-01

    Hepatotoxicity from paracetamol is of great concern because of the considerable number of patients who develop severe toxicity from this drug. A group of senior medical practitioners, academics and scientists were brought together on June 29 and 30, 2009 by the Food and Drug Administration of USA (FDA) with the aim of providing advice on how to limit the number of cases of hepatotoxicity due to paracetamol in USA. The most contentious recommendations were the reduction in the dose of paracetamol to 650 mg and the elimination of prescription combination products of paracetamol and opiates. The first recommendation indicates that many members of the committee consider, despite much evidence to the contrary, that therapeutic doses of paracetamol (up to 4 g daily) are associated with a significant incidence of hepatotoxicity. The second recommendation, if accepted by FDA, will require major changes in the therapeutic use of paracetamol and opiates. Adoption of these two recommendations may lead to the increased use of NSAIDs with the potential of increasing incidence of NSAIDs-related adverse reactions.

  18. Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat.

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P; Marinelli, Enrico

    2016-04-16

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by "the 3Ks", while trying to clarify the numerous aspects that still need to be addressed.

  19. Incidence and distribution of pathogens in early-onset neonatal sepsis in the era of antenatal antibiotics.

    Science.gov (United States)

    Kuhn, Pierre; Dheu, Céline; Bolender, Chantal; Chognot, Didier; Keller, Laurence; Demil, Houria; Donato, Lionel; Langer, Bruno; Messer, Jean; Astruc, Dominique

    2010-09-01

    In 2001 France issued a new set of guidelines for the use of antenatal antibiotics (AA). These guidelines recommended intrapartum antimicrobial prophylaxis (IAP) to prevent group B streptococcal (GBS) disease and AA to prolong pregnancy in the event of preterm premature rupture of membranes (AA for PPROM). This study aims to determine the effects of AA, recommended by national guidelines, on the incidence and distribution of pathogens in early-onset neonatal sepsis (EONS). We performed a population-based, prospective, observational study of level II and III perinatal centres throughout the region of Alsace, a northeastern area of France, between March 2004 and February 2005. The study population included all neonates with confirmed or probable EONS, who were treated with antibiotics for at least 5 days. We analysed exposure to AA, as well as clinical and microbiological data obtained from medical records. A total of 20 131 neonates were born during the study period, and 217 were included in the study. Of these, 24 subjects had confirmed sepsis, 140 had probable sepsis and 53 had possible EONS. The overall incidence of confirmed EONS was 1.19 per 1000 births. The infecting bacteria was GBS in 15 of 24 (62.5%) confirmed EONS cases (incidence: 0.75 per 1000 births) and in 81 of 140 (58%) probable sepsis cases. Escherichia coli was identified in 6 of 24 (25%) cases of confirmed EONS (incidence: 0.3 per 1000 births) and in 30 of 140 (21%) cases of clinical sepsis. Among E. coli infections (n= 36), amoxicillin resistance (n= 18) was statistically linked with AA use (P = 0.045). This link was significant in cases of PPROM (P = 0.015), but not when IAP was administered to prevent GBS disease (P = 0.264). IAP was not performed in 18 of 60 (30%) cases and 32 of 93 (34%) cases, despite positive screening or the presence of risk factors for EONS, respectively. Group B streptococcus remains the predominant pathogen in the era of AA. Aminopenicillin-resistant E. coli infections

  20. Learning from an early start but late end epidemics via an incidence rate restricted bivariate distribution and data analysis

    Directory of Open Access Journals (Sweden)

    Ramalingam Shanmugam

    2015-09-01

    Full Text Available Background: An ideal expectation of public health administrators or field medical workers is to have a late start and quick ending of any epidemic. Instead, when an epidemic starts early but ends late, it is where much can be learned from the incidences. A case in point for discussion in this article is the pattern of 2009 H1N1 epidemic. Methods: With a parameter to portray an existing health environment as a deterrent for an epidemic like H1N1 to outbreak in any location at a week, a bivariate distribution is created and is used to analyze the data for a learning so that it helps to prevent a too long prevailing future epidemic. This new distribution is named Incidence Rate Restricted Bivariate Distribution (IRRBGD. Statistical properties of IRRBGD are derived and illustrated using 2009 H1N1 incidences in all five continental regions (Africa, Asia, Europe, Americas, and Oceanic across on earth. Results: The Asian continent, compared to other four continental regions, had most vulnerability for H1N1 incidences. The odds for no H1N1 to occur is lowest only in Oceanic among the four continental regions, namely Africa, Europe, Americas, and Oceanic. Since the beginning of the year 2009 with 52 weeks, the week number, Y in which the H1N1 appeared first and the number, X of weeks the H1N1 continued on in a region are consistently highly correlated in all five continental regions. Conclusions: From the data analyses of 2009 H1N1 incidences, no continental region is risk free with respect another round of H1N1 epidemic in future. The medical community and public healthcare administrators ought to identify the common and region specific unique deterrents of the epidemic like H1N1. The impact of such deterrents to H1N1 is captured in our model and analysis. By increasing the deterrent level, the outbreak of an epidemic like H1N1 could be delayed, according to our model and data information. [Int J Res Med Sci 2015; 3(9.000: 2181-2189

  1. Nursing strategies to reduce the incidence of early childhood caries in culturally diverse populations.

    Science.gov (United States)

    Hallas, Donna; Fernandez, Jill; Lim, Lily; Carobene, Macy

    2011-06-01

    In the United States, early childhood caries (ECC) is a major unmet health care need adversely affecting the overall health of young children from diverse ethnic populations. Nurses who work in the newborn nursery, pediatrics, public, and community health centers have a unique opportunity to positively influence a change in this epidemic of ECC. Guided by Leininger's theory of cultural care, these authors describe ways to implement a comprehensive culturally sensitive oral health education program for parents of newborns and infants. Interventions based on the best available evidence for oral health education, a culturally sensitive caries risk assessment, recommendations for fluoride varnish treatments, and ways for parents to establish a dental home for the infant by 12 months old are presented. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Cotinine versus questionnaire: early-life environmental tobacco smoke exposure and incident asthma

    Directory of Open Access Journals (Sweden)

    Carlsten Chris

    2012-12-01

    Full Text Available Abstract Background The use of biomarkers has expanded considerably, as an alternative to questionnaire-based metrics of environmental tobacco smoke (ETS; few studies have assessed the affect of such alternative metrics on diverse respiratory outcomes in children, and we aimed to do so. Methods We evaluated various measures of birth-year ETS, in association with multiple respiratory endpoints early years of life, in the novel context of a birth cohort at high risk for asthma. We administered questionnaires to parents, both at the end of pregnancy and at one year of life, and measured cotinine in cord blood (CCot; in 275 children and in urine (UCot; obtained at 12 months in 365 children, each by radioimmunoassay. Multiple logistic regression was used to assess the association of the various metrics with recurrent wheeze at age 2 and with bronchial hyperresponsiveness (BHR and asthma at age 7. Results Self-reported 3rd trimester maternal smoking was associated with significantly increased risk for recurrent wheeze at age 2 (odds ratio 3.5 [95% confidence interval = 1.2,10.7]; the risks associated with CCot and 3rd trimester smoking in any family member were similar (OR 2.9 [1.2,7.0] and 2.6 [1.0,6.5], respectively. No metric of maternal smoking at 12 months appeared to significantly influence the risk of recurrent wheeze at age 2, and no metric of ETS at any time appeared to significantly influence risk of asthma or BHR at age 7. Conclusions Biomarker- and questionnaire-based assessment of ETS in early life lead to similar estimates of ETS-associated risk of recurrent wheeze and asthma.

  3. A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

    OpenAIRE

    Shih, Tung-Yuan; Pai, Chien-Yi; Yang, Ping; Chang, Wen-Liang; Wang, Ning-Chi; Hu, Oliver Yoa-Pu

    2013-01-01

    Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identifi...

  4. Large animal hepatotoxic and nephrotoxic plants.

    Science.gov (United States)

    Oladosu, L A; Case, A A

    1979-10-01

    The hepatotoxic and nephrotoxic plants of large domestic animals have been reviewed. The most important ones are those widely distributed as weeds over pastures, negelcted forests and grasslands, those used as ornamentals, the nitrate concentrating forage crops, and the cyanophoric plants. Crotolaria spp, the ragwort (Senecia jacobaea), the lantana spp. and heliotopum are common hepatoxic plants. Amaranthus retroflexus, Datura stramonium, Solanum rostratum, and the castor oil plant (Ricinus communis) are nephrotoxic plants.

  5. Black Cohosh Hepatotoxicity with Autoimmune Hepatitis Presentation

    Science.gov (United States)

    Franco, Diana L.; Kale, Santosh; Lam-Himlin, Dora M.; Harrison, M. Edwyn

    2017-01-01

    Herbal medicines have been used for the treatment of various ailments since time immemorial. Black cohosh (BC) is well known for the treatment of postmenopausal symptoms, with conflicting evidence supporting its safety and benefits. We present a rare case of BC-induced autoimmune hepatitis (AIH) with hepatotoxicity in a 69-year-old female. To our knowledge, this represents the third case of BC-induced AIH. PMID:28203134

  6. BEAP profiles as rapid test system for status analysis and early detection of process incidents in biogas plants.

    Science.gov (United States)

    Refai, Sarah; Berger, Stefanie; Wassmann, Kati; Hecht, Melanie; Dickhaus, Thomas; Deppenmeier, Uwe

    2017-03-01

    A method was developed to quantify the performance of microorganisms involved in different digestion levels in biogas plants. The test system was based on the addition of butyrate (BCON), ethanol (ECON), acetate (ACON) or propionate (PCON) to biogas sludge samples and the subsequent analysis of CH4 formation in comparison to control samples. The combination of the four values was referred to as BEAP profile. Determination of BEAP profiles enabled rapid testing of a biogas plant's metabolic state within 24 h and an accurate mapping of all degradation levels in a lab-scale experimental setup. Furthermore, it was possible to distinguish between specific BEAP profiles for standard biogas plants and for biogas reactors with process incidents (beginning of NH4(+)-N inhibition, start of acidification, insufficient hydrolysis and potential mycotoxin effects). Finally, BEAP profiles also functioned as a warning system for the early prediction of critical NH4(+)-N concentrations leading to a drop of CH4 formation.

  7. Revisiting 'progressive stroke': incidence, predictors, pathophysiology, and management of unexplained early neurological deterioration following acute ischemic stroke.

    Science.gov (United States)

    Seners, Pierre; Baron, Jean-Claude

    2017-04-28

    Early neurological deterioration (END) following acute ischemic stroke is a serious clinical event strongly associated with poor outcome. Regarding specifically END occurring within 24 h following stroke onset, apart from straightforward causes such as symptomatic intracranial haemorrhage and malignant edema, the cause of END remains unclear in more than a half of cases. In the latter situation, patients are often referred to as 'progressive stroke', a default clinical category that does not imply underlying mechanisms, precluding informed management. In this review article, we summarize the available evidence on the incidence, predictors, and associated factors of unexplained END, and discuss its underlying pathophysiology. We particularly address the hemodynamic and thrombotic mechanisms that likely play a critical role in unexplained END, and in turn highlight potential new avenues to prevent and manage this ominous event.

  8. Impact of Early Blood Transfusion After Kidney Transplantation on the Incidence of Donor-Specific Anti-HLA Antibodies.

    Science.gov (United States)

    Ferrandiz, I; Congy-Jolivet, N; Del Bello, A; Debiol, B; Trébern-Launay, K; Esposito, L; Milongo, D; Dörr, G; Rostaing, L; Kamar, N

    2016-09-01

    Little is known about the impact of posttransplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of donor-specific antibodies (DSAs). The aims of our study were to determine the 1-year incidence of DSAs (assessed using a solid-phase assay) and antibody-mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non-HLA-sensitized patients who had received an ABO-compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1-year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.

  9. Alpha methyldopa induced hepatotoxicity in pregnancy

    Directory of Open Access Journals (Sweden)

    Padmasri Ramalingappa

    2014-06-01

    Full Text Available We report a case of gestational hepatitis due to alpha-methyldopa and briefly review the literature on alpha-methyldopa-induced hepatotoxicity in pregnancy. A 32 year old woman, primigravida with 34 weeks of gestation with pre eclampsia, presented with symptoms of nausea, dark coloured urine and jaundice. She was on alpha methyldopa (Aldomet 250 mg thrice a day since the last five weeks. Laboratory investigations revealed raised bilirubin, serum aspartate transaminases and serum alanine transaminases. Platelets were normal. Peripheral smear did not show haemolysis. With the exclusion of viral, haemolytic and obstructive causes, drug induced jaundice was considered as a differential diagnosis. Alpha methyldopa was withdrawn and replaced with nifedipine for her pre eclampsia treatment. Her repeat bilirubin level done two weeks later showed a drop. She went into labour at 38 weeks and delivered vaginally. In postpartum follow up her liver tests returned to normal in two weeks, about six weeks after stopping methyldopa. Hepatotoxicity should be considered as one of the adverse drug reaction of alpha methyldopa. It is not possible at present to predict which patients will develop liver disease following the administration of this drug. An awareness of the possibility of methyldopa induced hepatotoxicity should be present in the clinician's mind and liver function tests should be done at regular intervals. The occasional occurrence of this harmful side effect is not a contraindication to the use of this antihypertensive agent. [Int J Reprod Contracept Obstet Gynecol 2014; 3(3.000: 805-807

  10. Early incidence of occupational asthma among young bakers, pastry-makers and hairdressers: design of a retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Guéant-Rodriguez Rosa-Maria

    2010-04-01

    Full Text Available Abstract Background Occupational exposures are thought to be responsible for 10-15% of new-onset asthma cases in adults, with disparities across sectors. Because most of the data are derived from registries and cross-sectional studies, little is known about incidence of occupational asthma (OA during the first years after inception of exposure. This paper describes the design of a study that focuses on this early asthma onset period among young workers in the bakery, pastry making and hairdressing sectors in order to assess early incidence of OA in these "at risk" occupations according to exposure duration, and to identify risk factors of OA incidence. Methods/Design The study population is composed of subjects who graduated between 2001 and 2006 in these sectors where they experience exposure to organic or inorganic allergenic or irritant compounds (with an objective of 150 subjects by year and 250 young workers with no specific occupational exposure. A phone interview focusing on respiratory and 'Ear-Nose-Throat' (ENT work-related symptoms screen subjects considered as "possibly OA cases". Subjects are invited to participate in a medical visit to complete clinical and lung function investigations, including fractional exhaled nitric oxide (FENO and carbon monoxide (CO measurements, and to collect blood samples for IgE (Immunoglobulin E measurements (total IgE and IgE for work-related and common allergens. Markers of oxidative stress and genetic polymorphisms exploration are also assessed. A random sample of 200 "non-cases" (controls is also visited, following a nested case-control design. Discussion This study may allow to describ a latent period between inception of exposure and the rise of the prevalence of asthma symptoms, an information that would be useful for the prevention of OA. Such a time frame would be suited for conducting screening campaigns of this emergent asthma at a stage when occupational hygiene measures and adapted

  11. Effect of early stellate ganglion blockade for facial pain from acute herpes zoster and incidence of postherpetic neuralgia.

    Science.gov (United States)

    Makharita, Mohamed Y; Amr, Yasser Mohamed; El-Bayoumy, Youssef

    2012-01-01

    The incidence of postherpetic neuralgia (PHN) has been reported to be 25% among those over the age of 50 years treated with antiviral medication. The role of sympathetic block in its prevention remains questionable. The aim of this study is to determine whether early stellate ganglion blockade for acute herpes zoster of the face will reduce the intensity and duration of acute herpetic pain, and if the blockade has the potential to prevent or reduce the incidence and/or severity of PHN. Randomized, controlled, double blind trial. Hospital, outpatient setting. Sixty-four patients over 50 years were assigned to receive a stellate ganglion block using either 8 mL saline (Group 1) or 6 mL bupivacaine 0.125% and 8 mg dexamethasone in a total volume of 8 mL (Group 2). All procedures were performed under fluoroscopy. All patients received pregabalin in a dose of 150 mg twice daily. Acetaminophen was available as needed. Pain assessment using the visual analog scale and amount of analgesic being taken was measured at the initial visit (basal), weekly for 6 weeks after the procedure and after 2, 3, and 6 months. Once a patient reported mild pain during the trial, pregabalin was tapered by 75 mg every other day; the patients who succeeded in this step were recorded in each group. The time of complete resolution of pain and incidence of persistent postherpetic pain was reported. Each patient's satisfaction was evaluated. There was a significantly shorter duration of pain noticed in Group 2 (P = 0.002). A significantly lower incidence of PHN was encountered in Group 2 after 3 months (P = 0.043) and 6 months (P = 0.035). Significantly more patient satisfaction was reported in Group 2 after 3 and 6 months. By the fourth week, 29 patients in Group 2 reported no pain. Two patients reported mild pain after 3 months which was resolved by the sixth month. In Group 1, 22 patients reported no pain by the sixth week and 8 patients reported moderate pain after 2 and 3 months; by the sixth

  12. [Incidence and causes of early end in awake surgery for language mapping not directly related to eloquence].

    Science.gov (United States)

    Villalba, Gloria; Pacreu, Susana; Fernández-Candil, Juan Luis; León, Alba; Serrano, Laura; Conesa, Gerardo

    2016-01-01

    The incidence and causes that may lead to an early end (unfinished cortical/subcortical mapping) of awake surgery for language mapping are little known. A study was conducted on 41 patients with brain glioma located in the language area that had awake surgery under conscious sedation. Surgery was ended early in 6 patients. The causes were: tonic-clonic seizure (1), lack of cooperation due to fatigue/sleep (4), whether or not word articulation was involved, a decreased level of consciousness for ammonia encephalopathy that required endotracheal intubation (1). There are causes that could be expected and in some cases avoided. Tumour size, preoperative aphasia, valproate treatment, and type of anaesthesia used are variables to consider to avoid failure in awake surgery for language mapping. With these results, the following measures are proposed: l) If the tumour is large, perform surgery in two times to avoid fatigue, 2) if patient has a preoperative aphasia, do not use sedation during surgery to ensure that sleepiness does not cause worse word articulation, 3) if the patient is on valproate treatment, it is necessary to rule out the pre-operative symptoms that are not due to ammonia encephalopathy. Copyright © 2015 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  13. Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.

    Science.gov (United States)

    Heinrich, Melissa M; Zembrzuski, Verônica M; Ota, Marcos M; Sacchi, Flavia P; Teixeira, Raquel L F; Cabello Acero, Pedro H; Cunha, Geraldo Marcelo; Souza-Santos, Reinaldo; Croda, Julio; Basta, Paulo C

    2016-12-01

    Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes.

  14. Nrf2 protects against furosemide-induced hepatotoxicity.

    Science.gov (United States)

    Qu, Qiang; Liu, Jie; Zhou, Hong-Hao; Klaassen, Curtis D

    2014-10-01

    Furosemide is a diuretic drug, but its reactive intermediates lead to acute liver injury in mice. Given the essential role of Nrf2 as a cellular defense regulator, we investigated whether Nrf2 would protect against furosemide-induced liver injury using the Nrf2 "gene-dose response" mouse model (Nrf2-null with Nrf2 knock-out, wild-type with normal expression of Nrf2, Keap1-KD with enhanced Nrf2 activation and Keap1-HKO mice with maximum Nrf2 activation). Twenty-four hours after furosemide administration (250mg/kg, i.p.), serum ALT activities and histopathological analysis indicated severe hepatotoxicity in Nrf2-null and WT mice, but significantly less in the Nrf2-overexpressing Keap1-KD and Keap1-HKO mice. Furosemide increased the mRNA of genes involved in the acute phase response (hemeoxygenase-1 and metallothionein-1), ER stress (C/Ebp-homologous protein and Growth arrest and DNA-damage-inducible protein), inflammatory cytokine (interleukin 1 beta), chemokines (macrophage inflammatory protein 2 and mouse keratinocyte-derived chemokine), as well as apoptosis (early growth response factor and BCL2-associated X protein) in livers of Nrf2-null and wild-type mice, but these genes increased less in mice with more Nrf2. The two genotypes of over-expressed Nrf2 mice had increased expression of the Nrf2 target genes Gclm, Gclc and Nqo1 prior to furosemide administration, and the expressions of these genes were increased further after furosemide administration. Thus, our findings provide strong evidence that over-expression of Nrf2 in Keap1-KD and Keap1-HKO mice and the increases in mRNA of a number of genes involved in anti-oxidative stress, anti-inflammation, anti-ER stress and anti-apoptosis protect against furosemide-induced hepatotoxicity.

  15. Inhibition of Glycogen Synthase Kinase 3 Accelerated Liver Regeneration after Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Bhushan, Bharat; Poudel, Samikshya; Manley, Michael W; Roy, Nairita; Apte, Udayan

    2017-03-01

    Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. Timely initiation of compensatory liver regeneration after APAP hepatotoxicity is critical for final recovery, but the mechanisms of liver regeneration after APAP-induced ALF have not been extensively explored yet. Previous studies from our laboratory have demonstrated that activation of β-catenin signaling after APAP overdose is associated with timely liver regeneration. Herein, we investigated the role of glycogen synthase kinase 3 (GSK3) in liver regeneration after APAP hepatotoxicity using a pharmacological inhibition strategy in mice. Treatment with specific GSK3 inhibitor (L803-mts), starting from 4 hours after 600 mg/kg dose of APAP, resulted in early initiation of liver regeneration in a dose-dependent manner, without modifying the peak regenerative response. Acceleration of liver regeneration was not secondary to alteration of APAP-induced hepatotoxicity, which remained unchanged after GSK3 inhibition. Early cell cycle initiation in hepatocytes after GSK3 inhibition was because of rapid induction of cyclin D1 and phosphorylation of retinoblastoma protein. This was associated with increased activation of β-catenin signaling after GSK3 inhibition. Taken together, our study has revealed a novel role of GSK3 in liver regeneration after APAP overdose and identified GSK3 as a potential therapeutic target to improve liver regeneration after APAP-induced ALF. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. The effect of rheumatoid arthritis-associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis.

    Science.gov (United States)

    Barra, Lillian J; Pope, Janet E; Hitchon, Carol; Boire, Gilles; Schieir, Orit; Lin, Daming; Thorne, Carter J; Tin, Diane; Keystone, Edward C; Haraoui, Boulos; Jamal, Shahin; Bykerk, Vivian P

    2017-05-01

    . RA is associated with an increased risk of cardiovascular events (CVEs). The objective was to estimate independent effects of RA autoantibodies on the incident CVEs in patients with early RA. Patients were enrolled in the Canadian Early Inflammatory Arthritis Cohort, a prospective multicentre inception cohort. Incident CVEs, including acute coronary syndromes and cerebrovascular events, were self-reported by the patient and partially validated by medical chart review. Seropositive status was defined as either RF or ACPA positive. Multivariable Cox proportional hazards survival analysis was used to estimate the effects of seropositive status on incident CVEs, controlling for RA clinical variables and traditional cardiovascular risk factors. . A total of 2626 patients were included: the mean symptom duration at diagnosis was 6.3 months ( s . d . 4.6), the mean age was 53 years ( s . d . 15), 72% were female and 86% met classification criteria for RA. Forty-six incident CVEs occurred over 6483 person-years [incidence rate 7.1/1000 person-years (95% confidence interval 5.3, 9.4)]. The CVE rate did not differ in seropositive vs seronegative subjects and seropositivity was not associated with incident CVEs in multivariable Cox regression models. Baseline covariates independently associated with incident CVEs were older age, a history of hypertension and a longer duration of RA symptoms prior to diagnosis. The rate of CVEs early in the course of inflammatory arthritis was low; however, delays in the diagnosis of arthritis increased the rate of CVEs. Hypertension was the strongest independent risk factor for CVEs. Results support early aggressive management of RA disease activity and co-morbidities to prevent severe complications.

  17. Statin Hepatotoxicity: Is it a Real Concern?

    Science.gov (United States)

    Sikka, Pranav; Saxena, K. K.; Kapoor, Seema

    2011-01-01

    Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are advised to discontinue statins for the fear of hepatotoxicity. Despite a lack of evidence that statins cause liver diseases, many physicians are reluctant to start statins in patients with an out-of-range liver enzymes value and this reluctance to initiate or interrupt the therapy with statins leads to dyslipidemia and its grave consequences. Further, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver function tests. PMID:22567196

  18. Statin Hepatotoxicity: Is it a Real Concern?

    Directory of Open Access Journals (Sweden)

    Pranav Sikka

    2011-01-01

    Full Text Available Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are advised to discontinue statins for the fear of hepatotoxicity. Despite a lack of evidence that statins cause liver diseases, many physicians are reluctant to start statins in patients with an out-of-range liver enzymes value and this reluctance to initiate or interrupt the therapy with statins leads to dyslipidemia and its grave consequences. Further, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver function tests.

  19. Lead hepatotoxicity: Selected aspects of pathobiochemistry

    Directory of Open Access Journals (Sweden)

    Mateusz Labudda

    2013-08-01

    Full Text Available Lead (Pb that belongs to heavy metals is one of the major pollution components of the environment. Occupational and environmental exposure to lead can cause its absorption by the body and consequently exert toxic effects in the liver. In this paper biochemical determinants of hepatotoxicity caused by lead are presented. Generation of reactive oxygen species, disturbances in the cellular antioxidant system, lipid peroxidation, inhibition of enzymatic proteins and intercellular signaling are also discussed. Med Pr 2013;64(4:565–568

  20. Prevention of hepatotoxicity due to anti tuberculosis treatment: A novel integrative approach

    Institute of Scientific and Technical Information of China (English)

    Meghna R Adhvaryu; Narsimha M Reddy; Bhasker C Vakharia

    2008-01-01

    AIM: To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity.METHODS: Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation.Isoniazid,rifampicin,pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment.Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant.Hemogram,bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result.RESULTS: Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316,P < 0.0001).Mean aspartate transaminase (AST) (195.93 ± 108.74 vs 85 ± 4.24,P < 0.0001),alanine transaminase (ALT) (75.74 ± 26.54 vs 41 ±1.41,P < 0.0001) and serum bilirubin (5.4 ± 3.38 vs 1.5± 0.42,P < 0.0001).A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137,P = 0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278,P = 0.0037) was observed.Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P < 0.0001).CONCLUSION: The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.

  1. Second cancer incidence risk estimates using BEIR VII models for standard and complex external beam radiotherapy for early breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Donovan, E. M.; James, H.; Bonora, M.; Yarnold, J. R.; Evans, P. M. [Joint Department of Physics, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton SM2 5PT (United Kingdom); Physics Department, Ipswich Hospital NHS Foundation Trust, Ipswich IP4 5PD (United Kingdom); Department of Academic Radiotherapy, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, United Kingdom and School of Radiotherapy, University of Milan, Milan 20122 (Italy); Department of Academic Radiotherapy, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton SM2 5PT (United Kingdom); Centre for Vision Speech and Signal Processing, University of Surrey, Guildford GU2 7XH (United Kingdom)

    2012-10-15

    Purpose: To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy (including cone beam CT verification) following breast conservation surgery for early breast cancer.Method: Doses from breast radiotherapy and kilovoltage cone beam CT (CBCT) exposures were obtained from thermoluminescent dosimeter measurements in an anthropomorphic phantom in which the positions of radiosensitive organs were delineated. Five treatment deliveries were investigated: (i) conventional tangential field whole breast radiotherapy (WBRT), (ii) noncoplanar conformal delivery applicable to accelerated partial beast irradiation (APBI), (iii) two-volume simultaneous integrated boost (SIB) treatment, (iv) forward planned three-volume SIB, and (v) inverse-planned three volume SIB. Conformal and intensity modulated radiotherapy methods were used to plan the complex treatments. Techniques spanned the range from simple methods appropriate for patient cohorts with a low cancer recurrence risk to complex plans relevant to cohorts with high recurrence risk. Delineated organs at risk included brain, salivary glands, thyroid, contralateral breast, left and right lung, esophagus, stomach, liver, colon, and bladder. Biological Effects of Ionizing Radiation (BEIR) VII cancer incidence models were applied to the measured mean organ doses to determine lifetime attributable risk (LAR) for ages at exposure from 35 to 80 yr according to radiotherapy techniques, and included dose from the CBCT imaging. Results: All LAR decreased with age at exposure and were lowest for brain, thyroid, liver, and bladder (<0.1%). There was little dependence of LAR on radiotherapy technique for these organs and for colon and stomach. LAR values for the lungs for the three SIB techniques were two to three times those from WBRT and APBI. Uncertainties in the LAR models outweigh any differences in lung LAR between the SIB methods. Constraints in the planning of the SIB methods ensured that

  2. 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.

  3. Association between Hypophosphatemia and Cardiac Arrhythmias in the Early Stage of Sepsis: Could Phosphorus Replacement Treatment Reduce the Incidence of Arrhythmias?

    Science.gov (United States)

    Schwartz, Andrei; Brotfain, Evgeni; Koyfman, Leonid; Kutz, Ruslan; Gruenbaum, Shaun E; Klein, Moti; Zlotnik, Alexander

    2014-06-01

    It is well known that new-onset arrhythmias are common in septic patients. It is thought that hypophosphatemia in the early stages of sepsis may contribute to the development of new arrhythmias. In this study, we hypothesized that intravenous (IV) phosphorus replacement may reduce the incidence of arrhythmias in critically ill patients. 34 adult septic patients with hypophosphatemia admitted to the general intensive care unit were treated with IV phosphorus replacement per ICU protocol, and the incidence of new arrhythmias were compared with 16 patients from previously published data. IV phosphorus replacement was associated with a significantly reduced incidence of arrhythmias (38% vs. 63%, p=0.04). There were no differences in observed mortality between subgroups, which may be due to the small sample size. This study demonstrated that IV phosphorus replacement might be effective in reducing the incidence of new arrhythmias in septic patients.

  4. [Herbals and herbal nutritional products hepatotoxicity].

    Science.gov (United States)

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Hernández-Rincón, Ileana; Barboza-Nobrega, María De Freitas

    2015-09-01

    Herbs and other botanicals have been used in different cultures with medicinal and dietary purposes for centuries. Contrary to the belief of being natural and safe products, their hepatotoxic potential is recognized in several studies worldwide, and represent a health problem that deserves greater attention. The reported prevalence of hepatotoxicity associated with botanicals is variable and depends on various factors such as population, period and design of the study. There have been reports of a total of 60 products with herbal medicinal and dietary purposes, which may cause liver damage; however, the pathophysiological mechanisms involved are not fully elucidated. Their clinical and histological features, not unlike liver injury associated with drugs in most patients, have a pattern of hepatocellular injury. Diagnosis is by exclusion, and represents a clinical challenge. It is essential the clinical suspicion and the differential diagnosis with other acute and chronic conditions. Hence, future researches are aimed at improving existing diagnostic methods and introducing new toxicological, genetic and immunological technologies. Treatment is complex and presents a challenge for the specialist, as there are no antidotes. Management based on the discontinued use of the product and in the symptomatic treatment, decreases the progression to an acute fulminant hepatic failure.

  5. Remission, continuation, and incidence of eating disorders during early pregnancy: A validation study on a population-based birth cohort

    Science.gov (United States)

    Watson, Hunna J.; Von Holle, Ann; Hamer, Robert M.; Berg, Cecilie Knoph; Torgersen, Leila; Magnus, Per; Stoltenberg, Camilla; Sullivan, Patrick; Reichborn-Kjennerud, Ted; Bulik, Cynthia M.

    2014-01-01

    Background The objective of this study was to validate previously published rates of remission, continuation, and incidence of broadly defined eating disorders during pregnancy. The previous rate modeling was done by our group (Bulik et al. 2007) and yielded participants halfway into recruitment of the planned 100,000 pregnancies in the Norwegian Mother and Child (MoBa) Cohort at the Norwegian Institute of Public Health. This study aimed to internally validate the findings with the completed cohort. Methods 77267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were included. Participants were split into a “training” sample (n=41243) based on participants in the MoBa version 2 dataset of the original study and a “validation” sample (n=36024) comprising individuals in the MoBa version 5 dataset that were not in the original study (Bulik et al. 2007). Internal validation of all original rate models involved fitting a calibration model to compare model parameters between the “training” and “validation” samples as well as bootstrap estimates of bias in the entire version 5 dataset. Results Remission, continuation, and incidence estimates from the “training” sample remained stable when evaluated via a split sample validation procedure. Pre-pregnancy prevalence estimates in the “validation” sample were 0.1% for anorexia nervosa, 1.0% for bulimia nervosa (BN), 3.3% for binge eating disorder (BED), and 0.1% for purging disorder (EDNOS-P). In early pregnancy, estimates were 0.2% for BN, 4.8% for BED, and eating disorders during pregnancy. Eating disorders during pregnancy were relatively common, occurring in nearly 1 in every 20 women, although almost all were cases of BED. Pregnancy was a window of remission from BN but a window of vulnerability for onset and continuation of BED. Training to detect the signs and symptoms of eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes

  6. PORTAL AND ARTERIAL FLUSHING WITH HTK AND TACROLIMUS CAN ATTENUATE THE INCIDENCE OF EARLY LIVER ALLOGRAFT DYSFUNCTION

    Directory of Open Access Journals (Sweden)

    A. E. Shcherba

    2015-01-01

    Full Text Available It was shown that Tacrolimus (Tac can suppress infl ammation and immune response involved in liver ischemia-reperfusion injury (IRI (Kristo I., Transpl Int., 2011. Aim. We hypothesize that back-table arterial and portal liver perfusion with Tac can infl uence the incidence and severity of early allograft dysfunction (EAD. A prospective randomized study was conducted (ClinicalTrials.gov Identifi er: NCT01887171.Materials and methods. Criteria of the inclusion: First liver transplantation from DBD donor with sequential portal-arterial reperfusion. At back-table portal vein and hepatic artery were perfused each by 500 ml of HTK solution containing 20 ng/ml Tac during 10–15 min followed by portal fl ushing with 200 ml 5% solution of Albumin containing 20 ng/ml Tac and by resting of liver in effl uent. No Tac was added in the control group. Primary Outcome: EAD (Olthoff KM, et al. Liver Transpl. 2010 and severe EAD (P.R.Salvalaggio, et al. Transpl. Proceedings, 2012.Results. No difference was found between groups (main vs. control in terms of MELD (16 vs. 16, steatosis (10 vs. 10%, ballooning (45 vs. 40% of liver grafts, recipient age (50 vs. 50 y.o., warm ischemia time (50 vs.50 min and total ischemia time (482.5 vs. 485.0 min. Median donor age was higher in the main group (44.5 vs. 39.0 y.o.. The overall rate of EAD was 27.9%. EAD rate was signifi cantly lower in the main group (6/43 vs. 18/43; p = 0.003. The rate of moderate-to-severe EAD was lower in the main group (1/43 vs. 10/43; p = 0.009. The median levels of AST and ALT in 24 h after reperfusion were signifi cantly lower in the intervention group (1004 vs. 1596; p = 0.03 and 449 vs. 759; p = 0.057.Conclusion. Portal and arterial back-table liver perfusion with HTK solution with Tacrolimus may contribute to lower EAD incidence and severity.

  7. Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats.

    Science.gov (United States)

    AlSharari, Shakir D; Al-Rejaie, Salim S; Abuohashish, Hatem M; Ahmed, Mohamed M; Hafez, Mohamed M

    2016-01-01

    Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-β/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-β), Mothers Against Decapentaplegic Homolog 2 (Smad-2), Mothers Against Decapentaplegic Homolog 4 (Smad-4), Bcl-2-binding component 3 (Bbc3), caspase-3, P53 and Interleukin-6 (IL-6) and decrease in the expression levels of Cyclin depended kinase inhibitor (P21) and Interleukin-3 (IL-3) in hepatic cells. Conclusion. TGF-β/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity.

  8. Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats

    Directory of Open Access Journals (Sweden)

    Shakir D. AlSharari

    2016-01-01

    Full Text Available Background and Objective. High-cholesterol diet (HCD intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-β/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-β, Mothers Against Decapentaplegic Homolog 2 (Smad-2, Mothers Against Decapentaplegic Homolog 4 (Smad-4, Bcl-2-binding component 3 (Bbc3, caspase-3, P53 and Interleukin-6 (IL-6 and decrease in the expression levels of Cyclin depended kinase inhibitor (P21 and Interleukin-3 (IL-3 in hepatic cells. Conclusion. TGF-β/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity.

  9. Confounding factors for early death in incident end-stage renal disease patients: Role of emergency dialysis start.

    Science.gov (United States)

    Descamps, Chrystèle; Labeeuw, Michel; Trolliet, Pierre; Cahen, Rémi; Ecochard, René; Pouteil-Noble, Claire; Villar, Emmanuel

    2011-01-01

    Hemodialysis (HD) has been associated with higher 1-year mortality than peritoneal dialysis (PD) after dialysis start. Confounding effects of late referral, emergency dialysis start, or start with central venous catheter on this association have never been studied concomitantly. Survival was studied among the 495 incident dialysed patients in our department from 1995 to 2006 and followed at least 1 year until December 31, 2007. Nested Cox models adjusted on patient characteristics explored factors associated with 1-year and ≥1-year mortality. Hemodialysis patients were 332 (67.1%), 104 (21.0%) were late referred (dialysis in emergency, and 144 (29.1%) started with central venous catheter. When adjusted only on age, sex, and comorbidities, HD was associated with poor 1-year outcome: adjusted hazard ratio (aHR) for death in HD vs. PD was 1.77, P=0.02. In fully adjusted model, among first dialysis feature variables, only emergency dialysis start was significantly associated with 1-year mortality: aHR 1.53, P=0.02. Dialysis modality was not associated with 1-year mortality rates in this fully adjusted model: aHR in HD vs. PD became 1.03, P=0.91. In ≥1-year period, HD was associated with lower mortality than PD (aHR 0.61, P=0.004), whereas other first dialysis features were not associated with death. Other factors associated with death were age, type 2 diabetes, peripheral vascular disease, heart failure, and hepatic failure. Negative association between HD and 1-year survival on dialysis was explained by confounders. Emergency dialysis start was strongly associated with early mortality on dialysis. Its prevention may improve patient survival. © 2011 The Authors. Hemodialysis International © 2011 International Society for Hemodialysis.

  10. The Relation between Hepatotoxicity and the Total Coumarin Intake from Traditional Japanese Medicines Containing Cinnamon Bark.

    Science.gov (United States)

    Iwata, Naohiro; Kainuma, Mosaburo; Kobayashi, Daisuke; Kubota, Toshio; Sugawara, Naoko; Uchida, Aiko; Ozono, Sahoko; Yamamuro, Yuki; Furusyo, Norihiro; Ueda, Koso; Tahara, Eiichi; Shimazoe, Takao

    2016-01-01

    Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049-0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual

  11. The Relation between Hepatotoxicity and the Total Coumarin Intake from Traditional Japanese Medicines Containing Cinnamon Bark

    Science.gov (United States)

    Iwata, Naohiro; Kainuma, Mosaburo; Kobayashi, Daisuke; Kubota, Toshio; Sugawara, Naoko; Uchida, Aiko; Ozono, Sahoko; Yamamuro, Yuki; Furusyo, Norihiro; Ueda, Koso; Tahara, Eiichi; Shimazoe, Takao

    2016-01-01

    Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049–0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual

  12. Possible hepatotoxicity of chronic marijuana usage

    Directory of Open Access Journals (Sweden)

    Paulo Borini

    Full Text Available CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Brazil PARTICIPANTS: The study was made among 123 patients interned in the Hospital Espírita de Marília from October 1996 to December 1998, divided into 3 groups: 26 (21% using only marijuana, 83 (67.5% using marijuana and crack, and 14 (11.4% consuming marijuana and alcohol. PROCEDURES AND MAIN MEASUREMENTS: Patients were examined clinically with special emphasis on types of drugs used, drug intake route, age when consumption began, length and pattern of usage, presence of tattooing, jaundice, hepatomegaly and splenomegaly. Serum determinations of total proteins, albumin, globulin, total and fractions of bilirubin, aspartate (AST and alanine (ALT aminotransferases, alkaline phosphatase (AP, gamma-glutamyltransferase and prothrombin activity were performed. RESULTS: Among users of only marijuana, hepatomegaly was observed in 57.7% and splenomegaly in 73.1%, and slightly elevated AST (42.3%, ALT (34.6% and AP (53.8%. The three groups did not differ significantly in the prevalence of hepatomegaly, splenomegaly and hepatosplenomegaly. The group using both marijuana and alcohol showed the highest prevalence of alterations and highest levels of aminotransferases. Mean AP levels were above normal in all groups. CONCLUSIONS: Chronic marijuana usage, on its own or in association with other drugs, was associated with hepatic morphologic and enzymatic alterations. This indicates that cannabinoids are possible hepatotoxic substances.

  13. Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Das S

    2011-06-01

    Full Text Available Suvadra Das, Partha Roy, Runa Ghosh Auddy, Arup MukherjeeDepartment of Chemical Technology, University of Calcutta, Kolkata, West Bengal, IndiaAbstract: Silymarin (Sm is a polyphenolic component extracted from Silybum marianum. It is an antioxidant, traditionally used as an immunostimulant, hepatoprotectant, and dietary supplement. Relatively recently, Sm has proved to be a valuable chemopreventive and a useful antineoplastic agent. Medical success for Sm is, however, constrained by very low aqueous solubility and associated biopharmaceutical limitations. Sm flavonolignans are also susceptible to ion-catalyzed degradation in the gut. Proven antihepatotoxic activity of Sm cannot therefore be fully exploited in acute chemical poisoning conditions like that in paracetamol overdose. Moreover, a synchronous delivery that is required for hepatic regeneration is difficult to achieve by itself. This work is meant to circumvent the inherent limitations of Sm through the use of nanotechnology. Sm nanoparticles (Smnps were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100® polymer (Rohm Pharma GmbH, Darmstadt, Germany. Process parameter optimization provided 67.39% entrapment efficiency and a Gaussian particle distribution of average size 120.37 nm. Sm release from the nanoparticles was considerably sustained for all formulations. Smnps were strongly protective against hepatic damage when tested in a paracetamol overdose hepatotoxicity model. Nanoparticles recorded no animal death even when administered after an established paracetamol-induced hepatic necrosis. Preventing progress of paracetamol hepatic damage was traced for an efficient glutathione regeneration to a level of 11.3 µmol/g in hepatic tissue due to Smnps.Keywords: silymarin, paracetamol, nanoparticle, glutathione, mouse hepatotoxicity

  14. A Rare Side Effect of Metformin: Metformin-Induced Hepatotoxicity

    OpenAIRE

    2007-01-01

    Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. While metformin-associated metabolic acidosis is a widely recognized side effect of this drug, metformin-induced hepatotoxicity has been rarely reported in the literature. We present herein the case of a 52-year-old male in whom metformin-associated lactic acidosis and metformin-induced hepatotoxicity developed.

  15. Mecanismos de hepatotoxicidade Mechanisms of hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Marcelo Chiara Bertolami

    2005-10-01

    Full Text Available Hepatopatia relacionada ao uso de drogas hipolipemiantes tem sido definida como um dano celular (aumento das enzimas AST e ALT sem alterações colestáticas (aumento de bilirrubinas e/ou fosfatase alcalina. Seis mecanismos são propostos para a hepatopatia: 1. Reações de alta energia no citocromo P450 comprometendo a homeostase do cálcio com a ruptura de fibrilas intracelulares e lise de hepatócitos. 2. Disfunção de proteínas transportadoras relacionadas com o fluxo de ácidos biliares (mecanismo proposto para a toxicidade hepática dos fibratos. 3. Reações imunes geradas pela formação de metabólitos das drogas hipolipemiantes formados no fígado. 4. Hepatoxicidade promovida por células T com inflamação adicional mediada por neutrófilos. 5. Apoptose mediada por TNF e Fas (imune-mediada. 6. Estresse oxidativo gerado por dano a organelas intracelulares. Ainda, idade avançada, consumo excessivo de álcool, altas doses de drogas hipolipemiantes, interação com outros fármacos, e doença hepática ativa prévia podem aumentar a hepatotoxidade.Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes without cholestatic alterations (bilirubin and or alkaline phosphatase increases. Six mechanisms were proposed for hepatotoxicity : 1. High energy reactions on P450 cytochrome impairing calcium homestasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity. 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated. 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of

  16. Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats.

    Science.gov (United States)

    Mochizuki, Masahiro; Shimizu, Satomi; Urasoko, Yoshinaka; Umeshita, Kazuhiko; Kamata, Takashi; Kitazawa, Takahiro; Nakamura, Daichi; Nishihata, Yoshito; Ohishi, Takumi; Edamoto, Hiroshi

    2009-04-01

    Carbon tetrachloride (CCl4) is well known to induce hepatotoxicity after being metabolized to trichloromethyl free radical ((.)CCl3) by CYP2E1. In the present study, the hepatotoxicity induced by a single oral dose (2,000 mg/kg) of CCl4 was compared between pregnant (gestation days (GD) 13 and 19) or postpartum (postpartum days (PPD) 1, 13 and 27) and non-pregnant rats. Hepatotoxicity in CCl4-treated pregnant rats evaluated by blood chemistry (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities) and histopathological finding (area of damaged hepatocytes) was minimal on GD19, being weaker than that in non-pregnant rats. CYP2E1 expression in non-treated pregnant rats decreased as pregnancy progressed and reached minimum level on GD19. Thus, the degree of CCl4-induced hepatotoxicity roughly corresponded to CYP2E1 levels during pregnancy. After delivery, hepatotoxicity in CCl4-treated lactating rats was maximal on PPD13, being stronger than that in non-pregnant rats, and then it decreased slightly on PPD27. The CYP2E1 level in the non-treated lactating rats tended to increase but remained at lower levels until PPD13 compared with that in non-pregnant rats. Thus, the degree of CCl4-induced hepatotoxicity did not correspond to CYP2E1 levels during lactation. This suggests that during lactation, there may be certain factors other than CYP2E1 expression responsible for the degree of CCl4-induced hepatotoxicity.

  17. 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.

  18. Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Ebbesen, Maria S.; Nygaard, Ulrikka; Rosthøj, Susanne

    2017-01-01

    Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine...

  19. Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide

    NARCIS (Netherlands)

    W. Taal (Walter); D. Brandsma (Dieta); H.G. de Bruin (Hein); J.E.C. Bromberg (Jacolien); A.T. Swaak-Kragten (Annemarie); P.A. Smitt (Peter); C.A. van Es (Corine); M.J. van den Bent (Martin)

    2008-01-01

    textabstractBACKGROUND. Radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) is now the standard of care for patients with newly diagnosed glioblastoma. The occurrence of pseudo-progression directly after RT is a recognized phenomenon, but to the authors' knowledge its incidence after

  20. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    OpenAIRE

    Flaminia Pantano; Roberta Tittarelli; Giulio Mannocchi; Simona Zaami; Serafino Ricci; Raffaele Giorgetti; Daniela Terranova; Busardò, Francesco P.; Enrico Marinelli

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, lea...

  1. High incidence of hydrocephalus following prenatal exposure to X-irradiation at early gestational stage in mice

    Energy Technology Data Exchange (ETDEWEB)

    Aolad, H.; Inouye, Minoru; Hayasaka, Shizu; Darmanto, W.; Murata, Yoshiharu [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine

    1998-10-01

    Hydrocephalus is one of the severe brain anomalies. Several causes of congenital hydrocephalus have been reported and, it is known that radiation is one of those. The current study was designed to obtain postnatally viable hydrocephalic offspring at a high incidence following X-radiation. This finding will be helpful to elucidate the mechanism of congenital hydrocephalus caused by X-radiation. Twenty pregnant Slc:ICR mice, 5 in each group, were exposed to X-irradiation at a dose of 1.0 Gy on gestational days 7 (G7), G8, G9 or G10. The incidence of hydrocephalus was high in the group exposed on G7. An additional 21 pregnant mice were then exposed to a dose of 1.2 Gy, 1.3 Gy, 1.4 Gy or 1.5 Gy X-radiation on G7. The highest incidence of hydrocephalic offspring was found following exposure to 1.4 Gy X-radiation. (author)

  2. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort.

    Directory of Open Access Journals (Sweden)

    Alan T Clarke

    Full Text Available Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment.The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions.Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4-2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0-2.2] for HDS.The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.

  3. Experimental models of hepatotoxicity related to acute liver failure

    Science.gov (United States)

    Maes, Michaël; Vinken, Mathieu; Jaeschke, Hartmut

    2015-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. PMID:26631581

  4. DIFFERENT MODELS OF HEPATOTOXICITY AND RELATED LIVER DISEASES: A REVIEW

    Directory of Open Access Journals (Sweden)

    Singh Robin

    2012-07-01

    Full Text Available The liver is among the most complex and important organs in the human body. Its primary function is to control the flow and safety of substances absorbed from the digestive system before distribution of these substances to the systemic circulatory system. Hepatotoxicity implies chemical-driven liver damage. Chemicals that cause liver injury are called hepatotoxins. Hepatic injury leads to disturbances in transport function of hepatocytes resulting in leakage of plasma membrane thereby causing an increased enzyme level in serum. There are many diseases that are related with hepatotoxicity caused by certain chemicals or hepatotoxins. Herbal medicines are great demand in various chemicals and drugs disordered hepatic, the developed world for primary health care because of their efficacy, safety, lesser side effects and narrow therapeutic window. This review focus on liver, its function, liver diseases and different models of hepatotoxicity.

  5. Power law incidence rate in epidemic models. Comment on: "Mathematical models to characterize early epidemic growth: A review" by Gerardo Chowell et al.

    Science.gov (United States)

    Allen, Linda J. S.

    2016-09-01

    Dr. Chowell and colleagues emphasize the importance of considering a variety of modeling approaches to characterize the growth of an epidemic during the early stages [1]. A fit of data from the 2009 H1N1 influenza pandemic and the 2014-2015 Ebola outbreak to models indicates sub-exponential growth, in contrast to the classic, homogeneous-mixing SIR model with exponential growth. With incidence rate βSI / N and S approximately equal to the total population size N, the number of new infections in an SIR epidemic model grows exponentially as in the differential equation,

  6. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation.

    Science.gov (United States)

    Frenzel, Christian; Teschke, Rolf

    2016-04-27

    Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

  7. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

    Directory of Open Access Journals (Sweden)

    Christian Frenzel

    2016-04-01

    Full Text Available Herb induced liver injury (HILI and drug induced liver injury (DILI share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM rarely causes elevated liver tests (LT. However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

  8. Biochemical effects of Calotropis procera on hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Ali Ismaiel Ali Abd Alrheam

    2015-12-01

    Full Text Available Introduction: Calotropis procera commonly known as Sodom apple is a 6-meter high shrub that belongs to the Aclepiadaceae plant family and is commonly found in West Africa and other tropical places. In Saudi Arabia the plant is commonly used in traditional medicine for the treatment of variety of diseases including fever, constipation, muscular spasm and joint pain. Aim: In the present study C. procera were investigated for the hepatoprotective activity. Material and Methods: Carbon tetrachloride is used to produce hepatotoxicity. Forty two male albino rats, weighting 150-200 gm divided into seven groups, each consisted of 6 rats. Carbon tetrachloride 2ml/kg was administered twice a week to all of the groups of animals except group I, which served as control and given the normal saline. Group II served as Carbon tetrachloirde control. Group III received Silymarin at 100 mg/kg/day dose, Group IV received aqueous leaves extracts C. procera 200mg/kg, Group V received chloroform leaves extracts C. procera 200mg/kg, Group VI received ethanol leaves extracts C. procera 200 mg/kg, Group VII received latex of C. procera 200mg/kg. The effect of aqueous, chloroform, ethanol leaves extract and latex C. procera on biochemical parameters of liver was measured. Results: The results showed that the aqueous, chloroform, ethanol leaves extract and latex C. procera produced significant decrease in Acid phosphatase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Total protein, Albumin and total bilirubin levels compared to the CCL4 treated group II. Conclusion: Calotropis procera appears to to have hepatoprotective activity and these may be due to enrich of the plant by phytoconstituents that activate and in hence a pharmacological response of different parts of the body and this study need further studies to shows the complete properties of the plant. [Biomed Res Ther 2015; 2(12.000: 446-453

  9. Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats

    OpenAIRE

    AlSharari, Shakir D.; Al-Rejaie, Salim S.; Abuohashish, Hatem M.; Ahmed, Mohamed M.; Hafez, Mohamed M

    2016-01-01

    Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The li...

  10. Increasing incidence of early onset type 1 (insulin-dependent) diabetes mellitus: a study of Danish male birth cohorts

    DEFF Research Database (Denmark)

    Green, A; Andersen, P K; Svendsen, Anders Jørgen

    1992-01-01

    To provide information of the incidence trends of Type 1 (insulin-dependent) diabetes mellitus we performed a cohort study of a series of Danish male birth cohorts. All male livebirths in Denmark between 1 January 1949 and 31 December 1964, were investigated regarding the development of Type 1...... diabetes during the first 20 years of life using the files of the Danish Conscript Board, supplemented by a search in the Danish National Registry of Deaths. Diagnosis was verified and clinical information obtained from medical records. The material is estimated to be more than 95% complete. A total...

  11. The incidence of metabolic syndrome in obese Czech children: the importance of early detection of insulin resistance using homeostatic indexes HOMA-IR and QUICKI.

    Science.gov (United States)

    Pastucha, D; Filipčíková, R; Horáková, D; Radová, L; Marinov, Z; Malinčíková, J; Kocvrlich, M; Horák, S; Bezdičková, M; Dobiáš, M

    2013-01-01

    Common alimentary obesity frequently occurs on a polygenic basis as a typical lifestyle disorder in the developed countries. It is associated with characteristic complex metabolic changes, which are the cornerstones for future metabolic syndrome development. The aims of our study were 1) to determine the incidence of metabolic syndrome (based on the diagnostic criteria defined by the International Diabetes Federation for children and adolescents) in Czech obese children, 2) to evaluate the incidence of insulin resistance according to HOMA-IR and QUICKI homeostatic indexes in obese children with and without metabolic syndrome, and 3) to consider the diagnostic value of these indexes for the early detection of metabolic syndrome in obese children. We therefore performed anthropometric and laboratory examinations to determine the incidence of metabolic syndrome and insulin resistance in the group of 274 children with obesity (128 boys and 146 girls) aged 9-17 years. Metabolic syndrome was found in 102 subjects (37 %). On the other hand, the presence of insulin resistance according to QUICKI 3.16 in 53 % of obese subjects. This HOMA-IR limit was exceeded by 70 % children in the MS(+) group, but only by 43 % children in the MS(-) group (pchildren without metabolic syndrome raises a question whether the existing diagnostic criteria do not falsely exclude some cases of metabolic syndrome. On the basis of our results we suggest to pay a preventive attention also to obese children with insulin resistance even if they do not fulfill the actual diagnostic criteria for metabolic syndrome.

  12. 暴恐事件网络舆情风险预警研究%Risk Early Warning Research of Network Public Opinion of Violence and Terrorist Incidents

    Institute of Scientific and Technical Information of China (English)

    瞿志凯; 张秋波; 兰月新; 焦扬; 袁野

    2016-01-01

    Purpose/Significance] To improve the scientificity and efficiency of the decision of the network public opinion of violence and terrorist incidents, achieve the defensive early warning, and seize the initiative and discourse power in the anti-terrorism consensus warfare and psychological warfare. [ Method/Process] This article, based on the study of violence and terrorism incidents and factors af-fecting the relevant network public opinion, builds a network public opinion risk early warning index system, including four dimensions of the violence-terrorism incidents, information, media, and netizensˊreaction, using AHP and ABC classification index to do the risk factor weight calculation and risk evaluation. [ Result/Conclusion] Through weighting on the index system, it identifies the high-risk warning factors of violence and terrorism incidents, and the high-risk warning factors can provide the key monitoring targets of the public opinion risk early warning system, making it strong for operability in meeting the requirements of actual combat, the coping strategies to be adopt-ed in real anti-terrorism activities are also presented.%[目的/意义]为提高暴恐事件网络舆情决策的科学性及时效性,实现防御性预警,夺取反恐舆论战及心理战的主动权和话语权。[方法/过程]在研究暴恐事件及网络舆情影响因素的基础上,构建了包含暴恐事件、信息特性、媒体报道、网民反应四个维度的暴恐事件网络舆情风险预警指标体系,并运用层次分析法、ABC分类法对风险指标进行权重计算及风险评估。[结果/结论]为舆情风险预警提供符合实战需求以及可操作性强的重点监测目标,获得舆情高风险因素,并结合高风险因素及反恐现实需求提出舆情应对策略,以期为暴恐事件网络舆情预警处置提供有价值的参考。

  13. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity.

    Science.gov (United States)

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

    2010-03-01

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  14. Retro-orbital blood acquisition facilitates circulating microRNA measurement in zebrafish with paracetamol hepatotoxicity.

    Science.gov (United States)

    Vliegenthart, Adriaan D B; Starkey Lewis, Philip; Tucker, Carl S; Del Pozo, Jorge; Rider, Sebastein; Antoine, Daniel J; Dubost, Valérie; Westphal, Magdalena; Moulin, Pierre; Bailey, Matthew A; Moggs, Jonathan G; Goldring, Chris E; Park, B Kevin; Dear, James W

    2014-06-01

    Paracetamol is the commonest cause of acute liver failure in the Western world and biomarkers are needed that report early hepatotoxicity. The liver-enriched microRNA (miRNA), miR-122, is a promising biomarker currently being qualified in humans. For biomarker development and drug toxicity screening, the zebrafish has advantages over rodents; however, blood acquisition in this model remains technically challenging. We developed a method for collecting blood from the adult zebrafish by retro-orbital (RO) bleeding and compared it to the commonly used lateral incision method. The RO technique was more reliable in terms of the blood yield and minimum amount per fish. This new RO technique was used in a zebrafish model of paracetamol toxicity. Paracetamol induced dose-dependent increases in liver cell necrosis, serum alanine transaminase activity, and mortality. In situ hybridization localized expression of miR-122 to the cytoplasm of zebrafish hepatocytes. After collection by RO bleeding, serum miR-122 could be measured and this miRNA was substantially increased by paracetamol 24 h after exposure, an increase that was prevented by delayed (3 h poststart of paracetamol exposure) treatment with acetylcysteine. In summary, collection of blood by RO bleeding facilitated measurement of miR-122 in a zebrafish model of paracetamol hepatotoxicity. The zebrafish represents a new species for measurement of circulating miRNA biomarkers that are translational and can bridge between fish and humans.

  15. Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro.

    Science.gov (United States)

    Van den Hof, Wim F P M; Ruiz-Aracama, Ainhoa; Van Summeren, Anke; Jennen, Danyel G J; Gaj, Stan; Coonen, Maarten L J; Brauers, Karen; Wodzig, Will K W H; van Delft, Joost H M; Kleinjans, Jos C S

    2015-04-01

    In order to improve attrition rates of candidate-drugs there is a need for a better understanding of the mechanisms underlying drug-induced hepatotoxicity. We aim to further unravel the toxicological response of hepatocytes to a prototypical cholestatic compound by integrating transcriptomic and metabonomic profiling of HepG2 cells exposed to Cyclosporin A. Cyclosporin A exposure induced intracellular cholesterol accumulation and diminished intracellular bile acid levels. Performing pathway analyses of significant mRNAs and metabolites separately and integrated, resulted in more relevant pathways for the latter. Integrated analyses showed pathways involved in cell cycle and cellular metabolism to be significantly changed. Moreover, pathways involved in protein processing of the endoplasmic reticulum, bile acid biosynthesis and cholesterol metabolism were significantly affected. Our findings indicate that an integrated approach combining metabonomics and transcriptomics data derived from representative in vitro models, with bioinformatics can improve our understanding of the mechanisms of action underlying drug-induced hepatotoxicity. Furthermore, we showed that integrating multiple omics and thereby analyzing genes, microRNAs and metabolites of the opposed model for drug-induced cholestasis can give valuable information about mechanisms of drug-induced cholestasis in vitro and therefore could be used in toxicity screening of new drug candidates at an early stage of drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Early regression of spermatogenesis in boars of an inbred Duroc strain caused by incident orchitis/epididymo-orchitis.

    Science.gov (United States)

    Noguchi, Junko; Nakai, Michiko; Kikuchi, Kazuhiro; Kaneko, Hiroyuki; Imaeda, Noriaki

    2013-01-01

    In the process of establishment of an inbred Duroc pig strain, males with size asymmetry of the testes were frequently observed. To clarify the possible causes of this asymmetry, we examined the testes and epididymides of 67 males of the F4-F7 generations at 35-100 weeks of age. Testicular weights showed a wide variation (120-610 g). When the weights of the testes were compared bilaterally, 35 of the 67 males showed more than a 10% difference. Histological examination of testes from this asymmetry group revealed a range of seminiferous tubule disruption including disappearance of all germ cells, but not Sertoli cells, in the epithelium. Focal lesions associated with the degenerated tubules were observed. Trends of incident fibrosis or hyalinization of these lesions were seen in aged males of the asymmetry group. Besides this abnormality of spermatogenesis, infiltration of mononuclear inflammatory cells around the tubule was frequently observed in the asymmetry group (32.9%, compared with 1.6% in males showing testis symmetry). In severe cases, the inflammatory cells were concentrated in the intertubular region instead of Leydig cells. Cellular infiltration was also observed around the epididymal duct and blood vessels, but its incidence did not differ between the symmetry and asymmetry groups. Testicular testosterone levels were significantly increased in the asymmetry group, but those of E2 and inhibin did not differ between the two groups. These histopathological features indicate that disruption of spermatogenesis after orchitis/epididymo-orchitis could induce testicular atrophy. Genetic predispositions for this trait may cause prevalent retrograde infections, resulting in orchitis/epididymo-orchitis.

  17. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.

    Science.gov (United States)

    Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

    2016-03-07

    Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  18. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

    Directory of Open Access Journals (Sweden)

    Xinmiao Yan

    2016-03-01

    Full Text Available Pyrrolizidine Alkaloids (PAs are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1 and glutathione peroxidase 1 (GPX1 targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  19. Activation of Nrf2 protects against triptolide-induced hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Jia Li

    Full Text Available Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF, has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2 in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN, attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

  20. Hepatotoxicity induced by cyproterone acetate: A report of three cases

    Institute of Scientific and Technical Information of China (English)

    Ioanna Savidou; Melanie Deutsch; Aspasia S Soultati; Dimitrios Koudouras; Georgia Kafiri; Spyridon P Dourakis

    2006-01-01

    Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency.Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis)were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.

  1. High GUD incidence in the early 20 century created a particularly permissive time window for the origin and initial spread of epidemic HIV strains.

    Directory of Open Access Journals (Sweden)

    João Dinis de Sousa

    Full Text Available The processes that permitted a few SIV strains to emerge epidemically as HIV groups remain elusive. Paradigmatic theories propose factors that may have facilitated adaptation to the human host (e.g., unsafe injections, none of which provide a coherent explanation for the timing, geographical origin, and scarcity of epidemic HIV strains. Our updated molecular clock analyses established relatively narrow time intervals (roughly 1880-1940 for major SIV transfers to humans. Factors that could favor HIV emergence in this time frame may have been genital ulcer disease (GUD, resulting in high HIV-1 transmissibility (4-43%, largely exceeding parenteral transmissibility; lack of male circumcision increasing male HIV infection risk; and gender-skewed city growth increasing sexual promiscuity. We surveyed colonial medical literature reporting incidences of GUD for the relevant regions, concentrating on cities, suffering less reporting biases than rural areas. Coinciding in time with the origin of the major HIV groups, colonial cities showed intense GUD outbreaks with incidences 1.5-2.5 orders of magnitude higher than in mid 20(th century. We surveyed ethnographic literature, and concluded that male circumcision frequencies were lower in early 20(th century than nowadays, with low rates correlating spatially with the emergence of HIV groups. We developed computer simulations to model the early spread of HIV-1 group M in Kinshasa before, during and after the estimated origin of the virus, using parameters derived from the colonial literature. These confirmed that the early 20(th century was particularly permissive for the emergence of HIV by heterosexual transmission. The strongest potential facilitating factor was high GUD levels. Remarkably, the direct effects of city population size and circumcision frequency seemed relatively small. Our results suggest that intense GUD in promiscuous urban communities was the main factor driving HIV emergence. Low

  2. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

    Energy Technology Data Exchange (ETDEWEB)

    Atienzar, Franck A., E-mail: franck.atienzar@ucb.com [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium); Novik, Eric I. [H mu rel Corporation, 675 U.S. Highway 1, North Brunswick, NJ 08902 (United States); Gerets, Helga H. [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium); Parekh, Amit [H mu rel Corporation, 675 U.S. Highway 1, North Brunswick, NJ 08902 (United States); Delatour, Claude; Cardenas, Alvaro [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium); MacDonald, James [Chrysalis Pharma Consulting, LLC, 385 Route 24, Suite 1G, Chester, NJ 07930 (United States); Yarmush, Martin L. [Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854 (United States); Dhalluin, Stéphane [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium)

    2014-02-15

    Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine model along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes.

  3. INCIDENCE AND RISK FACTORS FOR EARLY SURGICAL SITE INFECTION IN ELECTIVE ORTHOPAEDIC IMPLANT SURGERIES: A PROSPECTIVE STUDY

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    Suneet

    2015-02-01

    Full Text Available BACKGROUND : Surgical site infections in orthopaedic implant surgery is devasting complication range from 1 - 2% to 22%. It leads to increase case cost , prolongs antibiotic use/abuse , increases morbidity and rehabilitation. METHOD : This prospective cross sectional study was conducted on 624 patients with closed fracture cases undergoing clean and elective orthopaedic implant surgeries admitted at Gandhi Medical College and Hamidia Hospital , Bhopal (Madhya Pradesh , India between ‘1st November 2013 to 31st October 2014’. RESULTS : The surgical site infection was diagnosed in 43 (6.89% pati ents within 30 days after surgery. Klebsiella was most common infective organism islolated in 39.53% cases. On data analysis SSI was significantly associated with increasing age , duration of hospital stay more than 7 days , duration of surgery more than 120 minutes , pre - operative Hb less than 12 gm% , diabetes mellitus , use of intra - operative negative suction and tourniquet. CONCLUSION : Incidence of SSI in implants surgeries are quite high , proper measure are needed to control it. In this study gram negative organism has emerged as major threat in contrast to staphylococcus aureus.

  4. The role of maternal stress in early pregnancy in the aetiology of gastroschisis: an incident case control study.

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    Stephen R Palmer

    Full Text Available OBJECTIVE: The incidence of gastroschisis, a congenital anomaly where the infant abdominal wall is defective and intestines protrude from the abdominal cavity, is increasing in many countries. The role of maternal stress in some adverse birth outcomes is now well established. We tested the hypothesis that major stressful life events in the first trimester are risk factors for gastroschisis, and social support protective, in a case-control study in the United Kingdom. METHODS: Gastroschisis cases and three controls per case (matched for maternal age were identified at routine 18-20 week fetal anomaly ultrasound scan, in 2007-2010. Face to face questionnaire interviews were carried out during the antenatal period (median 24 weeks gestation asking about serious stressful events and social support in the first trimester. Data were analysed using conditional logistic regression. RESULTS: Two or more stressful life events in the first trimester (adjusted OR 4.9; 95% CI 1.2-19.4, and moving address in the first trimester (aOR 4.9; 95% CI 1.7-13.9 were strongly associated with risk of gastroschisis, independent of behavioural risk factors including smoking, alcohol, and poor diet. Perceived availability of social support was not associated with reduced risk of gastroschisis (aOR 0.8; 95% CI 0.2-3.1. CONCLUSIONS: Stressful maternal life events in the first trimester of pregnancy including change of address were strongly associated with a substantial increase in the risk of gastroschisis, independent of stress related high risk behaviours such as smoking, alcohol consumption and poor diet. This suggests that stress pathways are involved in the aetiology of gastroschisis.

  5. FEEDING INCIDENCE, GROWTH AND SURVIVAL RATE IN THE EARLY STAGE OF THE RED-SPOTTED GROUPER, Epinephelus akaara, IN RELATION TO TANK COLOR

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    Eri Setiadi

    2006-12-01

    Full Text Available The red-spotted grouper, Epinephelus akaara, is one of marine fish species targeted for mariculture in Japan. The artificial mass seedling production of these species has been largely successful. However, the survival is still unstable. The effect of tank colors on the feeding incidence, feeding proportion, growth and survival rates in the early stage of the red-spotted grouper were examined. The results showed the feeding incidence, feeding proportion, growth, and survival rates at different tank colors were highly significantly different (P<0.001. Post hoc multiple comparisons based on Tukey’s test showed significant differences (P<0.05 regarding feeding incidence between yellow (70.45% compared to white (55.83%, black (48.42%, green (41.67%, blue (35.17%, and red (32.50%. The highest feeding proportion (number of rotifer in the stomach/larvae was found at yellow (5.62, followed by white (2.47, black (1.97, green (1.92, blue (1.71, and red (1.28. The specific growth rate showed significant differences (P<0.05 were found at yellow (2.14% and white (1.84% compared to black (1.46%, green (1.20%, blue (1.15%, and red (1.13%. The survival rate at yellow color (1.22% was the highest, followed by white (1.09%, black (0.79%, green (0.57%, blue (0.38%, and red (0.37%. Yellow was suitable as tank wall color for rearing of red-spotted grouper larvae.

  6. Research on Early Warning Model of the Stroke Incidence%脑卒中发病预警模型研究

    Institute of Scientific and Technical Information of China (English)

    夏英

    2012-01-01

    以2012年全国大学生数学建模竞赛c题为背景,对脑卒中住院病例中的高危人群进行了统计分析,用主成分分析法建立高危人群的预警模型,并给出发病率高低判断的程序流程图及一些干预措施.%Based on the 2012 National Undergraduate Mathematical Contest in modeling C ( MCM), the article gives data filtering on stroke impatients in high-risk. The principal component analysis method is used to estab lish early warning model of populations at risk. Program flow diagram to judge the incidence level and some inter vention measures are given.

  7. Early Psychological Preventive Intervention For Workplace Violence: A Randomized Controlled Explorative and Comparative Study Between EMDR-Recent Event and Critical Incident Stress Debriefing.

    Science.gov (United States)

    Tarquinio, Cyril; Rotonda, Christine; Houllé, William A; Montel, Sébastien; Rydberg, Jenny Ann; Minary, Laetitia; Dellucci, Hélène; Tarquinio, Pascale; Fayard, Any; Alla, François

    2016-11-01

    This randomized controlled trial study aims to investigate the efficacy of an early psychological intervention called EMDR-RE compared to Critical Incident Stress Debriefing on 60 victims of workplace violence, which were divided into three groups: 'EMDR-RE' (n = 19), 'CISD' (n = 23), and 'delayed EMDR-RE' (n = 18). EMDR-RE and CISD took place 48 hours after the event, whilst third intervention was delayed by an additional 48 hours. Results showed that after 3 months PCLS and SUDS scores were significantly lower with EMDR-RE and delayed EMDR-RE compared to CISD. After 48 hours and 3 months, none of the EMDR-RE-treated victims showed PTSD symptoms.

  8. Early rheumatoid arthritis in Italy: study of incidence based on a two-level strategy in a sub-area of Florence (Scandicci-Le Signe).

    Science.gov (United States)

    Benucci, Maurizio; Cammelli, Emanuela; Manfredi, Mariangela; Saviola, Gianantonio; Baiardi, Paola; Mannoni, Alessandro

    2008-06-01

    The concept of Early Arthritis represents a new diagnostic-therapeutic strategy in modern rheumatology. Even if many Early Arthritis clinics are starting up, we do not yet know the frequency of this pathology in the Italian population. With the collaboration of 20 general practictioners (GPs) operating in the municipalities of Scandicci, Lastra a Signa and Signa, we assessed the incidence of rheumatoid arthritis and of new cases of Early Rheumatoid Arthritis (ERA) in the period from 1.09.2005 to 31.08.2006. The general population over 18 years old in the three municipalities according to the political electoral lists in April 2006 was as follows: Scandicci 42,474 (Males 20,290; Females 22,184), Lastra a Signa 15,368 (M 7,458; F 7,910) and Signa 13,372 (M 6,439; F 6,933). The total number of patients followed by the 20 GPs was 32,521 according to the records of ASL10 Florence. In one year 920 patients were referred by their GPs to a rheumatologist with suspected early undifferentiated arthritis according to Emery's criteria. The patients underwent a rheumatological examination and the rheumatoid factor IgM, hidden rheumatoid factors (IgG and IgA) and IgG antibodies anti-CCP (anti-cyclic citrullinate peptides) with a semiquantitative immuno-enzymatic test ELISA were investigated. In one year we observed 32 new cases of Rheumatoid Arthritis, of which 8 were males and 24 were females. The rate of incidence with respective intervals of confidence of 95% was 0.98 per thousand (0.64-1.32 per thousand). The average age was 47.7 +/- 10.5 in the females and 54.9 +/- 10.3 in the males. The patients had an average history of illness in months of 5.2 +/- 1.3 F versus 4.6 +/- 1.1 M, number of tender joints 6.2 +/- 2.3 F versus 5.3 +/- 2.2 M, number of swollen joints 4.8 +/- 1.4 F versus 4.2 +/- 1.5 M, a global assessment of 64.3 +/- 10 F versus 53 +/- 12 M, ESR (mm/h) 49.2 +/- 11.3 F versus 43.3 +/- 12.5 M, CRP (mg/dl) 2.8 +/- 1.3 F versus 2.3 +/- 1.4 M, DAS28 5.55 +/- 1.2 F

  9. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P.; Marinelli, Enrico

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. PMID:27092496

  10. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    Directory of Open Access Journals (Sweden)

    Flaminia Pantano

    2016-04-01

    Full Text Available The 3Ks (kava, kratom and khat are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed.

  11. Immunosuppression, hepatotoxicity and depression of antioxidant status by arecoline in albino mice.

    Science.gov (United States)

    Dasgupta, Romi; Saha, Indraneel; Pal, Suman; Bhattacharyya, Arindam; Sa, Gaurisankar; Nag, Tapas C; Das, Tania; Maiti, B R

    2006-10-03

    There are about 600 million betel quid chewers in the world. Betal quid chewing is one of the major risk factors of hepatocarcinoma, oropharyngeal and esophagus cancers. Arecoline, the main Areca alkaloid of the betel nut is reported to have cytotoxic, genotoxic and mutagenic effects in various cells. It shows strong correlation to the incidence of oral submucosal fibrosis, leukoplakia and oral cancer, and has also been found to impose toxic manifestations in immune, hepatic and other defense systems of the recipient. The precise molecular mechanisms underlying the toxic effects of arecoline deserve investigation. To clarify the action of arecoline on defense systems, immune, hepatic and detoxification system were studied in mice. Cell count and cell cycle of the splenocytes were studied for evaluating cell immunity. Liver function test (LFT) was followed by assaying different enzyme systems from serum (SGPT, SGOT and ALP) and liver (GST for detoxication enzyme, SOD and catalase for antioxidant enzymes and GSH for non-enzymatic antioxidant) and by ultrastructural studies of hepatocytes. Here we report that arecoline arrested splenic lymphocyte cell cycle at lower concentration with induced apoptosis at higher concentration thereby causing immunosuppression in arecoline recipients. Besides, it resulted in hepatotoxicity in arecoline recipient mice by disrupting the hepatocyte ultrastructure, as judged by liver ultrastructural studies that showed decreased nuclear size, RER with profusely inflated cysternae and abundance of lipid droplets, and by up regulating hepatotoxic marker enzymes (SGOT and SGPT) in serum. Arecoline also caused depression of antioxidants, i.e., superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and glutathione-S-transferase (GST) that are known to neutralize reactive oxygen species. All these above-mentioned results led us to conclude that arecoline attacks multiple targets to finally generate systemic toxicity in mice.

  12. 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 ...

  13. The Possible Efficacy of Artichoke in Fluconazole Related Hepatotoxicity

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    Hüseyin Kurt

    2014-01-01

    Full Text Available Although fluconazole related hepatotoxicity (FRH is rare, mortal acute hepatic necrosis and jaundice were reported in immunocompromised states such as acquired immunodeficiency syndrome (AIDS and bone marrow transplant (BMT. We present a case of a patient with multiple sclerosis who developed hepatotoxicity with the use of a single 150 mg fluconazole tablet for fungal vaginitis, 10 days after methylprednisolone pulse treatment. Our patient’s alanine aminotransferase (ALT and aspartate aminotransferase (AST levels were decreased, 1200 U/L and 800 U/L, respectively, and bilirubin levels were consistent at 37 mg/dL. Artichoke which has anticholestatic and antioxidant properties was used by our patient. She consumed a 30 mg artichoke leaf extract tea 3 times a day. The bilirubin levels significantly declined at the end of the first week and all liver function tests were normalized within 2 months.

  14. Hepatotoxicity by Drugs: The Most Common Implicated Agents

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    Einar S. Björnsson

    2016-02-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov. According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  15. Hepatotoxicity caused by montelukast in a paediatric patient.

    Science.gov (United States)

    Lebensztejn, Dariusz M; Bobrus-Chociej, Anna; Kłusek, Monika; Uscinowicz, Miroslawa; Lotowska, Joanna; Sobaniec-Lotowska, Maria; Kaczmarski, Maciej

    2014-01-01

    Montelukast is a selective and competitive cysteinyl leukotriene receptor antagonist (CystLTRA) which is increasingly used for the treatment of allergic asthma. Recently, hepatotoxicity has been reported with this drug in adult patients, but only one letter to the editor has reported a case of probable montelukast-induced hepatotoxicity in a child. We present a case of a 3.5-year-old boy, receiving treatment with montelukast, who developed hepatocellular injury. The exclusion of other causes of increased activity of aminotransferases (viral, metabolic, autoimmune), improvement after dechallenge, the morphological findings and previous reports of comparable cases support the diagnosis of montelukast-induced liver injury in this boy. Physicians should strictly analyse indications for this drug and be aware of potential drug-induced liver disease caused by this agent. Therefore, the periodical assessment of aminotransferases should be recommended during treatment with this leukotriene modifier.

  16. Hepatotoxicity by Drugs: The Most Common Implicated Agents.

    Science.gov (United States)

    Björnsson, Einar S

    2016-02-06

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  17. 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.

  18. Propylthiouracil Hepatotoxicity Seen with Jaundice and its Treatment by Steroids

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    Oguzhan Aksu

    2014-08-01

    Full Text Available Propylthiouracil (PTU is widely used in the treatment of hyperthyroidism and rarely leads to hepatotoxicity by an unknown mechanism. The hepatic damage caused by propylthiouracil is generally subclinical, but very rarely, it may be associated with severe liver injury and submassive hepatic necrosis. Although discontinuing of the drug result in full recovery in most cases, hyperbilirubinemia and liver damage may increasingly continue in spite of discontinuation of the drug.

  19. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    Science.gov (United States)

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  20. Effect of coriander on thioacetamide-induced hepatotoxicity in rats.

    Science.gov (United States)

    Moustafa, Abdel Halim A; Ali, Ehab Mostafa M; Moselhey, Said S; Tousson, Ehab; El-Said, Karim S

    2014-08-01

    Thioacetamide (TAA) is a potent hepatotoxin that causes centrilobulal necrosis and nephrotoxic damage following acute administration. Prolonged exposure to TAA can result in bile duct proliferation and liver cirrhosis histologically similar to that caused due to viral hepatitis infection. Coriander in food increases the antioxidant content, acting as a natural antioxidant and inhibiting undesirable oxidation processes. The present study investigated the antioxidant activity of Coriandrum sativum on TAA-induced hepatotoxicity in the male rats. Phenolic content and antioxidant activity were evaluated in the coriander leaves and seeds. Forty-eight adult male rats were divided into four groups. Group I (control), group II (TAA injected rats), group III (TAA injected rats fed coriander leaves) and group IV (TAA injected rats fed coriander seeds). The results revealed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were significantly increased in the groups II, III and IV as compared to the normal control. Oxidative stress in the group II was manifested by a significant rise in nitric oxide (NO), thiobarbituric acid reactive substance (TBARS) levels and myloperoxidase (MPO) activities in the liver tissues as compared with the control group. Rats fed with coriander leaves and seeds showed a decrease in the serum ALT, AST and ALP activities and in the liver NO and TBARS levels as compared to the group II. Histopathological study revealed that coriander feeding attenuated TAA-induced hepatotoxicity in the rats. In conclusion, coriander leaves attenuate hepatotoxicity induced by TAA more than that of seeds due to the higher content of phenolic compounds and antioxidants in the leaves of coriander. Liver of rats intoxicated with TAA exhibited advanced CIRRHOSIS: in the form of macronodular and micronodular structure surrounded by fibrous tissue. Treatment with coriander leaves and seeds helps in improving

  1. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    OpenAIRE

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were ad...

  2. 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

  3. Methotrexate Hepatotoxicity; the Danger Not to Be Ignored

    Directory of Open Access Journals (Sweden)

    M Baghbanian

    2013-06-01

    Full Text Available Introduction: Methotrexate is used increasingly for treatment of some diseases such as rheumatoid arthritis, psoriasis and Crohn. Bone marrow suppression, mucocutaneous lesions, pneumonitis, and hepatotoxicity are major side effects of this drug. Since methotrexate toxicity is dose dependent and is usually administered with low dose via a weekly regimen, its side effects are not commonly seen. But due to long term prescription of this drug over the recent years especially for rheumatoid arthritis, growing cases of methotrexate hepatotoxicity are referred to Gastroenterologist. High dose of drug, high age, alcohol consumption, renal failure and preexisting liver disease are main risk factors for this toxicity. In this study, in addition to presenting two cases with cirrhosis and two cases with hepatitis linked to methotrexate, the clinical aspects on this field are discussed. Conclusions: Methotrexate hepatotoxicity is not a theoretical issue that can be ignored because it can lead to cirrhosis and liver failure. We can prevent the onset of this growing side effect with appropriate patient selection and investigating the patients’ liver function before and during Methotrexate therapy. Periodic testing the liver enzymes is used for monitoring the liver condition, but because interpretation of these tests is sometimes difficult, liver biopsy is needed in particular cases.

  4. Antioxidant modulation of nevirapine induced hepatotoxicity in rats.

    Science.gov (United States)

    Awodele, Olufunsho; Popoola, Temidayo; Rotimi, Kunle; Ikumawoyi, Victor; Okunowo, Wahab

    2015-03-01

    HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART). However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP) containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day), vitamin C (8 mg/kg/day), vitamin E (5 mg/kg/day) and/or NVP (6 mg/kg/day) for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (prats. A significantly (prats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART.

  5. Acetaminophen-induced hepatotoxicity: Preventive effect of trans anethole.

    Science.gov (United States)

    da Rocha, Bruno Ambrósio; Ritter, Alessandra M Versuti; Ames, Franciele Queiroz; Gonçalves, Odinei Hess; Leimann, Fernanda Vitória; Bracht, Lívia; Natali, Maria Raquel Marçal; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Ap

    2017-02-01

    The hepatotoxicity induced by APAP is caused by the excessive production of N-acetyl-para-benzoquinone imine (NAPQI), which, when reacting with hepatic proteins proved to cause irreversible lesions. Associated with this process, an intense inflammatory process is also evidenced, characterized by the increased cell influx and production/release of inflammatory mediators. Trans anethole, an aromatic compounds has been showed anti-inflammatory efficacy by inhibit the cellular recruitment and synthesis/releases of many proinflammatory mediators such as prostaglandin (PGE2), cytokines (TNF, IL-1) and nitrico oxide (NO). The aim of this study is to investigate the effect of trans anethole on some inflammatory parameters that are involved in hepatotoxicity induced by high doses of acetaminophen. Our results demonstrate that treatment with AN at doses 125 and 250mg/kg once a day for seven days prevented the changes caused by the APAP overdose, showing less intensity in the histological changes (necrosis, size of hepatocyte area and inflammatory infiltration), and corroborating the findings of serum activities of transaminases and phosphatases and the activity of the enzyme myeloperoxidase. In addition, the treatment prevented the up-regulation of proinflammatory mediators such as NO, TNF, IL-1α, MIP-1α and MCP-1 and induced the up-regulation of anti-inflammatory cytokines (IL-4 and IL-10). Thus, our results demonstrate a possible protective effect of trans anethole on the hepatotoxicity induced by APAP. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. Hepatotoxicity of NONI juice: Report of two cases

    Institute of Scientific and Technical Information of China (English)

    Vanessa Stadlbauer; Peter Fickert; Carolin Lackner; Jutta Schmerlaib; Peter Krisper; Michael Trauner; Rudolf E Stauber

    2005-01-01

    NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses.No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice.A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acutehepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice.

  7. Hepatotoxic potential of asarones: In vitro evaluation of hepatotoxicity and quantitative determination in herbal products

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    Dhavalkumar Narendrabha Patel

    2015-02-01

    Full Text Available α and β asarones are natural constituents of some aromatic plants, especially species of the genus Acorus. In addition to beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of β-asarone, a limit of exposure from herbal products of approximately 2 μg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of β-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of β-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4 to 25 times greater amounts of β-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE2 cells confirmed the cytotoxicity of -asarone (IC50 = 40.0 ± 2.0 µg/mL which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxicity effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety. Further investigations of the toxicity of asarones are

  8. Early

    Directory of Open Access Journals (Sweden)

    Kamel Abd Elaziz Mohamed

    2014-04-01

    Conclusion: Early PDT is recommended for patients who require prolonged tracheal intubation in the ICU as outcomes like the duration of mechanical ventilation length of ICU stay and hospital stay were significantly shorter in early tracheostomy.

  9. High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome

    Directory of Open Access Journals (Sweden)

    Minicucci Fabio

    2010-02-01

    Full Text Available Abstract Background Neurotoxicity is a recognized complication of cyclosporine A (CSA treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT is 4-11%. Methods We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD. Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD prophylaxis with CSA, methylprednisolone, methotrexate and ATG. Results All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40. Brain magnetic resonance imaging (MRI performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250. CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065. Conclusions Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in

  10. Anti-hepatotoxic and anti-oxidant defense potential of Tridax procumbens

    Directory of Open Access Journals (Sweden)

    Hemalatha Reddipalli

    2008-01-01

    Full Text Available Tridax procumbens is a widely occurring medicinal herb used by ethnomedical practitioners. With increased use of chemicals and alcohol besides growing incidence of viruses and autoimmune diseases, the incidence of liver injury is growing for which conventional drugs used for treatment are often inadequate. Various models are adopted in pharmological studies for inducing hepatitis/ liver injury similar to those observed in human viral hepatitis, diabetes and oxidative stress. D-galactosamine with lipopolysacchride (LPS, carbontetrachloride (CCl 4 and paracetamol intoxication, diabetes induced with alloxan are widely used on rodents for this purpose. In vitro studies on Tridax procumbens (TP revealed the anti-oxidant potential of the herb with chloroform fraction of the ethanolic extract showing maximum activity. It is also reported to possess anti-oxidant minerals such as iron, magnesium, copper and zinc. In vivo studies on rodents on the anti-oxidant potential of TP induced through LPS, CCl 4, alloxan and paracetamol intoxication induced hepatitis confirmed the results from in vitro studies as a potential anti-hepatotoxic herb.

  11. Hepatotoxicity of antiretrovirals in patients with human immunodeficiency virus and viral hepatitis coinfections

    Directory of Open Access Journals (Sweden)

    P Parenti

    2012-11-01

    Full Text Available Background: Antiretroviral drugs used to treat HIV may cause hepatotoxicity. The high prevalence of persons with chronic hepatitis B or C coinfected, raised aminotransferases have many causes and neither specific markers is a indicator of liver injury, difficulties in interpreting the hepatotoxicity. Objective: We evaluated hepatotoxicity in HIV/HCV- and/or HBV-coinfected patients, risk factors and severity. Methods: Prospective study of HIV-1 patients with start HAART in Hospital Provincial del Centenario from Rosario, Argentina. Patients were classified into two groups, HCV and/or HBV coinfected vs. no coinfected. The major endpoint was hepatotoxicity defined as Benichou's Score within the first 6 months. This score is among the few validated, but little used in clinical practice. Secondary endpoints were risk factors and severity of hepatotoxicity. Results: 140 patients were included, 39% coinfected and 61% no coinfected. Females were similar in both groups; 21% and 27% respectively. The hepatotoxicity within the first 6 month was 44.3%, 75% in coinfected patients and 25% in no-coinfected. RR 3.97 (95% confidence interval 2.34–6.75, p<0.0001. The hepatotoxicity was associated with the use of illicit drugs and alcohol, symptoms, high level aminotransferases previous to HAART and NNRTI+PI. 3% of hepatotoxicity was severe. Conclusions: 44% of HIV patients experienced hepatotoxicity, 75% in coinfected vs 25% in no coinfected. The relative risk of hepatoxocity was almost 4 times higher among in chronic hepatitis-coinfected patients, compared with those with HIV non-coinfected. In multivariate analysis, the risk factors were illicit drugs, alcohol, symptoms, high level aminotransferases and NRTI+PI. Only 3% of hepatotoxicity was severe. The Benichou's Score is better than level of aminotransferase for evaluated hepatotoxicity, so it would be recommended for use in clinical practice.

  12. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Dan; Wu, Chun-qi [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Li, Ze-jun [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Guang Dong Pharmaceutical University, Guangzhou 510006 (China); Liu, Yue; Fan, Xing [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Wang, Quan-jun, E-mail: wangquanjunbeijing@163.com [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Ding, Ri-gao, E-mail: dingrigao@nic.bmi.ac.cn [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China)

    2015-04-15

    Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for hepatotoxicity.

  13. Infliximab exerts no direct hepatotoxic effect on HepG2 cells in vitro.

    NARCIS (Netherlands)

    Vries, H.S. de; Heij, T. de; Schaap-Roelofs, H.M.J.; Morsche, R.H.M. te; Peters, W.H.M.; Jong, D.J. de

    2012-01-01

    BACKGROUND: Infliximab-induced hepatotoxicity is reported in several case studies involving patients with inflammatory bowel disease (IBD) and a direct hepatotoxic effect has been proposed. OBJECTIVE: The aim of this study was to determine the direct in vitro toxicity of infliximab. As a proof of

  14. 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

  15. Contaminant hepatotoxins as culprits for kava hepatotoxicity--fact or fiction?

    Science.gov (United States)

    Teschke, Rolf; Sarris, Jerome; Lebot, Vincent

    2013-03-01

    The culprit of kava hepatotoxicity will continue to remain a mystery in humans, if the underlying reaction is of idiosyncratic, unpredictable, and dose-independent nature due potentially to some metabolic aberration in a few individuals emerging from kava use. In addition, kava hepatotoxicity is presently not reproducible experimentally in preclinical models, as demonstrated by studies showing whole kava extracts are not hepatotoxic. This led us to propose our 'working hypothesis' that contaminant hepatotoxins including moulds might have caused rare kava hepatotoxicity in humans. Further studies are now warranted to proof or disproof our working hypothesis, because kava hepatotoxicity possibly based on contaminant hepatotoxins could be a preventable disease. In the meantime, however, for minimizing toxicity risk in kava users, a pragmatic approach should focus on the medicinal use of an aqueous extract derived from peeled rhizomes and roots of a non-mouldy noble kava cultivar, limited to maximum 250-mg kavalactones daily for acute or intermittent use.

  16. Metabolic detoxification determines species differences in coumarin-induced hepatotoxicity.

    Science.gov (United States)

    Vassallo, Jeffrey D; Hicks, Sarah M; Daston, George P; Lehman-McKeeman, Lois D

    2004-08-01

    Hepatotoxicity of coumarin is attributed to metabolic activation to an epoxide intermediate, coumarin 3,4-epoxide (CE). However, whereas rats are most susceptible to coumarin-induced hepatotoxicity, formation of CE is greatest in mouse liver microsomes, a species showing little evidence of hepatotoxicity. Therefore, the present work was designed to test the hypothesis that detoxification of CE is a major determinant of coumarin hepatotoxicity. CE can either rearrange spontaneously to o-hydroxyphenylacetaldehyde (o-HPA) or be conjugated with gluatathione (GSH). o-HPA is hepatotoxic and is further detoxified by oxidation to o-hydroxyphenylacetic acid (o-HPAA). In vitro experiments were conducted using mouse liver microsomes to generate a constant amount of CE, and cytosols from F344 rats, B6C3F1 mice, and human liver were used to characterize CE detoxification. All metabolites were quantified by HPLC methods with UV detection. In rats and mice, GSH conjugation occurred non-enzymatically and through glutathione-S-transferases (GSTs), and the kinetics of GSH conjugation were similar in rats and mice. In rat liver cytosol, oxidation of o-HPA to o-HPAA was characterized with a high affinity K(m) of approximately 12 microM, and a V(max) of approximately 1.5 nmol/min/mg protein. In contrast, the K(m) and V(max) for o-HPA oxidation in mouse liver cytosol were approximately 1.7 microM and 5 nmol/min/mg protein, respectively, yielding a total intrinsic clearance through oxidation to o-HPAA that was 20 times higher in mouse than in rats. Human cytosols (two separate pools) detoxified CE through o-HPA oxidation with an apparent K(m) of 0.84 microM and a V(max) of 5.7 nmol/min/mg protein, for a net intrinsic clearance that was more than 50 times higher than the rat. All species also reduced o-HPA to o-hydroxyphenylethanol (o-HPE), but this was only a major reaction in rats. In the presence of a metabolic reaction replete with all necessary cofactors, GSH conjugation accounted

  17. Green Tea Extract-induced Acute Hepatotoxicity in Rats.

    Science.gov (United States)

    Emoto, Yuko; Yoshizawa, Katsuhiko; Kinoshita, Yuichi; Yuki, Michiko; Yuri, Takashi; Yoshikawa, Yutaka; Sayama, Kazutoshi; Tsubura, Airo

    2014-10-01

    Although green tea is considered to be a healthy beverage, hepatotoxicity associated with the consumption of green tea extract has been reported. In the present study, we characterized the hepatotoxicity of green tea extract in rats and explored the responsible mechanism. Six-week-old IGS rats received a single intraperitoneal (ip) injection of 200 mg/kg green tea extract (THEA-FLAN 90S). At 8, 24, 48 and 72 hrs and 1 and 3 months after exposure, liver damage was assessed by using blood-chemistry, histopathology, and immunohistochemistry to detect cell death (TUNEL and caspase-3) and proliferative activity (PCNA). Analyses of malondialdehyde (MDA) in serum and the liver and of MDA and thymidine glycol (TG) by immunohistochemistry, as oxidative stress markers, were performed. Placental glutathione S-transferase (GST-P), which is a marker of hepatocarcinogenesis, was also immunohistochemically stained. To examine toxicity at older ages, 200 mg/kg green tea extract was administered to 18-wk-old female rats. In 6-wk-old rats, 12% of males and 50% of females died within 72 hrs. In 18-wk-old rats, 88% died within 72 hrs. The serum levels of aspartate aminotransferase, alanine aminotransferase and/or total bilirubin increased in both males and females. Single-cell necrosis with positive signs of TUNEL and caspase-3 was seen in perilobular hepatocytes from 8 hrs onward in all lobular areas. PCNA-positive hepatocytes increased at 48 hrs. MDA levels in the serum and liver tended to increase, and MDA- and TG-positive hepatocytes were seen immunohistochemically. GST-P-positive hepatocellular altered foci were detected in one female rat at the 3-month time point. In conclusion, a single injection of green tea extract induced acute and severe hepatotoxicity, which might be associated with lipid peroxidation and DNA oxidative stress in hepatocytes.

  18. 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.

  19. Methotrexate Hepatotoxicity in Psoriatics: Report of 104 Patients from Nova Scotia, with Analysis of Risks from Obesity, Diabetes and Alcohol Consumption During Long Term Follow-Up

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    DA Malatjalian

    1996-01-01

    Full Text Available BACKGROUND AND DESIGN: Methotrexate (MTX hepatotoxicity in psoriatic patients is well recognized, but there are discrepancies in the reported incidence and associated risk factors. This retrospective study describes 104 Nova Scotian patients with psoriasis seen between 1979 and 1990. Patients received MTX over one to 11 years (mean 3.38, with baseline and annual follow-up liver biopsies. Clinical data were obtained by chart review. Statistical analysis evaluated the risks associated with obesity, diabetes, alcohol consumption and duration of therapy, with the histological grade of liver biopsies.

  20. Gadolinium chloride pretreatment ameliorates acute cadmium-induced hepatotoxicity.

    Science.gov (United States)

    Kyriakou, Loukas G; Tzirogiannis, Konstantinos N; Demonakou, Maria D; Kourentzi, Kalliopi T; Mykoniatis, Michael G; Panoutsopoulos, Georgios I

    2013-08-01

    Cadmium is a known industrial and environmental pollutant. It causes hepatotoxicity upon acute administration. Features of cadmium-induced acute hepatoxicity encompass necrosis, apoptosis, peliosis and inflammatory infiltration. Gadolinium chloride (GdCl3) may prevent cadmium-induced hepatotoxicity by suppressing Kupffer cells. The effect of GdCl3 pretreatment on a model of acute cadmium-induced liver injury was investigated. Male Wistar rats 4-5 months old were injected intraperitoneally with normal saline followed by cadmium chloride (CdCl2; 6.5 mg/kg) or GdCl3 (10 mg/kg) followed by CdCl2 (6.5 mg/kg; groups I and II, respectively). Rats of both the groups were killed at 9, 12, 16, 24, 48 and 60 h after cadmium intoxication. Liver sections were analyzed for necrosis, apoptosis, peliosis and mitoses. Liver regeneration was also evaluated by tritiated thymidine incorporation into hepatic DNA. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also determined. Hepatic necrosis, hepatocyte and nonparenchymal cell apoptosis and macroscopic and microscopic types of peliosis hepatis were minimized by gadolinium pretreatment. Serum levels of AST and ALT were also greatly diminished in rats of group II. Tritiated thymidine incorporation into hepatic DNA was increased in gadolinium pretreatment rats. Kupffer cell activation was minimal in both the groups of rats. Gadolinium pretreatment attenuates acute cadmium-induced liver injury in young Wistar rats, with mechanisms other than Kupffer cell elimination.

  1. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Jacevic, Vesna; Djordjevic, Aleksandar; Srdjenovic, Branislava; Milic-Tores, Vukosava; Segrt, Zoran; Dragojevic-Simic, Viktorija; Kuca, Kamil

    2017-03-16

    Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

  2. Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats.

    Science.gov (United States)

    Aly, Hamdy A A; Mansour, Ahmed M; Hassan, Memy H; Abd-Ellah, Mohamed F

    2016-08-01

    The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016.

  3. Hepatotoxic Alterations Induced by Inhalation of Trichloroethylene (TCE) in Rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective Trichloroethylene (TCE) is one of the most potent organic unsaturated solvents being used in dry cleaning, metal degreasing, thinner for paints varnishes and electroplating, etc. and has been reported to be a hepatotoxicant through oral and dermal exposure. However, its inhalation toxicity data is very limited in the literature due to the fact that the exposure levels associated with these effects were usually not reported. Hence, inhalation toxicity study was carried out for hepatotoxic studies. Method Inhalation toxicity studies was carried out by exposing rats to TCE for 8, 12 and 24 weeks in a dynamically operated whole body inhalation chamber. Sham treated control rats were exposed to compressed air in the inhalation chamber for the same period. Results Significant increase in liver weight (liver enlargement) appearance of necrotic lesions with fatty changes and marked necrosis were observed after longer duration (12 and 24 weeks) of TCE exposure. The lysosomal rupture resulted in increased activity of acid and alkaline phosphatase alongwith reduced glutathione content and total increased sulfhydryl content in liver tissue. Conclusion TCE exposure through Inhalation route induces hepatotoxicity in terms of marked necrosis with fatty changes and by modulating the lysosomal enzymes.

  4. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Results: Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. Conclusion: The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system. PMID:26862277

  5. Application of Serum Enzyme Biomakers in Hepatotoxicity Evaluation SHENG%酶生物标志物在肝毒性评价中的应用

    Institute of Scientific and Technical Information of China (English)

    盛云华; 周绮; 姚广涛

    2011-01-01

    In the research and development of new drug, many drug canfliflates have been out because of severe drug adverse reaction, among which drug-induced hepatotoxicity account for a higher proportion.The liver has the most abundant enzymes, with combining determination of serum enzyme, we can understand the state of the liver timely. In this paper , the application of tranditional makers of serum enzyme and potential hiomakers of hepatotoxicity are summarized ,then we hope to predict or discovery hepatotoxicity in an early stage and take measure timely through combing determination of the tranditional and potential biomakers.%在新药研发过程中,很多候选药物由于严重的不良反应而遭淘汰,各类不良反应中药物引起的肝毒性最多.肝脏是体内含酶最丰富的器官,通过联合检测血清中酶的变化可以及时了解肝脏的病理生理状态.现就肝毒性传统血清酶生物标志物和潜在的血清酶生物标志物在肝毒性评价中的应用予以综述,以期通过联合检测血清酶,做到早期发现毒性,早采取措施.

  6. Anti-proliferative activities of sinigrin on carcinogen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Jie, Meng; Cheung, Wan Man; Yu, Vivian; Zhou, Yanling; Tong, Pak Ho; Ho, John W S

    2014-01-01

    Liver cancer is one of the leading causes of cancer death worldwide. A very high incidence of new liver cancer cases is diagnosed every year, and metastasis has been found to correlate to poor prognoses in humans. Better treatments for liver cancer are thus clearly needed. Sinigrin is one of the major ingredients present in Brassica nigra, which has been used in combination with other herbs for treatment of various diseases. The anti-proliferative activities of sinigrin were studied in a model of carcinogen-induced hepatotoxicity in rats. Rats were orally administered with sinigrin on a daily basis for three months before sacrifice. Sinigrin was found to significantly inhibit the proliferation of liver tumor cells; the number of surface tumors in the rat liver was dramatically reduced. Sinigrin induced apoptosis of liver cancer cells through up-regulation of p53 and down-regulation of Bcl-2 family members and caspases. Our findings indicated that the liver functions were gradually restored after treatment with sinigrin and that the agent did not cause liver toxicity. Cell cycle analysis indicated that sinigrin caused cell cycle arrest in G0/G1 phase. The results suggest that sinigrin exerts important anti-proliferative activities in carcinogen-induced hepatocarcinogenesis in rats, and highlight the potential of sinigrin as an anti-cancer agent for liver cancer.

  7. Hepatotoxic Potential of Therapeutic Oligonucleotides Can Be Predicted from Their Sequence and Modification Pattern

    Science.gov (United States)

    Hagedorn, Peter H.; Yakimov, Victor; Ottosen, Søren; Kammler, Susanne; Nielsen, Niels F.; Høg, Anja M.; Hedtjärn, Maj; Meldgaard, Michael; Møller, Marianne R.; Ørum, Henrik; Koch, Troels

    2013-01-01

    Antisense oligonucleotides that recruit RNase H and thereby cleave complementary messenger RNAs are being developed as therapeutics. Dose-dependent hepatic changes associated with hepatocyte necrosis and increases in serum alanine-aminotransferase levels have been observed after treatment with certain oligonucleotides. Although general mechanisms for drug-induced hepatic injury are known, the characteristics of oligonucleotides that determine their hepatotoxic potential are not well understood. Here, we present a comprehensive analysis of the hepatotoxic potential of locked nucleic acid-modified oligonucleotides in mice. We developed a random forests classifier, in which oligonucleotides are regarded as being composed of dinucleotide units, which distinguished between 206 oligonucleotides with high and low hepatotoxic potential with 80% accuracy as estimated by out-of-bag validation. In a validation set, 17 out of 23 oligonucleotides were correctly predicted (74% accuracy). In isolation, some dinucleotide units increase, and others decrease, the hepatotoxic potential of the oligonucleotides within which they are found. However, a complex interplay between all parts of an oligonucleotide can influence the hepatotoxic potential. Using the classifier, we demonstrate how an oligonucleotide with otherwise high hepatotoxic potential can be efficiently redesigned to abate hepatotoxic potential. These insights establish analysis of sequence and modification patterns as a powerful tool in the preclinical discovery process for oligonucleotide-based medicines. PMID:23952551

  8. Gene expression profiling reveals potential key pathways involved in pyrazinamide-mediated hepatotoxicity in Wistar rats.

    Science.gov (United States)

    Zhang, Yun; Jiang, Zhenzhou; Su, Yijing; Chen, Mi; Li, Fu; Liu, Li; Sun, Lixin; Wang, Yun; Zhang, Shuang; Zhang, Luyong

    2013-08-01

    Pyrazinamide (PZA) is an important sterilizing prodrug that shortens the duration of tuberculosis therapy. However, hepatotoxicity has been reported during clinical trials investigating PZA. To determine the hepatotoxic effects of PZA in vivo and to further investigate the underlying cellular mechanism, we profiled the gene expression patterns of PZA-treated rat livers by microarray analysis. Wistar rats of both sexes were orally administered PZA at doses of 0.5, 1.0 and 2.0 g kg(-1) for 28 days. Body weight, absolute and relative liver weight, biochemical analysis, histopathology, oxidative stress parameters in liver homogenates and changes in global transcriptomic expression were evaluated to study the hepatotoxic effects of PZA. Our results confirm the dose-dependent and sex-related hepatotoxicity of PZA. Female rats were more sensitive to PZA-induced hepatotoxicity than males. Furthermore, changes in the activity of major antioxidant enzymes and nonenzymatic antioxidants (superoxide dismutase, total antioxidant capacity, glutathione and malondialdehyde), indicating the development of oxidative stress, were more significant in the PZA-treated group. PZA-induced gene expression changes were related to pathways involved in drug metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, oxidative stress and apoptosis. Real-time polymerase chain reaction confirmed the regulation of selected genes involved in PZA-hepatotoxicity (Ephx1, Cyp2b1, Gstm1, Gstp1, Fabp7, Acaa1, Cpt-1b, Cyp8b1, Hmox1 and Ntrk1). We observed for the first time that these genes have effects on PZA-induced hepatotoxicity. In addition, drug metabolism and PPAR signaling pathways may play an important role in PZA hepatotoxicity. Taken together, these findings will be useful for future PZA hepatotoxicity studies.

  9. Prevalence, Incidence, Prognosis, Early Stroke Risk, and Stroke-Related Prognostic Factors of Definite or Probable Transient Ischemic Attacks in China, 2013

    Directory of Open Access Journals (Sweden)

    Bin Jiang

    2017-06-01

    Full Text Available The epidemiological characteristics of transient ischemic attacks (TIAs in China are unclear. In 2013, we conducted a nationally representative, door-to-door epidemiological survey on TIA in China using a complex, multistage, probability sampling design. Results showed that the weighted prevalence of TIA in China was 103.3 [95% confidence interval (CI: 83.9–127.2] per 100,000 in the population, 92.4 (75.0–113.8 per 100,000 among men, and 114.7 (87.2–151.0 per 100,000 among women. The weighted incidence of TIA was 23.9 (17.8–32.0 per 100,000 in the population, 21.3 (14.3–31.5 per 100,000 among men, and 26.6 (17.0–41.7 per 100,000 among women. No difference in average prognosis was found between TIA and stroke in the population. Weighted risk of stroke among TIA patients was 9.7% (6.5–14.3%, 11.1% (7.5–16.1%, and 12.3% (8.4–17.7% at 2, 30, and 90 days, respectively. The risk of stroke was higher among male patients with a history of TIA than among female patients with a history of TIA (OR: 2.469; 95% CI: 1.172–5.201; P = 0.018, and higher among TIA patients with hypertension than among TIA patients without hypertension (OR: 2.671; 1.547–4.613; P < 0.001. It can be concluded that there are an estimated 1.35 million TIA patients nationwide, with 0.31 million new cases of TIA annually in China. TIA patients were not better managed prior to a stroke event. Early risk of stroke among TIA patients is high. Sex and hypertension may be stroke-associated prognostic factors among TIA patients. TIA clinics and surveillance should be integrated into the national health-care system.

  10. Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid.

    Science.gov (United States)

    Levy, R H; Rettenmeier, A W; Anderson, G D; Wilensky, A J; Friel, P N; Baillie, T A; Acheampong, A; Tor, J; Guyot, M; Loiseau, P

    1990-09-01

    The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA), formed by a cytochrome P450-mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4-ene-VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4-ene-VPA was increased twofold in the valproic acid-carbamazepine and valproic acid-phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4-ene-VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4-ene-VPA, in humans. The increased formation of 4-ene-VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid-related hepatotoxicity during polytherapy with P450 inducers.

  11. Visual Function in Older Eyes in Normal Macular Health: Association with Incident Early Age-Related Macular Degeneration 3 Years Later

    OpenAIRE

    Owsley, Cynthia; Clark, Mark E.; Carrie E. Huisingh; Curcio, Christine A.; McGwin, Gerald

    2016-01-01

    Purpose In older eyes in normal macular health, we examined associations between impaired photopic acuity, mesopic acuity, spatial contrast sensitivity, light sensitivity, and the presence of low luminance deficit (difference between photopic and mesopic acuity) at baseline and incident AMD 3 years later. Associations were compared with an association between delayed rod-mediated dark adaptation and incident AMD, previously reported for this cohort. Methods Enrollees were 60 years or older. E...

  12. A study of effect of Nigella sativa oil in paracetamol induced hepatotoxicity in albino rats

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    Manik S. Ghadlinge

    2014-06-01

    Conclusion: This study demonstrated that NS oil has hepatoprotective effect. NS oil administration can prevent or reverse the hepatotoxicity induced by paracetamol. [Int J Basic Clin Pharmacol 2014; 3(3.000: 539-546

  13. Stavudine- and nevirapine-related drug toxicity while on generic fixed-dose antiretroviral treatment: incidence, timing and risk factors in a three-year cohort in Kigali, Rwanda.

    Science.gov (United States)

    van Griensven, Johan; Zachariah, Rony; Rasschaert, Freya; Mugabo, Jules; Atté, Edi F; Reid, Tony

    2010-02-01

    This cohort study was conducted to report on the incidence, timing and risk factors for stavudine (d4T)- and nevirapine (NVP)-related severe drug toxicity (requiring substitution) with a generic fixed-dose combination under program conditions in Kigali, Rwanda. Probability of 'time to first toxicity-related drug substitution' was estimated using the Kaplan-Meier method and Cox-proportional hazards modeling was used to identify risk factors. Out of 2190 adults (median follow-up: 1.5 years), d4T was replaced in 175 patients (8.0%) for neuropathy, 69 (3.1%) for lactic acidosis and 157 (7.2%) for lipoatrophy, which was the most frequent toxicity by 3 years of antiretroviral treatment (ART). NVP was substituted in 4.9 and 1.3% of patients for skin rash and hepatotoxicity, respectively. Use of d4T 40 mg was associated with increased risk of lipoatrophy and early (strategies.

  14. Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity.

    Science.gov (United States)

    Sun, Jinchun; Slavov, Svetoslav; Schnackenberg, Laura K; Ando, Yosuke; Greenhaw, James; Yang, Xi; Salminen, William; Mendrick, Donna L; Beger, Richard

    2014-07-01

    It has been estimated that 10% of acute liver failure is due to "idiosyncratic hepatotoxicity". The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague-Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

  15. Effect of honey on hepatotoxicity induced by antitubercular drugs in albino rats

    OpenAIRE

    Rakhamaji D. Chandane; Jugalkishor B. Jaju; Manik S. Ghadlinge; Rama R. Bhosale; Ajay R. Chandrakapure

    2013-01-01

    Background: Drug-induced hepatotoxicity is a potentially serious adverse effect of antituberculosis treatment (ATT) regimens containing isoniazid, rifampicin and pyrazinamide. Many in vitro and in vivo studies revealed that honey possess antioxidant property and hepotoprotective property but there is no systematic work available to test the effect of honey on antitubercular drugs induced hepatotoxicity in rats. Hence present study was carried out to explore the prophylactic and therapeutic ef...

  16. 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.

  17. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes.

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    Sophie Candon

    Full Text Available Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

  18. Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats

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    Zim M.C.A.

    2002-01-01

    Full Text Available Few data are available in the literature regarding the effect of pentosan polysulfate (PPS on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4 has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1 hepatic fibrosis induction with CCl4 (N = 36 rats; 2 evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats; 3 evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats; 4 evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36 developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8 and 1 mg/kg PPS (N = 8 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45. PPS (40 mg/kg alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks. This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis.

  19. Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats.

    Science.gov (United States)

    Zim, M C A; Silveira, T R; Schwartsmann, G; Cerski, T; Motta, A

    2002-11-01

    Few data are available in the literature regarding the effect of pentosan polysulfate (PPS) on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4) has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1) hepatic fibrosis induction with CCl4 (N = 36 rats); 2) evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats); 3) evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats); 4) evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats) using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days) male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8% CCl4 (N = 36) developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8) and 1 mg/kg PPS (N = 8) 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45). PPS (40 mg/kg) alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks). This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis.

  20. Ipomoea aquatica Extract Shows Protective Action Against Thioacetamide-Induced Hepatotoxicity

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    A. Hamid A. Hadi

    2012-05-01

    Full Text Available In the Indian system of traditional medicine (Ayurveda it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD rats were orally fed with I. aquatica (250 and 500 mg/kg for two months along with administration of TAA (i.p injection 200 mg/kg three times a week for two months. The results showed that the treatment of I. aquatica significantly lowered the TAA-induced serum levels of hepatic enzyme markers (ALP, ALT, AST, protein, albumin, bilirubin and prothrombin time. The hepatic content of activities and expressions SOD and CAT that were reduced by TAA were brought back to control levels by the plant extract supplement. Meanwhile, the rise in MDA level in the TAA receiving groups also were significantly reduced by I. aquatica treatment. Histopathology of hepatic tissues by H&E and Masson trichrome stains displayed that I. aquatica has reduced the incidence of liver lesions, including hepatic cells cloudy swelling, infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by TAA in rats. Therefore, the results of this study show that the protective effect of I. aquatica in TAA-induced liver damage might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects. Moreover, it confirms a scientific basis for the traditional use of I. aquatica for the treatment of liver disorders.

  1. Protective effects of Nasturtium officinale against gamma-irradiation-induced hepatotoxicity in C57 mice

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    M. Karami

    2015-04-01

    Full Text Available Background and objectives: Nasturtium officinale W.T.Aiton (Brassicaceae is used as an edible vegetable in various parts of Iran. The aim of the present study was to investigate the protective activity of the methanolic extract of Nasturtium officinale against gamma-radiation-induced hepatotoxicity in terms of histopathological changes. Methods: Male C57 mice were divided into 10 groups. Groups 1 and 2 received saline solution intra-peritoneally (IP for 15 days (subacute and 2 h (acute before whole body γ-irradiation (6 Gy. Groups 3 to 5 (subacute and 6 to 8 (acute received the extract at doses of 20 mg/kg, 50 mg/kg and 100 mg/kg body weight IP, respectively. Group 9 served as radiation group. Group 10 received nothing. Finally, sections of the liver tissue were evaluated for any histopathologic changes. Total phenolic and flavonoid contents were determined using Folin Ciocalteu andaluminium chloride methods. Results: Pre-treatment with 100 mg/kg body weight per day for 15 days and 2 h before γ-radiation significantly lowered incidence of inflammation (portal and periportal inflammation. Furthermore, liver cells necrosis, edema and congestion were slightly reduced. The total phenolic and total flavonoid contents of the extract were 11.3 ± 0.4 mg gallic acid equivalents and 9.4 ± 0.7 mg quercetin equivalents per gram of dried extract. Conclusion: This protection can be attributed to the presence of phenols and isothiocyanates in the extract of N. officinale which act as antioxidants and anti-inflammatory agents.

  2. Ipomoea aquatica extract shows protective action against thioacetamide-induced hepatotoxicity.

    Science.gov (United States)

    Alkiyumi, Salim Said; Abdullah, Mahmood Ameen; Alrashdi, Ahmed Salim; Salama, Suzy Munir; Abdelwahab, Siddig Ibrahim; Hadi, A Hamid A

    2012-05-22

    In the Indian system of traditional medicine (Ayurveda) it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA)-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD) rats were orally fed with I. aquatica (250 and 500 mg/kg) for two months along with administration of TAA (i.p injection 200 mg/kg three times a week for two months). The results showed that the treatment of I. aquatica significantly lowered the TAA-induced serum levels of hepatic enzyme markers (ALP, ALT, AST, protein, albumin, bilirubin and prothrombin time). The hepatic content of activities and expressions SOD and CAT that were reduced by TAA were brought back to control levels by the plant extract supplement. Meanwhile, the rise in MDA level in the TAA receiving groups also were significantly reduced by I. aquatica treatment. Histopathology of hepatic tissues by H&E and Masson trichrome stains displayed that I. aquatica has reduced the incidence of liver lesions, including hepatic cells cloudy swelling, infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by TAA in rats. Therefore, the results of this study show that the protective effect of I. aquatica in TAA-induced liver damage might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects. Moreover, it confirms a scientific basis for the traditional use of I. aquatica for the treatment of liver disorders.

  3. Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Jinchun Sun

    2014-07-01

    Full Text Available It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride, two idiosyncratic hepatotoxicants (felbamate and dantrolene, and three non-hepatotoxicants (meloxicam, penicillin and metformin. Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h, 7 (24 h and 20 (6 h and 24 h metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

  4. Incident HIV during pregnancy and early postpartum period: a population-based cohort study in a rural area in KwaZulu-Natal, South Africa.

    Science.gov (United States)

    Chetty, Terusha; Vandormael, Alain; Thorne, Claire; Coutsoudis, Anna

    2017-07-26

    The evidence on the effect of pregnancy on acquiring HIV is conflicting, with studies reporting both higher and lower HIV acquisition risk during pregnancy when prolonged antiretroviral therapy was accessible. The aim of this study was to assess the pregnancy effect on HIV acquisition where antiretroviral therapy was widely available in a high HIV prevalence setting. This is a retrospective cohort study nested within a population-based surveillance to determine HIV incidence in HIV-uninfected women from 15 to 49 years from 2010 through 2015 in rural KwaZulu-Natal. HIV incidence per 100 person-years according to pregnancy status (not pregnant, pregnant, to eight weeks postpartum) were measured in 5260 HIV-uninfected women. Hazard ratios (HR) were estimated by Cox proportional hazards regression with pregnancy included as a time varying variable. Overall, pregnancy HIV incidence was 4.5 per 100 person-years (95% CI 3.4-5.8), higher than non-pregnancy (4.0; 95% CI 3.7-4.3) and postpartum incidences (4.2 per 100 person-years; 95% CI 2.3-7.6). However, adjusting for age, and demographic factors, pregnant women had a lower risk of acquiring HIV (HR 0.4; 95% CI 0.2-0.9, P = 0.032) than non-pregnant women; there were no differences between postpartum and non-pregnant women (HR 1.2; 95% CI 0.4-3.2; P = 0.744). In models adjusting for the interaction of age and gravidity, pregnant women under 25 years with two or more pregnancies had a 2.3 times greater risk of acquiring HIV than their older counterparts (95% CI 1.3-4.3; P = 0.008). Pregnancy had a protective effect on HIV acquisition. Elevated HIV incidence in younger women appeared to be driven by those with higher gravidity. The sexual and biological factors in younger women should be explored further in order to design appropriate HIV prevention interventions.

  5. [Critical incidents].

    Science.gov (United States)

    Scheidegger, D

    2005-03-01

    In medicine real severe mishaps are rare. On the other hand critical incidents are frequent. Anonymous critical incident reporting systems allow us to learn from these mishaps. This learning process will make our daily clinical work safer Unfortunately, before these systems can be used efficiently our professional culture has to be changed. Everyone in medicine has to admit that errors do occur to see the need for an open discussion. If we really want to learn from errors, we cannot punish the individual, who reported his or her mistake. The interest is primarily in what has happened and why it has happened and not who has committed this mistake. The cause for critical incidents in medicine is in over 80% the human factor Poor communication, work under enormous stress, conflicts and hierarchies are the main cause. This has been known for many years, therefore have already 15 years ago high-tech industries, like e.g. aviation, started to invest in special courses on team training. Medicine is a typical profession were until now only the individual performance decided about the professional career Communication, conflict management, stress management, decision making, risk management, team and team resource management were subjects that have never been taught during our preor postgraduate education. These points are the most important ones for an optimal teamwork. A multimodular course designed together with Swissair (Human Aspect Development medical, HADmedical) helps to cover, as in aviation, the soft factor and behavioural education in medicine and to prepare professionals in health care to work as a real team.

  6. 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.

  7. 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.

  8. 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.

  9. Efeito da adubação sobre a incidência de traça-do-tomateiro e alternaria em plantas de tomate Effect of fertilization on the incidence of leafminer and early blight on tomato plants

    Directory of Open Access Journals (Sweden)

    Germano L.D. Leite

    2003-09-01

    Full Text Available Avaliou-se o efeito de quatro níveis de adubação nitrogenada e potássica (NK na resposta do tomateiro Lycopersicon esculentum, c.v Santa Clara, ao ataque de mancha de alternaria (Alternaria solani, e da traça-do-tomateiro (Tuta absoluta, em casa de vegetação, em três diferentes idades da planta. O delineamento experimental foi blocos casualizados com sete repetições, no esquema fatorial 3 x 4. Foram avaliados a altura da planta (cm, área foliar (cm² e o número de cachos por planta, flores por cacho, flores abortadas por cacho, frutos por cacho, frutos com mancha de alternaria por cacho, frutos atacados por traça-do-tomateiro por cacho, peso dos frutos por planta e minas de traça-de-tomateiro. A maior percentagem de frutos atacados pela traça foi observado em plantas de tomate cultivadas com altas doses de N. Com o aumento do número de flores ocorreu menor número de frutos atacados por alternaria. Tanto o ataque de A. solani como o de traça-do-tomateiro foi concentrado em frutos de menor peso, sendo que quanto maior o número de flores atacadas por A. solani, menor foi o ataque da traça aos frutos. O ataque da traça aos frutos foi maior em plantas de dois meses do que em plantas de quatro meses de idade, sendo o mesmo observado para o número de minas da traça-do-tomateiro.The effect of NK fertilization on tomato plants (Lycopersicon esculentum, cv. "Santa Clara", over early blight (Alternaria solani and the leafminer (Tuta absoluta attack in greenhouse, in the different plant ages, was evaluated. The 3 x 4 factorial experiment was established in a randomized blocks design with seven replicates. Plant height (cm, leaf area (cm² and number of raceme per plant, number of flowers per raceme, flower drop per raceme, number of fruits per raceme, damaged fruits per raceme by early blight and leafminer, fruit weight per plant and number of mines of leafminer were evaluated. Greater percentage of fruits damaged by leafminer was

  10. Role of metabolism in 1-bromopropane-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lee, Sang Kyu; Kang, Mi Jeong; Jeon, Tae Won; Ha, Hyun Woo; Yoo, Jin Woo; Ko, Gyu Sub; Kang, Wonku; Jeong, Hye Gwang; Lyoo, Won Seok; Jeong, Tae Cheon

    2010-01-01

    A possible role of metabolism in 1-bromopropane (1-BP)-induced hepatotoxicity was investigated in male ICR mice. The depletion of glutathione (GSH) by formation of GSH conjugates was associated with increased hepatotoxicity in 1-BP-treated mice. The formation of S-propyl and 2-hydroxypropyl GSH conjugates were identified in the liver following 1-BP treatment. In addition, the formation of reactive metabolites of 1-BP by certain cytochrome P-450 (CYP) may be involved in 1-BP-induced hepatotoxicity. The decreased content of hepatic GSH produced by 1-BP was associated not only with increased activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but also with elevated levels of hepatic thiobarbituric acid-reactive substance (TBARS) in mice where metabolic enzymes were induced by pretreatment with phenobarbital. In addition, the hepatotoxicity induced by 1-BP was prevented by pretreatment with SKF-525A. Taken together, the formation of reactive metabolites by CYP and depletion of GSH may play important roles in hepatotoxicity induced by 1-BP.

  11. Sequence motifs associated with hepatotoxicity of locked nucleic acid--modified antisense oligonucleotides.

    Science.gov (United States)

    Burdick, Andrew D; Sciabola, Simone; Mantena, Srinivasa R; Hollingshead, Brett D; Stanton, Robert; Warneke, James A; Zeng, Ming; Martsen, Elena; Medvedev, Alexander; Makarov, Sergei S; Reed, Lori A; Davis, John W; Whiteley, Laurence O

    2014-04-01

    Fully phosphorothioate antisense oligonucleotides (ASOs) with locked nucleic acids (LNAs) improve target affinity, RNase H activation and stability. LNA modified ASOs can cause hepatotoxicity, and this risk is currently not fully understood. In vitro cytotoxicity screens have not been reliable predictors of hepatic toxicity in non-clinical testing; however, mice are considered to be a sensitive test species. To better understand the relationship between nucleotide sequence and hepatotoxicity, a structure-toxicity analysis was performed using results from 2 week repeated-dose-tolerability studies in mice administered LNA-modified ASOs. ASOs targeting human Apolipoprotien C3 (Apoc3), CREB (cAMP Response Element Binding Protein) Regulated Transcription Coactivator 2 (Crtc2) or Glucocorticoid Receptor (GR, NR3C1) were classified based upon the presence or absence of hepatotoxicity in mice. From these data, a random-decision forest-classification model generated from nucleotide sequence descriptors identified two trinucleotide motifs (TCC and TGC) that were present only in hepatotoxic sequences. We found that motif containing sequences were more likely to bind to hepatocellular proteins in vitro and increased P53 and NRF2 stress pathway activity in vivo. These results suggest in silico approaches can be utilized to establish structure-toxicity relationships of LNA-modified ASOs and decrease the likelihood of hepatotoxicity in preclinical testing.

  12. Sequence motifs associated with hepatotoxicity of locked nucleic acid—modified antisense oligonucleotides

    Science.gov (United States)

    Burdick, Andrew D.; Sciabola, Simone; Mantena, Srinivasa R.; Hollingshead, Brett D.; Stanton, Robert; Warneke, James A.; Zeng, Ming; Martsen, Elena; Medvedev, Alexander; Makarov, Sergei S.; Reed, Lori A.; Davis, John W.; Whiteley, Laurence O.

    2014-01-01

    Fully phosphorothioate antisense oligonucleotides (ASOs) with locked nucleic acids (LNAs) improve target affinity, RNase H activation and stability. LNA modified ASOs can cause hepatotoxicity, and this risk is currently not fully understood. In vitro cytotoxicity screens have not been reliable predictors of hepatic toxicity in non-clinical testing; however, mice are considered to be a sensitive test species. To better understand the relationship between nucleotide sequence and hepatotoxicity, a structure–toxicity analysis was performed using results from 2 week repeated-dose-tolerability studies in mice administered LNA-modified ASOs. ASOs targeting human Apolipoprotien C3 (Apoc3), CREB (cAMP Response Element Binding Protein) Regulated Transcription Coactivator 2 (Crtc2) or Glucocorticoid Receptor (GR, NR3C1) were classified based upon the presence or absence of hepatotoxicity in mice. From these data, a random-decision forest-classification model generated from nucleotide sequence descriptors identified two trinucleotide motifs (TCC and TGC) that were present only in hepatotoxic sequences. We found that motif containing sequences were more likely to bind to hepatocellular proteins in vitro and increased P53 and NRF2 stress pathway activity in vivo. These results suggest in silico approaches can be utilized to establish structure–toxicity relationships of LNA-modified ASOs and decrease the likelihood of hepatotoxicity in preclinical testing. PMID:24550163

  13. Integrated analysis of transcriptomics and metabonomics profiles in aflatoxin B1-induced hepatotoxicity in rat.

    Science.gov (United States)

    Lu, Xiaoyan; Hu, Bin; Shao, Li; Tian, Yu; Jin, Tingting; Jin, Yachao; Ji, Shen; Fan, Xiaohui

    2013-05-01

    The aim of this work was to identify mechanisms and potential biomarkers for predicting the development and progression of aflatoxin B1 (AFB1)-induced acute hepatotoxicity. In this study, microarray analysis and metabolites profiles were used to identify shifts in gene expression and metabolite levels associated with the affected physiological processes of rats treated with AFB1. Histopathological examinations and serum biochemical analysis were simultaneously performed; the results indicated that hepatotoxicity occurred in higher dosage groups. However, gene expression analysis and metabolite profiles are more sensitive than general toxicity studies for detecting AFB1-induced acute hepatotoxicity as the patterns of low-dose AFB1-treated rats in these two technique platforms were more similar to the rats in higher dosage groups than to the control rats. Integrated analysis of the results from general toxicity studies, transcriptomics and metabonomics profiles suggested that p53 signaling pathway induced by oxidative damage was the crucial step in AFB1-induced acute hepatotoxicity, whereas gluconeogenesis and lipid metabolism disorder were found to be the major metabolic effects after acute AFB1 exposure. The genes and metabolites significantly affected in common in rat liver or serum of three doses AFB1 treatments served as potential biomarkers for detecting AFB1-induced acute hepatotoxicity.

  14. Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats.

    Science.gov (United States)

    Wang, Jiaying; Jiang, Zhenzhou; Ji, Jinzi; Wang, Xinzhi; Wang, Tao; Zhang, Yun; Tai, Ting; Chen, Mi; Sun, Lixin; Li, Xia; Zhang, Luyong

    2013-08-01

    Triptolide (TP), a major component of TWHF, is widely used to treat rheumatoid arthritis, systemic lupus erythematosus, nephritis and leprosy. However, its clinical use is limited by hepatotoxicity. To further elucidate the underlying mechanism of its hepatotoxic effects, hepatic gene expression profiles were analyzed. TP (1000 and 300 μg/kg) was orally administered to Wistar rats for 14 days. Current study indicated that female rats were more sensitive to TP-induced hepatotoxicity than males. Genome-wide microarray analyses identified 3329 differentially expressed genes in liver of female rats. Analyses of these genes identified over-represented functions associated with insulin signaling pathway, glucose metabolism, cell cycle, oxidative stress and apoptosis, which were consistent with the results of significant increase of Caspase-3 activity and reduction of serum glucose, GSH/GSSG ratio, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, liver glycogen. In addition, it was observed for the first time that glucocorticoids and IGF1 might get involved in TP-induced hepatotoxicity. These data suggest that TP treatment could alter the hepatic redox status, reduce serum glucose and induce hepatocyte apoptosis, consistent with the differential expression of genes involved in insulin signaling pathway, glucose metabolism pathway and cell stress pathway, all of which might contribute to the overall TP-induced hepatotoxicity.

  15. Treatment of Non-Small-Cell Lung Cancer with Erlotinib following Gefitinib-Induced Hepatotoxicity: Review of 8 Clinical Cases

    Directory of Open Access Journals (Sweden)

    Yukihiro Yano

    2012-01-01

    Full Text Available Objective. Gefitinib often induces liver damage. A few reports have described that the subsequent administration of erlotinib was associated with less hepatotoxicity, but the safety and efficacy of this treatment are still not fully investigated. Therefore, we evaluated retrospectively the patients with erlotinib following gefitinib-induced hepatotoxicity. Methods and Patients. We retrospectively reviewed the medical records between December 2007 and March 2010. The patients were evaluated including the following information: age, gender, histology of lung cancer, performance status, smoking status, epidermal growth factor receptor (EGFR mutation status, liver metastasis, viral hepatitis, alcoholic liver injury, clinical response, and hepatotoxicity due to EGFR tyrosine kinase inhibitors. Results. We identified 8 patients with erlotinib following gefitinib-induced hepatotoxicity. All achieved disease control by gefitinib. Hepatotoxicity was grades 2 and 3 in 3 and 5 patients, respectively. The median duration of treatment with gefitinib was 112.5 days and the median time to gefitinib-induced hepatotoxicity was 51.5 days. The median duration of treatment with erlotinib was 171.5 days. Grade 1 and 2 erlotinib-induced hepatotoxicity was observed in 2 and 1 patient, respectively. Conclusions. Erlotinib administration with careful monitoring is thought to be a good alternative strategy for patients who respond well to gefitinib treatment but experience hepatotoxicity.

  16. 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.

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

    Science.gov (United States)

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

    2012-01-01

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

  18. The hepatotoxicity of multi-walled carbon nanotubes in mice

    Science.gov (United States)

    Ji, Zongfei; Zhang, Danying; Li, Ling; Shen, Xizhong; Deng, Xiaoyong; Dong, Ling; Wu, Minhong; Liu, Yuanfang

    2009-11-01

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg-1 by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- α, NF-κB signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  19. Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Atawia, Reem T; Esmat, Ahmed; Elsherbiny, Doaa A; El-Demerdash, Ebtehal

    2017-02-01

    This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg(-1) , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg(-1) , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg(-1) ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg(-1) ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg(-1) ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg(-1) didn't show significant efficacy above 3 mg kg(-1) which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

  20. The hepatotoxicity of multi-walled carbon nanotubes in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ji Zongfei; Zhang Danying; Shen Xizhong; Dong Ling [Department of Gastroenterology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Li Ling; Deng Xiaoyong; Wu Minhong; Liu Yuanfang, E-mail: xydeng@shu.edu.c, E-mail: dltalk@tom.co [Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai 200444 (China)

    2009-11-04

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg{sup -1} by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- {alpha}, NF-{kappa}B signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  1. 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.

  2. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  3. 抗真菌药肝毒性的文献计量学分析%Bibliometric analysis on hepatotoxicity due to antifungal drugs

    Institute of Scientific and Technical Information of China (English)

    白艳; 李悦; 刘斌; 王昆; 梅和坤; 张颖; 王瑾; 王睿

    2014-01-01

    ,and PubMed,Embase,Web of Science,Chinese Academic Periodical Full-text Database China HowNet Chinese Academic Journal( CNKI ) and Chinese Biomedical Literature database( CBMdisc)were searched. All literature on hepatotoxicity due to antifungal drugs were selected. A database of literature accepted for final bibliometric study was established by using Microsoft Excel. The parameters of bibliometrics such as published time( years),the top 5 countries and institutes in publishing,literature′s type,published time( years),top 5 journals in publishing number,top 10 articles in terms of cited frequency were studied. The main content and hotspot of literature were analyzed. The clinical manifestations, mechanism, incidence and prophylactico-therapeutic measures of hepatotoxicity due to antifungal drugs were summarized. Results A total of 221 articals(193 in English,28 in Chinese)were enrolled in the study,of which 116 were original articles,49 reviews and 56 case reports. The published time of first original publication of hepatotoxicity due to antifungal drugs were 1976. The journal which published largest number of articles was Mycoses. The highest citation number of individual article was 531. The main clinical manifestations were weak,right upper quadrant pain,diarrhea,jaundice,cholestasis and fever. The severe cases could cause liver failure. Laboratory examination showed elevated serum transaminases,bilirubin, and alkaline phosphatase. The incidence of liver toxicity due to azole antifungals was higher,the incidence of liver toxicity due to amphotericin B was lower. The antifungal drugs should be used with caution in patients with hypohepatia. For the patients who used antifungal drugs for long time,the liver function should be monitored regularly. If liver injury occurs,the antifungal drugs should be stopped immediately. Some patients′liver function test results could return to the normal levels before administration of the symptomatic treatment and the supportive

  4. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

    OpenAIRE

    Ko, Je-Won; Lee,In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological al...

  5. A critical analysis of the hepatotoxicity cases described in the literature related to Herbalife (r) products

    OpenAIRE

    Flávio Ailton Duque Zambrone; Cristiana Leslie Corrêa; Ligia Mesquita Sampaio do Amaral

    2015-01-01

    Abstract The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r) products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r) products were retrieved. All of the s...

  6. A strategy to improve the detection of drug-induced hepatotoxicity Una estrategia para mejorar la detección de hepatotoxicidad por medicamentos

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    A. Ruiz Montero

    2005-03-01

    Full Text Available Aims: to report a new strategy for the detection of hepatotoxic adverse drug reactions (ADRs in hospitalized patients improving the results obtained with other methods. Design: the model is based on the identification of a single alert signal in various target clinical departments over a 12-month period. Each patient was later interviewed following a set protocol. The main results analyzed were the drugs suspected of ADR; causal relationship between suspected drugs and ADRs; ADR severity, and incidence of hepatotoxic ADR/100,000 inhabitants. Subjects: population served by a university-affiliated urban teaching hospital (519,381 inhabitants. Results: The overall ratio of confirmed/suspected ADRs was high (35/80. The most commonly reported drug was amoxicillin-clavulanic acid (4 cases. With regard to causality, 2 suspected cases were classified as definite and 14 as probable. The distribution according to the severity of hepatotoxicity was 6 severe and 29 mild cases. The incidence of hepatotoxic ADRs/100,000 inhabitants as revealed by our method was much higher versus voluntary report (6.74 and 1.79, respectively. Conclusions: our method has proven effective for improving the detection of hepatotoxic ADRs, and may be extended to other types of adverse reactions.Objetivos: comunicar una nueva estrategia para la detección de reacciones hepatotóxicas por medicamentos que mejora los resultados obtenidos con otros métodos utilizados. Diseño: el modelo se basa en la identificación de una señal de alerta simple en los pacientes de varios servicios diana, durante 12 meses. Cada paciente fue posteriormente entrevistado siguiendo un protocolo específico. Se analizaron: los fármacos sospechosos de producir hepatotoxicidad, la relación de causalidad entre el fármaco sospechoso y la hepatotoxicidad, la gravedad y la incidencia de hepatotoxicidad medicamentosa/100.000 habitantes. Pacientes: la población del área de influencia de nuestro hospital

  7. Desfolha, população de plantas e precocidade do milho afetam a incidência e a severidade de podridões de colmo Defoliation, plant population, and earliness of maize affect the incidence and severity of stalk rots

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    Luiz Eduardo Bassay Blum

    2003-10-01

    Full Text Available As relações entre fonte e dreno interferem sobre a ocorrência de podridões de colmo na cultura do milho (Zea mays. O estudo foi conduzido em Lages, SC, para avaliar o efeito da desfolha, população de plantas e híbridos sobre as podridões do colmo do milho. O delineamento experimental foi de blocos ao acaso com parcelas sub-subdivididas e três repetições. Os híbridos P32R21 (superprecoce, Premium (precoce e C333B (tardio foram testados sem desfolha e com 50% de desfolha no estágio de espigamento nas populações de 25.000, 50.000, 75.000 e 100.000 plantas ha-1. Avaliaram-se a incidência e a severidade das podridões do colmo causadas por Colletotrichum graminicola, Diplodia maydis e Fusarium moniliforme. O híbrido P32R21 foi o mais afetado pelos fungos causadores de podridões. Nos híbridos P32R21 e Premium, as plantas desfolhadas foram mais severamente infectadas pelos patógenos do que as intactas. O aumento da população de plantas aumentou a intensidade (incidência ou severidade de podridões de colmo nas plantas intactas e diminuiu a ocorrência nas desfolhadas.The relationship between source and sink interferes on maize (Zea mays stalk rot occurrence. This study was conducted in Lages, SC, Brazil, to evaluate the effect of defoliation, plant population, and hybrids on the intensity (incidence or severity of maize stalk rots. The experiment was set in a randomized complete block design (three replications with a split-split-plot arrangement. The hybrids P32R21 (very early, Premium (early and C333B (late were tested without defoliation and with 50% defoliation on ear formation stage at plant populations of 25,000, 50,000, 75,000, and 100,000 plants ha-1. The incidence and severity of Colletotrichum graminicola, Diplodia maydis and Fusarium moniliforme stalk rots were evaluated. The hybrid P32R21 was the most affected by stalk rots. Defoliation enhanced rots on P32R21 and Premium. Enhancements in plant population increased

  8. 早发型重度子痫前期发病及临床特点%The incidence of early onset severe preeclampsia and the clinical features

    Institute of Scientific and Technical Information of China (English)

    李玲; 王冬梅

    2009-01-01

    子痫前期(preeclampsia)是妊娠期特发的常见的并发症,严重威胁母儿健康,尤其是重度子痫子痫前期(severe pre-eclampsia),是导致孕产妇和国生儿病率及死亡率增加的常见原因之一.有学者将发病于32孕周前或34孕周前的重度子痫前期称为早发型重度子痫前期(early onset severe pre-eclampsia),在此后发病者称为晚发型重度子痫前期(late onset severe pre-eclampsia),本文就关于早发型重度子痫前期临床发病特点研究进展作一综述.

  9. Hepatotoxicity associated with agomelatine and other antidepressants: Disproportionality analysis using pooled pharmacovigilance data from the Uppsala Monitoring Centre.

    Science.gov (United States)

    Gahr, Maximilian; Zeiss, René; Lang, Dirk; Connemann, Bernhard J; Schönfeldt-Lecuona, Carlos

    2015-07-01

    Since its marketing approval, the attention to the hepatic side-effect profile of the antidepressant agomelatine (AGM) has gradually increased. Several cases of severe hepatotoxic adverse drug reactions (ADR) have been reported and the European Medicines Agency has released a safety warning regarding AGM-associated hepatotoxicity. However, there are insufficient data for an adequate safety assessment of AGM-related hepatotoxicity. Therefore, we performed a quantitative signal detection analysis using pharmacovigilance data from the Uppsala Monitoring Centre from the WHO that records ADR data from worldwide sources; we calculated reporting odds ratios (ROR) as measures for disproportionality within a case/non-case approach for AGM and several other antidepressants. AGM was statistically associated with an increased risk of hepatotoxicity (ROR 6.4 [95%CI 5.7-7.2]) as well as both positive controls: amineptine (ROR 38.4 [95%CI 33.8-43.6]) and nefazodone (ROR 3.2 [95%CI 3.0-3.5]). Following amineptine, AGM was associated with the second highest ROR, followed by tianeptine (ROR 4.4 [95%CI 3.6-5.3]), mianserin (ROR 3.6 [95%CI 3.3-3.9]), and nefazodone. These results support the hypothesis that AGM is associated with relevant hepatotoxicity. However, the used data and applied method do not allow a quantitative evaluation of hepatotoxicity or assessment of substance-specific differences regarding the extent of hepatotoxicity. © 2015, The American College of Clinical Pharmacology.

  10. Hepatotoxicity induced by greater celandine (Chelidonium majus L.): a review of the literature.

    Science.gov (United States)

    Pantano, F; Mannocchi, G; Marinelli, E; Gentili, S; Graziano, S; Busardò, F P; di Luca, N M

    2017-03-01

    The available literature assessing Chelidonium majus L. (CM) hepatotoxicity potential, and its risk to benefit assessment has been reviewed in this paper. Identification of significant scientific literature was performed via the following research databases: Cochrane Central, Google Scholar, EMBASE, Medline, Science Direct, Scopus, Web of Science, using the following keywords: "Chelidonium majus", "greater celandine", "Hepatotoxicity", "Liver" "Injury", "Toxicity" individually investigated and then again in association. CM named also greater celandine, swallow-wort, or bai-qu-cai (Chinese), has been used for a long time in traditional Chinese medicine and phytotherapy. Its extracts have been claimed to display a wide variety of biological activities: antimicrobial, anti-inflammatory, spasmolytic, antineoplastic, hepatoprotective, and analgesic. Moreover, herbal medicine suggests this plant have numerous additional effects which have not yet been scientifically evaluated, such as antitussive, diuretic, and eye-regenerative. However, despite its claimed hepatoprotective effects, several hepatotoxicity cases have been reported to be probably or highly probably connected with CM exposure, after their evaluation through liver-targeted causality assessment methods. CM hepatotoxicity has been defined as a distinct form of herb-induced liver injury (HILI), due to an idiosyncratic reaction of the metabolic type. This evidence has to be considered in relationship with the absence of considerable benefits of CM therapy. Therefore, the risk to benefit ratio of the use of herbal products containing greater celandine can actually be considered as negative.

  11. Hepatoprotective Activity of Herbal Preparation (Hp-4 against Alcohol Induced Hepatotoxicity in Mice

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    P. Padmanabhan

    2014-03-01

    Full Text Available Free radicals include both Reactive Oxygen Species (ROS and Reactive Nitrogen Species (RNS.When free radicals are produced in a regulated manner in a healthy human body it is scavenged efficiently by antioxidant defense system. But excess generation of pro-oxidants by continuous chain reaction in the form of ROS and RNS cause several human diseases. The shift of the balance in the favour of pro-oxidants results in a condition called “oxidative stress”. Alcohol is primarily metabolized in the liver to generate ROS and RNS, leading to diseases such as cirrhosis, fatty liver and chronic hepatitis. Alcohol induced damage is associated with oxidative stress. The excess generation of prooxidants and reduced antioxidant levels provide an effective model of Hepatotoxicity which is noteworthy. Recent trend is to discover polyherbal formulation of medicinal plants which have hepatoprotective function. In the present study 80% alcoholic extract of leaves of Aloe vera, Bacopa monniera, Moringa oleifera and rhizome of Zingiber officinale were utilized to prepare Herbal Preparation or HP-4.Further the hepatoprotective effects of HP-4 was tested in alcohol induced Hepatotoxicity in mice. Silymarin is a well known hepatoprotective drug was used as a standard for comparison. Biochemical and histopathological studies provided ample evidence that HP-4 provided a hepatoprotective role in alcohol induced hepatotoxicity which was comparable to drug Silymarin. The presence of phytochemicals in HP-4 provided a synergistic, supra-additive and co-operative effects in the hepatoprotective function in alcohol induced hepatotoxicity mice model.

  12. Hepatoprotective activity of Eclipta alba against carbon tetrachloride-induced hepatotoxicity in albino rats

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    Ravindra S. Beedimani

    2015-06-01

    Conclusion: The results of the study confirmed the hepatoprotective activity of aqueous extracts of E. alba at doses of 250 mg/kg and 500 mg/kg against CCl4 induced hepatotoxicity in rats. However, the dose adjustments may be necessary to optimize the similar hepatoprotective efficacy in clinical settings. [Int J Basic Clin Pharmacol 2015; 4(3.000: 404-409

  13. Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis.

    Science.gov (United States)

    Ali, Nemat; Rashid, Summya; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2014-01-01

    Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX-induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl-2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done.

  14. The protective effect of intraperitoneal medical ozone preconditioning and treatment on hepatotoxicity induced by methotrexate.

    Science.gov (United States)

    Aslaner, Arif; Çakır, Tuğrul; Çelik, Betül; Doğan, Uğur; Akyüz, Cebrail; Baştürk, Ahmet; Polat, Cemal; Gündüz, Umut; Mayir, Burhan; Şehirli, Ahmet Özer

    2015-01-01

    The aim of this study is to determine the effects of medical ozone preconditioning and treatment on the methotrexate acute induced hepatotoxicity in rats that has not reports elsewhere. Eighteen rats were randomly assigned into three equal groups; control, Mtx and Mtx with ozone. Hepatotoxicity was performed with a single dose of 20 mg/kg Mtx to group 2 and group 3 at the fifteenth day. The medical ozone preconditioning was administered intraperitonealy in group 3 for fifteen days and more five days after inducing Mtx. The other rats of the group 1 and 2 received saline injection. At the twentyfirst day the blood and the liver tissue samples were obtained to measure the levels of liver enzymes ALT and AST, proinflamatory cytokines TNF-α, IL-1β, malondialdehyde, glutathione and myeloperoxidase. And the histolopatological examination was evaluated for injury score. In our study Mtx administration caused a significant increase on the liver enzymes ALT and AST, the tissue MDA and MPO activity and significant decrease in the tissue GSH. Moreover the both pro-inflammatory cytokines were significantly increased in the Mtx group. Medical ozone preconditioning and treatment reversed all these biochemical parameters and histopathological changes of the hepatotoxicity induced by Mtx. We conclude that medical ozone ameliorates Mtx induced hepatotoxicity in rats.

  15. Hepatoprotective effect of Origanum vulgare in Wistar rats against carbon tetrachloride-induced hepatotoxicity.

    Science.gov (United States)

    Sikander, Mohammad; Malik, Shabnam; Parveen, Kehkashan; Ahmad, Maqsood; Yadav, Deepak; Hafeez, Zubair Bin; Bansal, Manish

    2013-04-01

    The effect of an aqueous extract of Origanum vulgare (OV) leaves extract on CCl4-induced hepatotoxicity was investigated in normal and hepatotoxic rats. To evaluate the hepatoprotective activity of OV, rats were divided into six groups: control group, O. vulgare group, carbon tetrachloride (CCl4; 2 ml/kg body weight) group, and three treatment groups that received CCl4 and OV at doses of 50, 100, 150 mg/kg body weight orally for 15 days. Alanine amino transferase (ALT), alkaline phosphatase (ALP), and aspartate amino transferase (AST) in serum, lipid peroxide (LPO), GST, CAT, SOD, GPx, GR, and GSH in liver tissue were estimated to assess liver function. CCl4 administration led to pathological and biochemical evidence of liver injury as compared to controls. OV administration led to significant protection against CCl4-induced hepatotoxicity in dose-dependent manner, maximum activity was found in CCl4 + OV3 (150 mg/kg body weight) groups and changes in the hepatocytes were confirmed through histopathological analysis of liver tissues. It was also associated with significantly lower serum ALT, ALP, and AST levels, higher GST, CAT, SOD, GPx, GR, and GSH level in liver tissue. The level of LPO also decreases significantly after the administration of OV leaves extract. The biochemical observations were supplemented with histopathological examination of rat liver sections. Thus, the study suggests O. vulgare showed protective activity against CCl4-induced hepatotoxicity in Wistar rats and might be beneficial for the liver toxicity.

  16. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats

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    M. Kasi Reddy

    2017-01-01

    Full Text Available Aim: The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN in comparison to silymarin (SLM against acetaminophen (APAP-induced hepatotoxicity in rats. Materials and Methods: Male Wistar albino rats (n=24 of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity, and 15 (at the end of treatment. Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Results: Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. Conclusion: The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

  17. Screening of herbal components for attenuating amiodarone-induced hepatotoxicity on gel-entrapped rat hepatocytes.

    Science.gov (United States)

    Deng, Xudong; Shen, Chong; Meng, Qin

    2014-01-01

    Amiodarone (AMD) is a hepatotoxic drug that has been widely used as a class III antiarrhythmic drug. Because, to date, only a few kinds of protectants are able to reduce AMD hepatotoxicity, this article utilized gel-entrapped rat hepatocytes to screen effective protectants from a series of herbal compounds for their effects against AMD-induced toxicity. Herbal compounds, including matrine, silibinin, glycyrrhizic acid, schisandrin B, epigallocatechin gallate and anisodamine, were cotreated with AMD to assess their protective effect, whereas vitamin E, which has been shown to be protective in rats, was selected as a control. It was found that vitamin E, as with its function in rats, provided the best protection in gel-entrapped rat hepatocytes, whereas silibinin, a major component of silymarin, could largely reduce AMD-induced hepatotoxicity, performing a similar function as silymarin in rats. The results illustrated that gel-entrapped hepatocytes may reflect the protective effects of drugs and serve as a reliable model for screening hepatoprotectants. Moreover, matrine, a widely used monomer of the traditional Chinese medicine, Sophora flavescens, for treatment of arrhythmia, was evidenced to show some effective protections against AMD hepatotoxicity. Taken together, gel-entrapped rat hepatocytes may provide a platform for screening effective candidates from the herbal component library.

  18. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats

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    Issam Salouege

    2014-01-01

    Conclusion: We have evaluated the protective effect of trimetazidine on an animal model of doxorubicin-induced cardiotoxicity and hepatotoxicity. The evaluation of these effects were assessed by several means; tissular distribution of doxorubicin, histological examination, assessment of liver function, and EF LV by scintigraphy that characterizes the originality of this study.

  19. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-12-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity.

  20. Caffeic acid, a phyto polyphenol mitigates fluoride induced hepatotoxicity in rats: A possible mechanism.

    Science.gov (United States)

    Kanagaraj, Vishnu Vignesh; Panneerselvam, Lakshmikanthan; Govindarajan, Vimal; Ameeramja, Jaishabanu; Perumal, Ekambaram

    2015-01-01

    Fluoride induced hepatotoxicity has been extensively studied in both humans and animals. However, the mechanism underlying in the hepatotoxicity of experimental fluorosis remains obscure. The severity of fluoride toxicity was reduced by oral administration of certain plant derived antioxidants. Caffeic acid (CA) a polyphenolic compound has diverse range of pharmacological activity in the biological system. Therefore, the present study was aimed to investigate the protective mechanism of CA, against fluoride induced hepatotoxicity in rats. The rats were treated with 300 ppm of NaF via drinking water ad libitum alone and in combination with CA at a dose of 50 mg/kg daily for 30 days by oral intubation. CA treatment significantly prevented fluoride induced hepatic damage as evident from the histopathological studies and declined levels of serum fluoride and liver marker enzymes. A significant decrease in the levels of enzymatic (SOD2, CAT, GPx, and GSTpi class) and nonenzymatic (GSH and Vitamin C) antioxidants along with increased ROS, lipid peroxidation, protein carbonyl content, and nitrate levels by fluoride were also prevented in these groups. In addition, CA inhibits fluoride induced apoptosis by altering the Bax and caspase-3p20 expressions. Further, fluoride induced upregulation of Nox4, p38α MAPK, Hsp60, and downregulation of Hsp27 are the indicators for the detection of oxidative damage, apoptosis, and mitochondrial stress was also modulated by CA. These findings reveal that CA supplementation has a protective effect against fluoride induced hepatotoxicity in rats.

  1. Calcium transport, thiol status, and hepatotoxicity following N-nitrosodimethylamine exposure in mice

    Energy Technology Data Exchange (ETDEWEB)

    Reitman, F.A.; Berger, M.L.; Minnema, D.J.; Shertzer, H.G.

    1988-01-01

    The hepatotoxicant N-nitrosodimethylamine (NDMA) is presumed to exert toxicity through reactive metabolites. NDMA is similar in this respect to numerous other hepatotoxicants, for which hepatotoxicity is also associated with a rapid depletion of soluble and/or protein thiols, and an inhibition of calcium transport systems. The authors examined the hypothesis that hepatotoxicity for NDMA is preceded by thiol depletion and/or inhibition of calcium transport in isolated liver subcellular fractions. Centrizonal liver necrosis in mice was evident at 24 but not at 12 h subsequent to intraperitoneal administration of 40 mg NDMA/kg. Hepatotoxicity was not preceded by depletion of liver protein-free sulfhydryls, nor by protein sulfhydryl depletion in liver whole homogenate, microsomal, or plasma membrane fractions. NDMA-mediated toxicity was also not preceded by inhibition of calcium uptake capability by microsomal, mitochondrial, or plasma membrane fractions. In contrast, carbon tetrachloride produced the expected rapid decrease in microsomal calcium uptake capability, followed by a centrizonal necrosis that was maximal at about 24 h. These studies suggest that the mechanism of NDMA hepatotoxicity may differ from that of a number of other hepatotoxicants (e.g., carbon tetrachloride, acetaminophen, bromobenzene) for which toxicity is also mediated through reactive metabolites.

  2. Allopurinol and 5-aminosalicylic acid influence thiopurine-induced hepatotoxicity in vitro

    NARCIS (Netherlands)

    Broekman, M.M.T.J.; Roelofs, H.M.; Wong, D.R.; Kerstholt, M.; Leijten, A.; Hoentjen, F.; Peters, W.H.M.; Wanten, G.J.A.; Jong, D.J. de

    2015-01-01

    INTRODUCTION: The use of thiopurines is frequently accompanied by hepatotoxicity. Studies on hepatocyte cultures showed a time- and dose-dependent increase of thiopurine toxicity. 5-Aminosalicylic acid (5-ASA) and allopurinol can influence thiopurine metabolism; however, it is unknown whether this a

  3. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

    Institute of Scientific and Technical Information of China (English)

    Raúl J Andrade; Mercedes Robles; Alejandra Fernández-Casta(n)er; Susana López-Ortega; M Carmen López-Vega; M Isabel Lucena

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and postcommercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice.To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be finetuned as further information is collected.

  4. Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Jung-Chun Lin

    Full Text Available Carbon tetrachloride (CCl4 is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2, and tumor necrosis factor-α (TNF-α], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response.

  5. Hepatotoxicity in HIV-infected children and adolescents on antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Ana Cecília Montes Gil

    Full Text Available CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART. We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6, A (29, B (78 and C (39. Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN, grade 2 (5.0-9.9 times ULN, grade 3 (10.0-15.0 times ULN and grade 4 (> 15.0 times ULN. To assess hepatotoxicity risk factors, odds ratios (OR and adjusted odds ratios (aOR for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152 patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI, 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85 and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25. No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.

  6. Herbal hepatotoxicity in traditional and modern medicine: Actual key issues and new encouraging steps

    Directory of Open Access Journals (Sweden)

    Rolf eTeschke

    2015-04-01

    Full Text Available Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  7. Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

    Institute of Scientific and Technical Information of China (English)

    Yuichi Yamazaki; Satoru Kakizaki; Norio Horiguchi; Hitoshi Takagi; Masatomo Mori; Masahiko Negishi

    2005-01-01

    AIM: To investigate the precise roles of CAR in CCl4-induced acute hepatotoxicity.METHODS: To prepare an acute liver injury model, CCl4 was intraperitoneally injected in CAR+/+ and CAR-/- mice.RESULTS: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR+/+ mice. On the other hand,androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR+/+ but not in CAR-/- mice. Thus, CAR activation caused CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR+/+ and CAR-/- mice. However, the expression of other CCl4-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3A11 in the presence of activator or inhibitor.CONCLUSION: The nuclear receptor CAR modulates CCl4-induced liver injury via induction of CCl4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drugdrug interaction even though such drugs themselves are not hepatotoxic.

  8. Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation.

    Science.gov (United States)

    Dalaklioglu, S; Genc, G E; Aksoy, N H; Akcit, F; Gumuslu, S

    2013-06-01

    Hepatotoxicity is one of the major complications of methotrexate (MTX) therapy. This study was carried out to evaluate the possible protective effect of resveratrol (trans-3,5,4'-trihydroxystilbene, RVT) against MTX-induced hepatotoxicity. Rats were randomly divided into four groups as control, MTX treated (7 mg/kg/day, intraperitoneally (i.p.), once daily for 3 consecutive days), MTX + RVT treated (20 mg/kg/day, i.p.), and RVT treated. First dose of RVT was administrated 3 days before the MTX injection and continued for 3 days. Histopathology of liver was evaluated by light microscopy. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. The levels of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and activities of hepatic antioxidant enzymes such as catalase (CAT) and glutathione-S-transferase (GST) were used to analyze the oxidative stress-mediated lipid peroxidation in liver sections. Our results showed that MTX administration significantly increased ALT, ASP, and ALP levels. TBARS, CAT, and GST levels were also markedly increased in liver after MTX administration. RVT treatment significantly prevented MTX-induced hepatotoxicity, as indicated by AST, ALT, and ALP levels and liver histopathology. Moreover, administration of RVT significantly decreased the elevated levels of TBARS and activities of CAT and GST in the liver compared to MTX-treated group. These results revealed that RVT may have a protective effect against MTX-induced hepatotoxicity by inhibiting oxidative stress-mediated lipid peroxidation. Consequently, RVT treatment might be a promising strategy against MTX-induced hepatotoxicity.

  9. 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.

  10. A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human.

    Science.gov (United States)

    Tamai, Satoshi; Iguchi, Takuma; Niino, Noriyo; Mikamoto, Kei; Sakurai, Ken; Sayama, Ayako; Shimoda, Hitomi; Takasaki, Wataru; Mori, Kazuhiko

    2017-01-01

    Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

  11. CYP2E1 mediated isoniazid-induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Jiang YUE; Ren-xiu PENG; Jing YANG; Rui KONG; Juan LIU

    2004-01-01

    AIM: To investigate the role of CYP2E1 in isoniazid (INH)-induced hepatotoxicity and the influence of rifampicin (RFP) on INH-induced liver injury. METHODS: Rats were treated with INH alone (100 mg/kg, ip) or co-administered with RFP (100 mg/kg, ig) for 10 d and 21 d. Hepatotoxicity was assayed by plasma enzymes (sALT, sAST) and histopathological examinations. Hepatic CYP2E1 activity was measured by aniline hydroxylase (ANH), and CYP2E1 mRNA expression was determined by RT-PCR. Plasma hydrazine concentration was determined by RP-HPLC.RESULTS: For a 10 d INH-treatment, hepatic CYP2E1 level was increased to 3.7-fold over the control; liver impairment appeared after 21 d treatment, while CYP2E1 and plasma hydrazine were, respectively, increased to 4.6-fold and 1.7-fold. However, in INH-RFP group for 10 d, CYP2E1 and plasma hydrazine were, respectively,decreased by 13 % and 18 % over INH group; similarly, hepatic injury is equal to INH group appeared after 21 d,and CYP2E1 was further decreased by 26 %. Correlation analysis showed that sALT had a positive correlation with plasma hydrazine and with CYP2E1 activity; CYP2E1 activity was also markedly correlated with plasma hydrazine.And compared with control, there is no difference in changes of CYP2E1 mRNA expression in INH and INH-RFP treatment for 21 d. CONCLUSION: The metabolite of INH, hydrazine, plays an important role in INH-induced hepatotoxicity in rats. The induction of CYP2E1 by hydrazine is involved in the hepatotoxicity of INH. RFP does not exacerbate INH-induced hepatotoxicity in short term, which relates to down-regulation of CYP2E1.

  12. 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.

  13. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats.

    Science.gov (United States)

    Hafez, Heba M; Ibrahim, Mohamed A; Ibrahim, Salwa A; Amin, Entesar F; Goma, Wafaey; Abdelrahman, Aly M

    2015-12-05

    Methotrexate (MTX), a chemotherapeutic and immunosuppressant drug, is generally well-tolerated by most patients. However, its cytotoxic nature contributes to life-threatening side effects including hepatotoxicity and nephrotoxicity. The present study investigated the possible role of tumor necrosis factor-alpha (TNF-α) inhibitor, etanercept and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine, on MTX-induced hepatotoxicity and nephrotoxicity in rats. Rats were divided into 7 groups: control group, etanercept group, aminoguanidine group, MTX group, MTX+etanercept group, MTX+aminoguanidine group, and MTX+etanercept+aminoguanidine group. MTX caused hepatotoxicity and nephrotoxicity as evidenced biochemically by significant increase in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine, respectively as well as by histopathological changes. Such effects were associated with significant changes in oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase, and glutathione (GSH)) as well as by upregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. Etanercept and aminoguanidine significantly attenuated MTX-hepatotoxicity and nephrotoxicity. The protective effect of either agent was associated with significant improvement in oxidative stress parameters as well as by downregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. The study suggested that inhibitors of either TNF-α and/or iNOS have protective effect in MTX-induced hepatotoxicity and nephrotoxicity. The protective effect of either agent relies, at least partially, on their antioxidant effects and decreased TNF-α, iNOS, and caspase-3 expressions.

  14. Efficacy of Rosmarinus officinalis leaves extract against cyclophosphamide-induced hepatotoxicity.

    Science.gov (United States)

    El-Naggar, Sabry A; Abdel-Farid, Ibrahim B; Germoush, Mousa O; Elgebaly, Hassan A; Alm-Eldeen, Abeer A

    2016-10-01

    Context Cyclophosphamide (CTX) is used to treat different cancer types, although it causes severe hepatotoxicity due to its oxidative stress effect. Rosmarinus officinalis, L. (Lamiaceae) has a therapeutic potential against hepatotoxicity due to its antioxidant activity. Objective The objective of this study is to investigate the phytochemical analysis of the methanol extract of Rosmarinus officianalis leaves (MEROL) and its efficacy against CTX-induced hepatotoxicity. Materials and methods The phytochemical analyses were assessed spectrophotometericaly. To assess the MEROL efficacy, 72 Swiss albino mice were divided into six groups. Group 1 was control, groups 2 and 3 included mice which were injected intraperitoneally (i.p.) with 100 or 200 mg/kg of MEROL at days 1, 4, 7, 10, 13 and 16; group 4 was injected (i.p.) with CTX (200 mg/kg) at day 17, groups 5 and 6 were injected (i.p.) with MEROL as groups 3 and 4 followed by 200 mg/kg CTX at day 17, respectively. At day 22, six mice from each group were sacrificed and the others were sacrificed at day 37. Results MEROL has a high content of total phenolics, saponins, total antioxidant capacity and DPPH radical scavenging activity. The median lethal dose (LD50) value of MEROL was 4.125 g/kg b.w. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 55 μg/mL. Pretreatment with 100 mg/kg MEROL for 16 d ameliorated CTX-induced hepatotoxicity represented in lowering the levels of the aspartate aminotransferase (AST) and lipid profile and minimizing the histological damage. Conclusions Pretreatment with 100 mg/kg b.w. MEROL mitigated CTX-induced hepatotoxicity due to its antioxidant activity.

  15. Survival advantage of peritoneal dialysis relative to hemodialysis in the early period of incident dialysis patients: a nationwide prospective propensity-matched study in Korea.

    Directory of Open Access Journals (Sweden)

    Ji-Young Choi

    Full Text Available BACKGROUND: The impact of dialysis modality on survival is still somewhat controversial. Given possible differences in patients' characteristics and the cause and rate of death in different countries, the issue needs to be evaluated in Korean cohorts. METHODS: A nationwide prospective observational cohort study (NCT00931970 was performed to compare survival between peritoneal dialysis (PD and hemodialysis (HD. A total of 1,060 end-stage renal disease patients in Korea who began dialysis between September 1, 2008 and June 30, 2011 were followed through December 31, 2011. RESULTS: The patients (PD, 30.6%; HD, 69.4% were followed up for 16.3 ± 7.9 months. PD patients were significantly younger, less likely to be diabetic, with lower body mass index, and larger urinary volume than HD patients. Infection was the most common cause of death. Multivariate Cox regression with the entire cohort revealed that PD tended to be associated with a lower risk of death compared to HD [hazard ratio (HR 0.63, 95% confidence interval (CI 0.36-1.08]. In propensity score matched pairs (n=278 in each modality, cumulative survival probabilities for PD and HD patients were 96.9% and 94.1% at 12 months (P=0.152 and 94.3% and 87.6% at 24 months (P=0.022, respectively. Patients on PD had a 51% lower risk of death compared to those on HD (HR 0.49, 95% CI 0.25-0.97. CONCLUSIONS: PD exhibits superior survival to HD in the early period of dialysis, even after adjusting for differences in the patients' characteristics between the two modalities. Notably, the most common cause of death was infection in this Korean cohort.

  16. Effect of Lagenaria siceraria fruit extract (Bottle gourd on hepatotoxicity induced by antitubercular drugs in albino rats

    Directory of Open Access Journals (Sweden)

    Satyajeet K. Funde

    2013-12-01

    Conclusion: Ethanolic extract of Lagenaria siceraria fruit possesses significant hepatoprotective and antioxidant activity in antitubercular drugs induced hepatotoxicity. [Int J Basic Clin Pharmacol 2013; 2(6.000: 728-734

  17. GENE EXPRESSION PROFILING IN THE LIVER OF CD-1 MICE TO CHARACTERIZE THE HEPATOTOXICITY OF TRIAZOLE FUNGICIDES

    Science.gov (United States)

    Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and ...

  18. Modulatory effects of dietary inclusion of garlic (Allium sativum on gentamycin–induced hepatotoxicity and oxidative stress in rats

    Directory of Open Access Journals (Sweden)

    Adedayo O. Ademiluyi

    2013-06-01

    Conclusions: These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  19. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats

    OpenAIRE

    Akbulut, Sami; Elbe, Hulya; Eris, Cengiz; Dogan, Zumrut; Toprak, Gulten; Otan, Emrah; Erdemli, Erman; Turkoz, Yusuf

    2014-01-01

    AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.

  20. Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats.

    Science.gov (United States)

    Singh, Brijesh Kumar; Tripathi, Madhulika; Chaudhari, Bhushan P; Pandey, Pramod K; Kakkar, Poonam

    2012-01-01

    Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; Pterpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.

  1. 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...

  2. A study of effect of Nigella sativa oil in paracetamol induced hepatotoxicity in albino rats

    OpenAIRE

    Manik S. Ghadlinge; Jugalkishor B. Jaju; Rakhamaji D. Chandane; Rakesh R. Jadhav; Rama R. Bhosle

    2014-01-01

    Background: Acetaminophen (paracetamol) toxicity is a common cause of drug induced hepatotoxicity in children and adults. Specific treatment of paracetamol induced hepatitis is available in the form of N acetylcysteine only. Nigella sativa (NS) is used for the treatment of various ailments. Many studies have shown that NS plant has hepatoprotective potential. Hence, this study study was carried out to explore the prophylactic and therapeutic effect of NS oil against hepatotoxicity induced by ...

  3. Is the global rise of asthma an early impact of anthropogenic climate change? Será o crescimento mundial de incidência da asma um impacto antecipado de mudanças climáticas antropogênicas?

    Directory of Open Access Journals (Sweden)

    Paul John Beggs

    2006-09-01

    Full Text Available The increase in asthma incidence, prevalence, and morbidity over recent decades presents a significant challenge to public health. Pollen is an important trigger of some types of asthma, and both pollen quantity and season depend on climatic and meteorological variables. Over the same period as the global rise in asthma, there have been considerable increases in atmospheric carbon dioxide concentration and global average surface temperature. We hypothesize anthropogenic climate change as a plausible contributor to the rise in asthma. Greater concentrations of carbon dioxide and higher temperatures may increase pollen quantity and induce longer pollen seasons. Pollen allergenicity can also increase as a result of these changes in climate. Exposure in early life to a more allergenic environment may also provoke the development of other atopic conditions, such as eczema and allergic rhinitis. Although the etiology of asthma is complex, the recent global rise in asthma could be an early health effect of anthropogenic climate change.O crescimento na incidência, prevalência e morbidade da asma durante as recentes décadas representa importante desafio para a saúde pública. Pólen é um importante desencadeador de alguns tipos de asma e tanto a sua quantidade como as especificidades das estações em que eles mais se disseminam dependem de variáveis climáticas e meteorológicas. No mesmo período em que se observa o incremento na incidência da asma houve considerável crescimento de concentração de dióxido de carbono na atmosfera e aumento da média de temperatura da superfície da terra. Nossa hipótese é a de que as mudanças antropogênicas do clima constituem um fator plausível para o incremento da incidência da asma. Maiores concentrações de dióxido de carbono e elevadas temperaturas podem aumentar a quantidade de pólen e induzir o aumento de variações climáticas que facilitam sua dispersão. Alergias a pólen podem aumentar

  4. Possible protective role of pregnenolone-16 alpha-carbonitrile in lithocholic acid-induced hepatotoxicity through enhanced hepatic lipogenesis.

    Science.gov (United States)

    Miyata, Masaaki; Nomoto, Masahiro; Sotodate, Fumiaki; Mizuki, Tomohiro; Hori, Wataru; Nagayasu, Miho; Yokokawa, Shinya; Ninomiya, Shin-ichi; Yamazoe, Yasushi

    2010-06-25

    Lithocholic acid (LCA) feeding causes both liver parenchymal and cholestatic damages in experimental animals. Although pregnenolone-16 alpha-carbonitrile (PCN)-mediated protection against LCA-induced hepatocyte injury may be explained by induction of drug metabolizing enzymes, the protection from the delayed cholestasis remains incompletely understood. Thus, the PCN-mediated protective mechanism has been studied from the point of modification of lipid metabolism. At an early stage of LCA feeding, an imbalance of biliary bile acid and phospholipid excretion was observed. Co-treatment with PCN reversed the increase in serum alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) activities and hepatic hydrophobic bile acid levels. LCA feeding decreased hepatic mRNA levels of several fatty acid- and phospholipid-related genes before elevation of serum ALT and ALP activities. On the other hand, PCN co-treatment reversed the decrease in the mRNA levels and hepatic levels of phospholipids, triglycerides and free fatty acids. PCN co-treatment also reversed the decrease in biliary phospholipid output in LCA-fed mice. Treatment with PCN alone increased hepatic phospholipid, triglyceride and free fatty acid concentrations. Hepatic fatty acid and phosphatidylcholine synthetic activities increased in mice treated with PCN alone or PCN and LCA, compared to control mice, whereas these activities decreased in LCA-fed mice. These results suggest the possibility that PCN-mediated stimulation of lipogenesis contributes to the protection from lithocholic acid-induced hepatotoxicity.

  5. Hypothyroidism incidence in and around pregnancy

    DEFF Research Database (Denmark)

    Andersen, Stine Linding; Carle, Allan; Olsen, Jørn;

    2016-01-01

    -2010 (overall IR 92.3/100,000/year) and 1,572 women developed hypothyroidism in the period from 2 years before to 2 years after birth of the first child birth in the study period. The incidence of hypothyroidism decreased during the pregnancy (incidence rate ratio (IRR) versus overall IR in the rest...... of hypothyroidism in and around pregnancy. The incidence declined during pregnancy followed by a sharp increase postpartum. Notably, hypothyroidism as opposed to hyperthyroidism showed no early pregnancy peak....

  6. To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory

    Science.gov (United States)

    Liu, Hongjie; Li, Tianhao; Zhan, Sha; Pan, Meilan; Ma, Zhiguo; Li, Chenghua

    2016-01-01

    Aims. To establish a logistic regression (LR) prediction model for hepatotoxicity of Chinese herbal medicines (HMs) based on traditional Chinese medicine (TCM) theory and to provide a statistical basis for predicting hepatotoxicity of HMs. Methods. The correlations of hepatotoxic and nonhepatotoxic Chinese HMs with four properties, five flavors, and channel tropism were analyzed with chi-square test for two-way unordered categorical data. LR prediction model was established and the accuracy of the prediction by this model was evaluated. Results. The hepatotoxic and nonhepatotoxic Chinese HMs were related with four properties (p flavors (p 0.05). There were totally 12 variables from four properties and five flavors for the LR. Four variables, warm and neutral of the four properties and pungent and salty of five flavors, were selected to establish the LR prediction model, with the cutoff value being 0.204. Conclusions. Warm and neutral of the four properties and pungent and salty of five flavors were the variables to affect the hepatotoxicity. Based on such results, the established LR prediction model had some predictive power for hepatotoxicity of Chinese HMs. PMID:27656240

  7. To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory.

    Science.gov (United States)

    Liu, Hongjie; Li, Tianhao; Chen, Lingxiu; Zhan, Sha; Pan, Meilan; Ma, Zhiguo; Li, Chenghua; Zhang, Zhe

    2016-01-01

    Aims. To establish a logistic regression (LR) prediction model for hepatotoxicity of Chinese herbal medicines (HMs) based on traditional Chinese medicine (TCM) theory and to provide a statistical basis for predicting hepatotoxicity of HMs. Methods. The correlations of hepatotoxic and nonhepatotoxic Chinese HMs with four properties, five flavors, and channel tropism were analyzed with chi-square test for two-way unordered categorical data. LR prediction model was established and the accuracy of the prediction by this model was evaluated. Results. The hepatotoxic and nonhepatotoxic Chinese HMs were related with four properties (p 0.05). There were totally 12 variables from four properties and five flavors for the LR. Four variables, warm and neutral of the four properties and pungent and salty of five flavors, were selected to establish the LR prediction model, with the cutoff value being 0.204. Conclusions. Warm and neutral of the four properties and pungent and salty of five flavors were the variables to affect the hepatotoxicity. Based on such results, the established LR prediction model had some predictive power for hepatotoxicity of Chinese HMs.

  8. Mechanisms of halocarbon-induced hepatotoxicity in the mouse. Final report, 1 April 1989-31 March 1990

    Energy Technology Data Exchange (ETDEWEB)

    Smith, M.A.; Gandy, J.

    1990-05-30

    Previous studies have shown that high-dose exposure to the halocarbon bromobenzene resulted in hepatotoxicity and lethality that was substantially diminished by co-treatment with the alpha-adrenergic antagonist, phentolamine. The purpose of this study was to compare the hepatoxicity resulting from exposure to the related halocarbons, chlorobenzene, bromobenzene and iodobenzene, and to determine whether the resulting hepatotoxicity could be antagonized by phentolamine. Halobenzene-induced changes in hepatic glutathione concentrations and serum concentrations of catecholamines were determined as possible mediators of hepatic damage. Iodobenzene administration resulted in toxicities similar to that seen with bromobenzene. Administration of either iodobenzene or bromobenzene resulted in hepatotoxicity as measured by serum alanine aminotransferase (ALT) activity about 1000 fold above normal values. Chlorobenzene was also capable of producing hepatotoxicity, but not to the same extent as iodobenzene. Chlorobenzene-induced hepatotoxicity resulted in serum ALT values approximately 100 fold above normals. Chlorobenzene, bromobenzene or iodobenzene administration significantly decreased hepatic glutathione concentrations to approximately 20% of control concentrations. Phentolamine co-treatments significantly decreased serum ALT activity for all three compounds suggesting that hepatotoxicity might be mediated through an alpha-adrenergic system.

  9. 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...

  10. Protective role of food supplement Spirulina fusiformis in chemical induced hepatotoxicity: A Bromobenzene model in rats

    Directory of Open Access Journals (Sweden)

    Evan Prince Sabina

    2014-03-01

    Full Text Available The present study evaluated the efficacy of Spirulina fusiformis in protecting against chemical induced hepatotoxicity in rats using Bromobenzene as the candidate toxin. A single oral dose of bromobenzene (BB (10mmol/kg b.w. resulted in significant (p< 0.05 decrease in antioxidant levels (catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidese, total reduced glutathione and total protein, and significant (p< 0.05 increase in the levels of serum bilirubin, liver enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase indicating the induction of hepatotoxicity. Spirulina fusiformis (400 mg/kg b.w was orally administered for 8 days prior to the administration of BB and was seen to protect the above parameters from significant changes upon challenge with bromobenzene. This was also confirmed by the histological examination of liver tissues after sacrifice. The protective effect of Spirulina fusiformis was comparable to that of the standard hepatoprotective drug sylimarin.

  11. Hepatotoxic effect of 1-bromopropane and its conjugation with glutathione in male ICR mice.

    Science.gov (United States)

    Lee, Sang Kyu; Jo, Sang Wook; Jeon, Tae Won; Jun, In Hye; Jin, Chun Hua; Kim, Ghee Hwan; Lee, Dong Ju; Kim, Tae-Oh; Lee, Eung-Seok; Jeong, Tae Cheon

    2005-10-01

    The hepatotoxic effects of 1-bromopropane (1-BP) and its conjugation with glutathione were investigated in male ICR mice. A single dose (1000 mg/kg, po) of 1-BP in corn oil to mice significantly increased serum activities of alanine aminotransferase and aspartate aminotransferase. Glutathione (GSH) content was dose-dependently reduced in liver homogenates 12 h after 1-BP treatment. In addition, 1-BP treatment dose-dependently increased levels of S-propyl GSH conjugate at 12 h after treatment, as measured by liquid chromatography-electrospray ionization tandem mass spectrometry. The GSH conjugate was maximally increased in liver at 6 h after 1-BP treatment (1000 mg/kg), with a parallel depletion of hepatic GSH content. Finally, 1-BP induced the production of malondialdehyde in liver. The present results suggest that 1-BP might cause hepatotoxicity, including lipid peroxidation via the depletion of GSH, due to the formation of GSH conjugates in male ICR mice.

  12. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

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    Mark I. Avigan

    2016-03-01

    Full Text Available In the United States (US, the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.

  13. HEPATOPROTECTIVE ACTIVITY OF ALSTONIA SCHOLARIS FRUITS AGAINST CARBON TETRACHLORIDE-INDUCED HEPATOTOXICITY IN RATS

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    K. RAVI SHANKAR, A. LAKSHMANA RAO, L. KALYANI

    2013-09-01

    Full Text Available The hepatoprotective activity of ethanolic extract of fruits of Alstonia scholaris was evaluated by carbon tetrachloride (CCL4-induced hepatotoxicity in rats. The toxicant CCL4 was used to induce hepatotoxicity at a dose of 2 ml/kg as 1:1 mixture with olive oil. The ethanolic extract of fruits of Alstonia scholaris was administered in the dose of 150 and 300 mg/kg/day orally for 5 days. Silymarin (50 mg/kg was used as standard drug. The hepatoprotective effect of the ethanolic extract was evaluated by the assessment of biochemical parameters such as SGOT, SGPT, SALKP, total bilirubin and histopathological studies of the liver. Treatment of animals with the ethanolic extract significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver as indicated by lower levels of serum bilirubin as compared with the normal and silymarin treated groups.

  14. Protective effect of alcoholic extract of Entada pursaetha DC. against CCl4-induced hepatotoxicity in rats.

    Science.gov (United States)

    Gupta, Gaurav; More, Amar Sunil; Kumari, Rashmi Rekha; Lingaraju, Madhu Cholenahalli; Kumar, Dhirendra; Kumar, Dinesh; Mishra, Santosh Kumar; Tandan, Surender Kumar

    2014-03-01

    The alcoholic extract of stem of E. pursaetha (PSE, 30, 100, 300 mg/kg body weight, po for 7 days) showed hepatoprotective activity against CCl4 (2 mL/kg body weight, ip)-induced hepatotoxicity. The extract exhibited a significant dose-dependent hepatoprotective effect comparable to standard drug silymarin, by preventing increase in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, and total bilirubin, lactate dehydrogenase; by lowering hepatic levels of malonaldehyde, nitrate-nitrite, myeloperoxidase activity; enhancing activities of antioxidant enzymes, superoxide dismutase, catalase and increasing reduced glutathione levels in liver, which suggests the antioxidant property of PSE. Histopathological studies also supported the above biochemical parameters. The results suggested that alcoholic extract of E. pursaetha possesses significant hepatoprotective activity in CCl4-induced acute hepatotoxicity in rats and this is likely to be mediated through its antioxidant activities.

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

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    Daniela Rodrigues

    2012-12-01

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

  16. Enoxaparin-induced hepatotoxicity: an under-recognised complication of enoxaparin therapy.

    Science.gov (United States)

    Pivarnik, Katie Ann; Schiffman, Fred; Sullivan, James; Finn, Arkadiy

    2016-09-23

    Low-molecular-weight heparins including enoxaparin are commonly used for anticoagulation as prophylaxis and treatment for deep vein thrombosis (DVT). Prescribers of enoxaparin monitor for common side effects, such as bleeding and thrombocytopenia, but hepatotoxicity, a less common and under-reported adverse effect, may be overlooked. This report describes a case of enoxaparin-induced hepatotoxicity in a 57-year-old man who was started on the drug for a DVT. Within 3 days of taking enoxaparin, elevated transaminases were noted, and the drug was discontinued after 6 days. Similar to other published reports, the patient's transaminases peaked 1 day after discontinuation of the drug and then trended down to normal over 32 days.

  17. Protective effect of stem bark of Ceiba pentandra linn. against paracetamol-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Nirmal K Bairwa

    2010-01-01

    Full Text Available The present study reports protective activity of ethyl acetate fraction of methanol extract of stem bark of Ceiba pentandra against paracetamol-induced liver damage in rats. The ethyl acetate fraction (400 mg/kg was administered orally to the rats with hepatotoxicity induced by paracetamol (3 gm/kg. Silymarin (100 mg/kg was used as positive control. High performance thin layer chromatography (HPTLC fingerprinting of ethyl acetate fraction revealed presence of its major chemical constituents. A significant (P < 0.05 reduction in serum enzymes GOT (ALT, aspartate aminotransferase (AST, GPT alkaline phosphatase (ALP, total bilirubin content and histopathological screening in the rats treated gave indication that ethyl acetate fraction of methanolic extract of Ceiba pentandra possesses hepatoprotective potential against paracetamol-induced hepatotoxicity in rats.

  18. Hepatoprotective effect of leaves of aqueous ethanol extract of Cestrum nocturnum against paracetamol-induced hepatotoxicity

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    M. Imran Qadir

    2014-06-01

    Full Text Available The hepatoprotective activities of Cestrum nocturnum (Queen of Night was evaluated against the paracetamol induced hepatotoxicity in the mice. Aqueous ethanol (30:70 extract of plant was obtained by maceration. Results showed that aqueous ethanol extract of C. nocturnum (250 mg/kg and 500 mg/kg produced significant (p<0.05 hepatoprotective activities against paracetamol induced liver injury in Swiss albino mice. Histopathalogical studied of liver further supported the hepatoprotective effects of C. notrunum. Phyto-chemical screening showed the presence of alkaloids, flavonoids, saponins, terpenes, phenolic compounds, carbohydrates and volatile oils. Most of the flavonoids have hepatoprotective activity. Therefore, the hepatoprotective activity of C. nocturnum may be due to the presence of flavonoids and phenolic components. It was concluded from the present study that aqueous ethanol extract of leaves of C. nocturnum has hepatoprotective activity against the paracetamol-induced hepatotoxicity in albino mice.

  19. Hepatotoxicity associated with microcystin/ Hepatotoxicidade associada à microcistina

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    Ana Paula Frederico Rodrigues Loureiro Bracarense

    2008-08-01

    Full Text Available Urban and industrial discharges, intense agricultural exploitation and fisheries have been causing the eutrophication in both drinking and recreational waters. A frequent consequence of eutrophication in waters is the massive development of cyanobacteria. The occurrence of these blooms induces a severe problem, as Microcystis aeruginosa, the most widespread distributed cyanobacteria, can produce microcystins (MC. Toxic effects of MC have been described in liver, lungs, stomach, and intestine. Deaths in wildlife, livestock and human beings were also associated with MC exposition. MC exposition can occurs directly by ingestion, inhalation, contact, intravenous inoculation of contaminated water (hemodialysis or indirectly, by the consumption of animals, as fish and mollusks, the majors ingestors of cyanobacteria and its toxins. The most toxic MC, an also the most common is microcystin-LR (MC-LR, that has the liver as the main target organ. Microcystin is taken up specifically into the liver by bile acid transporters and, after entering the cytoplasm, inhibit protein phosphatases 1 and 2A, which leads to the increase in protein phosphorylation. This effect has two main consequences: the destruction of cytoskeleton directly causing cytotoxic effects, and deregulation of cell division, leading to tumor-promoting activity. Acute exposition to MC induces severe intrahepatic hemorrhage, necrosis and apoptosis, while chronic exposure can cause hepatic or intestinal neoplasia. It has been documented that MC hepatotoxicity is closely associated with intracellular reactive oxygen species formation. Natural degradation of microcystins depends on the solar radiation and bacteria. If degradation is insufficient, MC will persist in the freshwater food chain. Microcystin contamination of waters is therefore a hazard to human and animal health, so efforts to avoid eutrophication of waters sources are essential, in order to minimize the risks to public health

  20. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

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    Gang Tan

    Full Text Available BACKGROUND: Hydrogen sulfide (H(2S displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2S in carbon tetrachloride (CCl(4-induced hepatotoxicity, cirrhosis and portal hypertension. METHODS AND FINDINGS: Sodium hydrosulfide (NaHS, a donor of H(2S, and DL-propargylglycine (PAG, an irreversible inhibitor of cystathionine γ-lyase (CSE, were applied to the rats to investigate the effects of H(2S on CCl(4-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2S, hepatic H(2S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4 significantly reduced serum levels of H(2S, hepatic H(2S production and CSE expression. NaHS attenuated CCl(4-induced acute hepatotoxicity by supplementing exogenous H(2S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, hyaluronic acid (HA, albumin, tumor necrosis factor (TNF-α, interleukin (IL-1β, IL-6 and soluble intercellular adhesion molecule (ICAM-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA expression. PAG showed opposing effects to NaHS on most of the above parameters. CONCLUSIONS: Exogenous H(2S attenuates CCl(4-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2S may present a promising approach, particularly for its prophylactic effects, against liver

  1. Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity.

    Science.gov (United States)

    Liu, Fang; Ichihara, Sahoko; Valentine, William M; Itoh, Ken; Yamamoto, Masayuki; Sheik Mohideen, Sahabudeen; Kitoh, Junzoh; Ichihara, Gaku

    2010-06-01

    1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.

  2. Clinical and Laboratory Findings of Lead Hepatotoxicity in the Workers of a Car Battery Manufacturing Factory

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    Bita Dadpour

    2016-02-01

    Full Text Available Background: Occupational lead poisoning is common in workers of some industries, but lead hepatotoxicity has rarely been reported. Several animal studies have revealed lead induced liver damage but clinical studies concerning the manifestations of lead induced liver toxicity in humans are scares. This study was designed to investigate the clinical manifestations and pathological parameters of hepatic dysfunction and its relationship with blood and urine lead concentrations in a car battery-manufacturing workers. Methods: This cross sectional study was carried out in Mashhad, Iran, during April-June 2011. One hundred and twelve workers underwent blood and urine sampling for determination of lead concentrations and liver function tests. Clinical signs and symptoms of possible lead hepatotoxicity were investigated. Results: Mean (±SD age of the workers was 28.78 (±5.17 yr with a daytime work of 8.67 (±1.41 h and mean work duration of 3.89 (±2.40 yr. Mean blood lead concentration (BLC and urine lead concentration (ULC were 398.95 (±177.41 µg/l and 83.67(±50 μg/l, respectively. We found no correlation between the clinical findings and BLC or ULC. A weak correlation (R: 0.27, P=0.087 between serum alkaline phosphatase concentration and BLC was obtained. No significant relationship was found between other liver function tests and BLC or ULC. Conclusion: We found no specific clinical and laboratory abnormalities of liver in the workers of car battery manufacturer who had chronic lead toxicity. Further investigations with more specific laboratory tests such as LDH5 and gamma glutamyl transferase (GGT as well as novel biomarkers of metal induced hepatotoxicity might be helpful in evaluating lead hepatotoxicity.

  3. Clinical and Laboratory Findings of Lead Hepatotoxicity in the Workers of a Car Battery Manufacturing Factory

    OpenAIRE

    Bita Dadpour; Reza Afshari; Seyed Reza Mousavi; Sina Kianoush; Mohamad Reza Keramati; Vali Allah Moradi; Mahmood Sadeghi; Faezeh Madani Sani; Mahdi Balali Mood

    2016-01-01

    Background: Occupational lead poisoning is common in workers of some industries, but lead hepatotoxicity has rarely been reported. Several animal studies have revealed lead induced liver damage but clinical studies concerning the manifestations of lead induced liver toxicity in humans are scares. This study was designed to investigate the clinical manifestations and pathological parameters of hepatic dysfunction and its relationship with blood and urine lead concentrations in a car battery-ma...

  4. Effect of Mallotus Philippensis Muell.-Arg leaves against hepatotoxicity of Carbon tetrachloride in rats

    OpenAIRE

    Ramakrishna S; Geetha K.M,; Bhaskar gopal P.V.V.S,; Ranjit kumar P; Charan Madav. P,; Umachandar. L

    2011-01-01

    Liver Toxicity is a major health problem of worldwide proportions. Herbal medicines derived from plant extracts are being increasingly utilized to treat a wide variety of clinical diseases. In the present study MEMP leaves is used to screen the hepatoprotective activity. Hepatotoxicity was induced in experimental animals by administration of carbon tetra chloride (CCl4) (25ml/kg, i.p.). Silymarin (25 mg/kg, p.o.) was used as the standard. Functional parameters like onset of sleep and duration...

  5. Preventive effect of zinc toward the hepatotoxicity of nickel in rats

    OpenAIRE

    Kechrid, Zine

    2013-01-01

    We studied the effect of zinc treatment on nickel sulphate-induced hepatotoxicity in male albino rats. Liver dysfunction parameters represented by aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), blood glucose, serum total protein and serum albumin were estimated. Liver glutathione level, catalase and GPx activities were also determined in liver as indicators of oxidative damage. Exposure of rats to nickel caused a significant a decrease in body weight and...

  6. Hepatoprotective potential of ethanolic extract of Pandanus odoratissimus root against paracetamol-induced hepatotoxicity in rats

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    Garima Mishra

    2015-01-01

    Full Text Available Background: Pandanus odoratissimus (Pandanaceae is popular in the indigenous system of medicines like Ayurveda, Siddha, Unani and Homoeopathy. In the traditional system of medicine various plant parts such as leaves, root, flowers, and oils are used as anthelmintic, tonic, stomachic, digestive and in the treatment of jaundice and various liver disorders. Objective: The aim was to investigate the hepatoprotective activity of ethanolic extract of the root of P. odoratissimus against paracetamol (PCM induced hepatotoxicity in rats. Materials and Methods: Hepatotoxicity was induced in male Wistar rat by PCM (2 g/kg b.w. p.o. for 7 days. The ethanolic extract of P. odoratissimus root was administered at the dose level of 200 mg/kg and 400 mg/kg b.w. orally for 7 days and silymarin (100 mg/kg b.w. p.o. as standard drug was administered once daily for a week. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, serum alkaline phosphatase, total and direct bilirubin and triglycerides. Histopathological study of rat liver was also done. Results: Experimental findings revealed that the extract at dose level of 200 mg/kg and 400 mg/kg of b.w. showed dose dependant hepatoprotective effect against PCM induced hepatotoxicity by significantly restoring the levels of serum enzymes to normal that was comparable to that of silymarin, but the extract at dose level of 400 mg/kg was found to be more potent when compared to that of 200 mg/kg. Besides, the results obtained from histopathological study also support the study. Conclusion: From the results, it can be concluded that ethanolic extract of the root of P. odoratissimus afforded significant protection against PCM induced hepatotoxicity in rats.

  7. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  8. A multiple endpoint approach to predict the hepatotoxicity of pharmaceuticals in vitro

    OpenAIRE

    Truisi, Germaine Loredana

    2014-01-01

    A new approach was evaluated to predict the hepatotoxic potential of pharmaceuticals. For this purpose, primary rat and human hepatocytes cultured in an optimised sandwich configuration were used; thus, allowing the long-term, repeat-dosing of drugs. The strategy based on the evaluation of multiple endpoints, including cytotoxicity, biokinetic profiling, transcriptomics and proteomics. Pharmaceuticals with known toxicities and pharmacokinetic properties were used as model compounds.

  9. The thermostable direct hemolysin from Grimontia hollisae causes acute hepatotoxicity in vitro and in vivo.

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    Yan-Ren Lin

    Full Text Available BACKGROUND: G. hollisae thermostable direct hemolysin (Gh-TDH is produced by most strains of G. hollisae. This toxin has been reported to be absorbed in the intestines in humans. Secondary liver injury might be caused by venous return of the toxin through the portal system. We aimed to firstly analyze the in vitro and in vivo hepatotoxicity of Gh-TDH. METHODS: Liver cells (primary human non-cancer cell and FL83B mouse cells were treated and mice (BALB/c were fed with this toxin to investigate its hepatotoxicity. Morphological examination and cytotoxicity assays using liver cells were also performed. Fluorescein isothiocyanate-conjugated toxin was used to analyze the localization of this protein in liver cells. Mice were subjected to liver function measurements and liver biopsies following toxin treatment and wild-type bacterial infection. PET (positron emission tomography/CT (computed tomography images were taken to assess liver metabolism during acute injury and recovery. RESULTS: The effect of hepatotoxicity was dose and time dependent. Cellular localization showed that the toxin was initially located around the cellular margins and subsequently entered the nucleus. Liver function measurements and liver biopsies of the mice following treatment with toxin or infection with wild-type Grimontia hollisae showed elevated levels of transaminases and damage to the periportal area, respectively. The PET/CT images revealed that the reconstruction of the liver continued for at least one week after exposure to a single dose of the toxin or bacterial infection. CONCLUSIONS: The hepatotoxicity of Gh-TDH was firstly demonstrated. The damage was located in the periportal area of the liver, and the liver became functionally insufficient.

  10. Amelioration of carbon tetrachloride induced hepatotoxicity in rats by standardized Feronia limonia. Linn leaf extracts

    OpenAIRE

    Devkar, Ranjitsinh V; Jadeja, Ravirajsinh N.; Jain, Mahendra; Kapadia, Rakhee; Mishra, S. H.; Menaka C. Thounaojam

    2012-01-01

    The hepatoprotective potential of standardized Feronia limonia (Family, Rutaceae) methanolic extract (FL-7) and chloroform soluble fraction (FL-9) were assessed against carbon tetrachloride (CCl4) induced oxidative stress and hepatotoxicity in rats. Rats treated with CCl4 recorded significant elevation in plasma markers of hepatic injury, alteration in hepatic antioxidant status and histopathological damages. However, rats pretreated with FL-7 (200 or 400 mg/kg, p.o.) and FL-9 (100 or 200 mg/...

  11. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways.

    Science.gov (United States)

    Zou, Hui; Liu, Xuezhong; Han, Tao; Hu, Di; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Zhu, Jiaqiao; Liu, Zong-ping

    2015-01-01

    It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.

  12. Aggravation of clozapine-induced hepatotoxicity by glycyrrhetinic acid in rats.

    Science.gov (United States)

    Jia, Ling-ling; Zhong, Ze-yu; Li, Feng; Ling, Zhao-li; Chen, Yang; Zhao, Wei-man; Li, Ying; Jiang, Shu-wen; Xu, Ping; Yang, Yang; Hu, Meng-yue; Liu, Li; Liu, Xiao-dong

    2014-01-01

    Clozapine (CLZ) was reported to be associated with hepatotoxicity. Glycyrrhetinic acid (GA) has a liver protective effect. Our preliminary experiments showed that GA aggravated rather than attenuated CLZ-induced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZ-induced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (nor-CLZ) and clozapine N-oxide (CLZ N-oxide). The results in vivo showed that 7-day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in γ-glutamyl transpeptidase (γ-GT) activity, liver weight, and serum AST in rats. Co-administration of GA enhanced the increases in hepatic TG, γ-GT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of nor-CLZ and CLZ N-oxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of nor-CLZ and CLZ N-oxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QT-PCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZ-induced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.

  13. Protective effect of stem bark of Ceiba pentandra linn. against paracetamol-induced hepatotoxicity in rats

    OpenAIRE

    Bairwa, Nirmal K.; Sethiya, Neeraj K.; Mishra, S. H.

    2010-01-01

    The present study reports protective activity of ethyl acetate fraction of methanol extract of stem bark of Ceiba pentandra against paracetamol-induced liver damage in rats. The ethyl acetate fraction (400 mg/kg) was administered orally to the rats with hepatotoxicity induced by paracetamol (3 gm/kg). Silymarin (100 mg/kg) was used as positive control. High performance thin layer chromatography (HPTLC) fingerprinting of ethyl acetate fraction revealed presence of its major chemical constituen...

  14. 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) ...

  15. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways.

    Directory of Open Access Journals (Sweden)

    Hui Zou

    Full Text Available It is known that cadmium (Cd induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC and activation of mitogen-activated protein kinase (MAPK pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA, administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK inhibitor (U0126 and a p38 inhibitor (SB202190 but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK inhibitor (SP600125. These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.

  16. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways

    Science.gov (United States)

    Han, Tao; Hu, Di; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Zhu, Jiaqiao; Liu, Zong-ping

    2015-01-01

    It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways. PMID:26070151

  17. Ipomoea aquatica Extract Shows Protective Action Against Thioacetamide-Induced Hepatotoxicity

    OpenAIRE

    Hadi, A. Hamid A.; Siddig Ibrahim Abdelwahab; Suzy Munir Salama; Salim Said Alkiyumi; Mahmood Ameen Abdullah; Ahmed Salim Alrashdi

    2012-01-01

    In the Indian system of traditional medicine (Ayurveda) it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA)-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD) rats were orally fed with ...

  18. 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...

  19. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats

    Science.gov (United States)

    Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p = 0.0017) and AST levels (p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  20. Mitigation of hepatotoxic effects of arsenic trioxide through omega-3 fatty acid in rats.

    Science.gov (United States)

    Mathews, Varghese V; Paul, Mv Sauganth; Abhilash, M; Manju, Alex; Abhilash, S; Nair, R Harikumaran

    2014-10-01

    Arsenic trioxide (As(2)O(3)) is an effective drug in the treatment of leukaemia and many solid tumours. In clinical trials, arsenic therapy is closely associated with hepatic toxicity. The present study was designed to investigate the efficacy of omega-3 fatty acid against As(2)O(3)-induced hepatotoxicity. A 4 mg/kg body weight (bw) of As(2)O(3) was orally administered to Wistar male rats for 45 days. Hepatotoxicity was evaluated by biochemical tests, antioxidant assays and histopathological examinations. Arsenic accumulation was found in the liver tissue of rats treated with As(2)O(3). Hepatoprotective efficacy of omega-3 fatty acid was analysed by the combination therapy with As(2)O(3). In vivo studies revealed a significant rise in lipid peroxidation with concomitant decline in reduced glutathione, glutathione-dependant antioxidant enzymes and antiperoxidative enzymes in the liver tissue of rats treated with arsenic. The supplementation of omega-3 fatty acid at a dose of 50 mg/kg bw with As(2)O(3) offers ameliorative effect against hepatocellular toxicity. Omega-3 fatty acid maintained hepatic marker enzymes, antioxidant enzymes and decreased lipid peroxidation. The combination treatment clearly reduced the hepatic structural abnormalities such as haemorrhage, necrosis and cholangiofibrosis in the rats treated with arsenic. This study concludes that the omega-3 fatty acid might be useful for the protection against As(2)O(3)-induced hepatotoxicity. © The Author(s) 2012.

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  2. Suspected Greater Celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe.

    Science.gov (United States)

    Teschke, Rolf; Glass, Xaver; Schulze, Johannes; Eickhoff, Axel

    2012-03-01

    In 21 published case reports, the use of the herb Greater Celandine (GC) (Chelidonium majus L.) has been causally related to liver injury, but a variety of confounding variables were evident that might have offset causality. This study reanalyses causality levels in these cases with a liver-specific causality evaluation method. All 21 cases were submitted to the liver-specific, standardized, structured, quantitative and updated scale of the Council for International Organizations of Medical Sciences. This scale considers, among other items, latency period, course of alanine aminotransferase after treatment discontinuation, risk factors, comedication and alternative causes. Using this method for assessment, causality for GC was highly probable in two and probable in six cases, with lower causality grading in the remaining 13 cases. In these patients, causality for GC was possible in 10 cases and excluded in three cases. On the basis of the eight cases with highly probable and probable causality gradings, GC hepatotoxicity represents an idiosyncratic reaction of the metabolic type, whereas immunologic or obligatory hepatotoxic features are lacking. In some cases, alternative diagnoses and poor data quality were confounding variables that reduced causality levels. Confounding variables reduced causality levels for GC in reported cases of liver injury, but there is still striking evidence for herb-induced liver injury by GC with high causality gradings. GC hepatotoxicity is caused by an idiosyncratic reaction of the metabolic form, but there is uncertainty with respect to its culprit(s).

  3. [Component analysis and acute hepatotoxicity of volatile oils from argy wormwood leaf extracted by different methods].

    Science.gov (United States)

    Liu, Hongjie; Bai, Yang; Hong, Yanlong; Zhang, Xun

    2010-06-01

    To analyze the chemical composition and compare acute hepatotoxicity of essential oils extracted from argy wormwood leaf in Guangdong by four different methods. Four extraction methods, including hydrodistillation extraction, supercritical fluid CO2 extraction, petroleum ether ultrasonic extraction and petroleum ether microwave extraction, were employed to prepare essential oil from argy wormwood leaf in Guangdong. The products were analyzed qualitatively and quantitatively using GC-MS and GC-FID. Sixty mice were divided into 5 groups according to different essential oils and took the same dose orally, then after 5 hours, hepatic functional parameters in serum were detected such as alanine aminotransferase (ALT) and so on, and morphologic change of hepatic tissues was observed. The extraction rate of the four methods and identified compounds was 1.02%, 80 (hydrodistillation extraction), 2.46%, 56 (supercritical fluid CO2 extraction), 3.17%, 45 (petroleum ether ultrasonic extraction) and 3.32%, 78 (petroleum ether microwave extraction) respectively. Totally 153 compounds were identified from those essential oils. Compared with that of the control group, some hepatic functional parameters of hydrodistillation and supercritical fluid CO2 extraction groups rose significantly (P extracted from argy wormwood leaf by different methods may have not only different chemical composition, but also different acute hepatotoxicity, and monoterpenes and benzenes in the essential oils might induce acute hepatotoxicity.

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

    Directory of Open Access Journals (Sweden)

    Jun Ho Shin

    2013-03-01

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

  5. A critical analysis of the hepatotoxicity cases described in the literature related to Herbalife (r products

    Directory of Open Access Journals (Sweden)

    Flávio Ailton Duque Zambrone

    2015-12-01

    Full Text Available Abstract The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r products were retrieved. All of the studies lacked sufficient information to some degree, whether related to patients' history, concomitant use of medication and/or other compounds (including alcohol, observations on interrupted use (dechallenge, results found with markers, viral serology and autoantibodies or observations concerning re-exposure to the products. In addition to these items, the lack of clear information on the type of products evaluated and their respective composition is an important factor to be considered. Furthermore, data quality was also questionable due to the presence of confounding factors, absence of proper exclusion of alternative explanations, and the use of questionable methods for attributing causality. Hence, an association between hepatotoxicity and consumption of these products cannot be proven based on the data collected and rigorous scientific analysis.

  6. In silico models for the prediction of dose-dependent human hepatotoxicity

    Science.gov (United States)

    Cheng, Ailan; Dixon, Steven L.

    2003-12-01

    The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

  7. 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.

  8. Hepatoprotective activity of quercetin against acrylonitrile-induced hepatotoxicity in rats.

    Science.gov (United States)

    Abo-Salem, Osama M; Abd-Ellah, Mohamed F; Ghonaim, Mabrouk M

    2011-01-01

    Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical-mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile-induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile-induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile-induced hepatotoxicity through its antioxidant activity.

  9. Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Alanazi, Abdulrazaq; Algfeley, Saleh G; Al-Hosaini, Khaled A; Korashy, Hesham M; Imam, Faisal; Nagi, Mahmoud N

    2017-04-01

    Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS. © 2016 Wiley Periodicals, Inc.

  10. Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats.

    Science.gov (United States)

    Basarslan, Fatmagul; Yilmaz, Nigar; Davarci, Isil; Akin, Mustafa; Ozgur, Mustafa; Yilmaz, Cahide; Ulutas, Kemal Turker

    2013-09-01

    Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress.

  11. Carvacrol suppresses the expression of inflammatory marker genes in D-galactosamine-hepatotoxic rats

    Institute of Scientific and Technical Information of China (English)

    Balakrishnan Aristatile; Abdullah H Al-Assaf; Kodukkur Viswanathan Pugalendi

    2013-01-01

    Objective:To unravel the mechanism of anti-inflammatory activity of carvacrol in D-galactosamine(D-GalN)-induced hepatotoxic rats.Methods:The mRNA and protein expression levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), inducible nitric oxide synthase(iNOS), cyclooxygenase-2(COX-2) and nuclear factor kappa-B(NF-κB) were assayed by semi-quantitative reverse transcriptase polymerase chain reaction(RTPCR) and western blot analysis.Results:We found that the mRNA and protein expressions ofTNF-α, IL-6, iNOS,COX-2 andNF-κB were significantly up-regulated inD-galactosamine induced hepatotoxic rats and treatment with carvacrol significantly down-regulated the expressions of these genes showing the mechanism behind the anti-inflammatory activity of carvacrol. Conclusions:All above results reveal that the carvacrol well known anti-inflammatory activities inD-galactosamine induced hepatotoxic rats.

  12. Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis, a candidate food supplement.

    Science.gov (United States)

    Martin, Sherry Joseph; Baskaran, Udhaya Lavinya; Vedi, Mahima; Sabina, Evan Prince

    2014-12-01

    Therapy using Isoniazid (INH) and Rifampicin (RIF) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment. In this study, we assessed the effect of Spirulina fusiformis on INH and RIF induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin. Induction of hepatotoxicity was measured by changes in the liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase). The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and lipid peroxidation levels. We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor (PXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of Spirulina fusiformis by in silico methods. The administration of INH and RIF resulted in significant (p Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with INH and RIF in a dose-dependent manner. This was corroborated by histological examination of the liver. The results of the in silico analyses further support the wet lab results.

  13. A fatal case of bupropion (Zyban hepatotoxicity with autoimmune features: Case report

    Directory of Open Access Journals (Sweden)

    Humayun Fawwaz

    2007-09-01

    Full Text Available Abstract Background Bupropion is approved for the treatment of mood disorders and as an adjuvant medication for smoking cessation. Bupropion is generally well tolerated and considered safe. Two randomized controlled trials of bupropion therapy for smoking cessation did not report any hepatic adverse events. However, there are three reports of severe but non-fatal bupropion hepatotoxicity published in the literature. Case Presentation We present the case of a 55-year old man who presented with jaundice and severe hepatic injury approximately 6 months after starting bupropion for smoking cessation. Laboratory evaluation demonstrated a mixed picture of hepatocellular injury and cholestasis. Liver biopsy demonstrated findings consistent with severe hepatotoxic injury due to drug induced liver injury. Laboratory testing was also notable for positive autoimmune markers. The patient initially had clinical improvement with steroid therapy but eventually died of infectious complications. Conclusion This report represents the first fatal report of bupropion related hepatotoxicity and the second case of bupropion related liver injury demonstrating autoimmune features. The common use of this medication for multiple indications makes it important for physicians to consider this medication as an etiologic agent in patients with otherwise unexplained hepatocellular jaundice.

  14. Evaluation of the Antidepressant Activity, Hepatotoxicity and Blood Brain Barrier Permeability of Methyl Genipin

    Directory of Open Access Journals (Sweden)

    Xin Che

    2016-07-01

    Full Text Available Geniposide (GE is the main bioactive component of Gardeniae Fructus. The hepatotoxicity of geniposide limited clinical application. In order to get a new geniposide derivative that has less hepatotoxicity and still possesses the antidepressant activity, a new C-1 hydroxyl methylation derivative named methyl genipin (MG was synthesized from geniposide. In the present study, we demonstrated that MG did not increase the liver index, alanine aminotransferase (ALT and aspirate aminotransferase (AST. Histopathological examination suggested that no toxic damages were observed in rats treated orally with MG (0.72 mmol/kg. More importantly, a 7-day treatment with MG at 0.13, 0.26, and 0.52 mmol/kg/day could reduce the duration of immobility. It showed that the antidepressant-like effects of MG were similar to GE in the tail suspension test and the forced swim test. Furthermore, we found MG could be detected in the brain homogenate of mice treated orally with MG 0.52 mmol/kg/day for 1 day by HPLC. The area under the curve (AUC of MG in the brain homogenate was enhanced to 21.7 times that of GE. The brain amount and distribution speed of MG were improved significantly after oral administration. This study demonstrated that MG possessed the antidepressant effects and could cross the blood–brain barrier, but had less hepatotoxicity.

  15. A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose

    Directory of Open Access Journals (Sweden)

    Kalsi SS

    2011-12-01

    Full Text Available Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen poisoning is common throughout the world. The management of nonstaggered (acute paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although

  16. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gandhi, Adarsh, E-mail: adarsh.gandhi@nih.gov [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Guo, Tao, E-mail: tguo4@jhu.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Shah, Pranav [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Baylor College of Medicine, Department of Pediatrics, 1102 Bates Avenue, Suite 530, Houston, TX 77030 (United States); Ghose, Romi, E-mail: rghose@uh.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States)

    2013-02-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies

  17. Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART na(i)ve Han Chinese with AIDS%奈韦拉平相关肝毒性的发病率及危险因素

    Institute of Scientific and Technical Information of China (English)

    高世成; 桂希恩; 邓莉平; 张永喜; 严亚军; 荣玉萍; 梁科; 杨蓉蓉

    2010-01-01

    目的 了解接受含奈韦拉平(NVP)的联合抗逆转录病毒治疗(cART)后获得性免疫缺陷综合征(AIDS)患者肝毒性的发生率,评估相关的危险因素.方法 回顾性研究本地区2003年3月2008年6月开始接受cART的AIDS患者的人口学和临床资料.单因素和多因素Logistic回归分析各变量与肝损害发生的相关性;Kaplan-Meier方法分析合并HCV感染和未合并HCV感染者肝损害的危险性.结果 330例患者中267例接受了基于NVP的cART,63例接受了基于依非韦仑(EFV)的cART,两组患者肝毒性发生率差异有统计学意义(49.8%比31.7%,x2=6.691,P-0.01).267例接受基于NVP的cART的患者,随访期间有133例(49.8%)出现了至少1次1级以上ALT升高,百人年发生率为28.5.基线期ALT升高(OR=14.368,P=0.017)、合并HCV感染(OR=3.009,P=0.000)与NVP相关肝毒性的发生显著相关.与未合并HCV感染者相比,合并HCV感染者发生肝毒性的可能性更大(x2=16.764,P=0.000).133例发生肝毒性反应的患者中,1例合并NVP相关重度皮疹死亡,尚未发现死于急性肝衰竭的病例,23例(17.3%)曾暂时停止cART或将NVP替换为EFV.结论 本队列接受含NVP的cART患者肝毒性较常见,基线期ALT水平升高、合开HCV感染是发生肝毒性反应的危险因素.%Objective To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. Methods 330 AIDS patients from March 2003 to June 2008at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. Results 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (x2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based c

  18. Multicenter study of skin rashes and hepatotoxicity in antiretroviral-naïve HIV-positive patients receiving non-nucleoside reverse-transcriptase inhibitor plus nucleoside reverse-transcriptase inhibitors in Taiwan

    Science.gov (United States)

    Wu, Pei-Ying; Cheng, Chien-Yu; Liu, Chun-Eng; Lee, Yi-Chien; Yang, Chia-Jui; Tsai, Mao-Song; Cheng, Shu-Hsing; Lin, Shih-Ping; Lin, De-Yu; Wang, Ning-Chi; Lee, Yi-Chieh; Sun, Hsin-Yun; Tang, Hung-Jen; Hung, Chien-Ching

    2017-01-01

    Objectives Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs. Methods Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study. According to the national HIV treatment guidelines, patients were assessed at baseline, 2 and 4 weeks of cART initiation, and subsequently every 8 to 12 weeks. Plasma HIV RNA load, CD4 cell count and aminotransferases were determined. The toxicity grading scale of the Division of AIDS (DAIDS) 2014 was used for reporting clinical and laboratory adverse events. Results During the 3.5-year study period, 2,341 patients initiated nNRTI-containing cART: NVP in 629 patients, EFV 1,363 patients, and RPV 349 patients. Rash of any grade occurred in 14.1% (n = 331) of the patients. In multiple logistic regression analysis, baseline CD4 cell counts (per 100-cell/μl increase, adjusted odds ratio [AOR], 1.125; 95% confidence interval [95% CI], 1.031–1.228) and use of NVP (AOR, 2.443; 95% CI, 1.816–3.286) (compared with efavirenz) were independently associated with the development of skin rashes. Among the 1,455 patients (62.2%) with aminotransferase data both at baseline and week 4, 72 (4.9%) developed grade 2 or greater hepatotoxicity. In multiple logistic regression analysis, presence of antibody for hepatitis C virus (HCV) (AOR, 2.865; 95% CI, 1.439–5.704) or hepatitis B surface antigen (AOR, 2.397; 95% CI, 1.150–4.997), and development of skin rashes (AOR, 2.811; 95% CI, 1

  19. Critical incident reporting systems.

    Science.gov (United States)

    Ahluwalia, Jag; Marriott, Lin

    2005-02-01

    Approximately 10% of all hospital admissions are complicated by critical incidents in which harm is caused to the patient - this amounts to more than 850,000 incidents annually. Critical incident reporting (CIR) systems refer to the structured reporting, collation and analysis of such incidents. This article describes the attributes required for an effective CIR system. Example neonatal trigger events and a management pathway for handling a critical incident report are described. The benefits and limitations of CIR systems, reactive and prospective approaches to the analysis of actual or potential critical incidents and the assessment of risk are also reviewed. Individual human error is but one contributor in the majority of critical incidents. Recognition of this and the fostering of an organisational culture that views critical incident reports as an opportunity to learn and to improve future patient care is vital if CIR systems are to be effective.

  20. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts.

    Science.gov (United States)

    Burel, Sebastien A; Hart, Christopher E; Cauntay, Patrick; Hsiao, Jill; Machemer, Todd; Katz, Melanie; Watt, Andy; Bui, Huynh-Hoa; Younis, Husam; Sabripour, Mahyar; Freier, Susan M; Hung, Gene; Dan, Amy; Prakash, T P; Seth, Punit P; Swayze, Eric E; Bennett, C Frank; Crooke, Stanley T; Henry, Scott P

    2016-03-18

    High affinity antisense oligonucleotides (ASOs) containing bicylic modifications (BNA) such as locked nucleic acid (LNA) designed to induce target RNA cleavage have been shown to have enhanced potency along with a higher propensity to cause hepatotoxicity. In order to understand the mechanism of this hepatotoxicity, transcriptional profiles were collected from the livers of mice treated with a panel of highly efficacious hepatotoxic or non-hepatotoxic LNA ASOs. We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs. This transcriptional signature was concurrent with on-target RNA reduction and preceded transaminitis. Remarkably, the mRNA transcripts commonly reduced by toxic LNA ASOs were generally not strongly associated with any particular biological process, cellular component or functional group. However, they tended to have much longer pre-mRNA transcripts. We also demonstrate that the off-target RNA knockdown and hepatotoxicity is attenuated by RNase H1 knockdown, and that this effect can be generalized to high affinity modifications beyond LNA. This suggests that for a certain set of ASOs containing high affinity modifications such as LNA, hepatotoxicity can occur as a result of unintended off-target RNase H1 dependent RNA degradation. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. Incident Information Management Tool

    CERN Document Server

    Pejovic, Vladimir

    2015-01-01

    Flaws of\tcurrent incident information management at CMS and CERN\tare discussed. A new data\tmodel for future incident database is\tproposed and briefly described. Recently developed draft version of GIS-­‐based tool for incident tracking is presented.

  2. Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis.

    Science.gov (United States)

    Kelleni, Mina T; Ibrahim, Salwa A; Abdelrahman, Aly M

    2016-06-01

    Methotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid drug whose efficacy is limited by its hepatotoxicity. The aim of this study was to investigate the possible protective role of captopril (100 mg/kg/day, p.o. for seven days), an angiotensin converting enzyme inhibitor, and telmisartan (10 mg/kg/day p.o. for seven days), an angiotensin II receptor blocker with peroxisome proliferative receptor gamma (PPARγ) agonism, in a model of MTX (single dose 20 mg/kg i.p. at the fifth day) induced hepatotoxicity in rats. Results of the present study revealed MTX-induced hepatotoxicity as demonstrated by increased level of liver enzymes and confirmed by histopathology. Pretreatment with captopril or telmisartan produced a significant hepatic protection manifested as a significant (p captopril/Telmisartan, if tolerated and not contraindicated, as preferable antihypertensive agents in patients receiving MTX in their chemotherapy protocols.

  3. Effect of methanol extract of Cuscuta reflexa aerial parts on hepatotoxicity induced by antitubercular drugs in rats

    Directory of Open Access Journals (Sweden)

    B R Balakrishnan

    2010-03-01

    Full Text Available Abstract: Evaluation of hepatoprotective activity of extracts of Cuscuta reflexa (Convolvulaceae on Isoniazid (INH and Rifambicin (RIF induced hepatotoxicity rats. Hepatotoxicity was observed by biochemical measurments: Serum alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP activities, ﻻ- GT the levels of total bilirubin were evaluated. There was a significant decrease in serum parameters in extract and standard drug treated groups. Histopathological changes were also observed in livers of animals that received extract and standard drug. Industrial relevance: The data generated in this study suggest that Cuscuta reflexa, could be very useful in the management of hepatoprotection on INH and RIF induced hepatotoxicity. Further studies will still be required at identifying the active hypoglycaemic phytoconstituents and their possible mechanism.

  4. Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports.

    Science.gov (United States)

    Teschke, Rolf; Glass, Xaver; Schulze, Johannes

    2011-12-01

    Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n=2), probable (n=6), possible (n=10), unlikely (n=1), and excluded (n=3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.

    Science.gov (United States)

    Karcioglu, Saliha Sena; Palabiyik, Saziye Sezin; Bayir, Yasin; Karakus, Emre; Mercantepe, Tolga; Halici, Zekai; Albayrak, Abdulmecit

    2016-03-01

    Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.

  6. Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats.

    Science.gov (United States)

    Khaldoun Oularbi, H; Richeval, C; Lebaili, N; Zerrouki-Daoudi, N; Baha, M; Djennas, N; Allorge, D

    2016-07-26

    In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity.

  7. Repression of acetaminophen-induced hepatotoxicity by a combination of celastrol and brilliant blue G.

    Science.gov (United States)

    Abdelaziz, Heba A; Shaker, Mohamed E; Hamed, Mohamed F; Gameil, Nariman M

    2017-06-05

    The sterile inflammatory response is an eminent contributor to acetaminophen (APAP)-hepatotoxicity in humans. Recent advances unraveled an axial role of the NLRP3-inflammasome in APAP-post injury inflammation. Nevertheless, the role of signaling events preceded the NLRP3-inflammasome activation, like the transcription factor NF-κB and the purinergic receptor P2X7, is still unclear and needs further elucidation. Here, we investigated the pharmacological inhibition of these upstream signaling molecules by celastrol and brilliant blue G (BBG) (separately or simultaneously) in APAP-hepatotoxicity in mice. The results indicated that both celastrol and BBG pretreatments, especially when combined together, curbed APAP-induced hepatocellular injury (ALT, AST and LDH) and death (necrosis and apoptosis). The underlying mechanisms of protection of such combination against APAP-challenge were attributed to their efficient cooperation in: i) preventing the consumption of hepatic antioxidants (reduced glutathione and superoxide dismutase); ii) limiting the overproduction of lipid peroxidation aldehydes (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite products; iii) attenuating the inflammatory cells accumulation in the liver, as evidenced by reducing the number of F4/80 positive cells/field in immunostaining and myeloperoxidase activity; iv) reversing the dysregulation in production of pro-inflammatory (TNF-α, IL-17A and IL-23) and anti-inflammatory (IL-10) cytokines; and v) enhancing the reparative capacity of injured hepatocytes, as demonstrated by increasing the percentage of PCNA positive hepatocytes per field of immunostaining. In conclusion, this murine study elicits a potential clinical applicability and therapeutic utility of celastrol and BBG combination in human cases of APAP-overdose hepatotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Chun-Hung Chiu

    2016-07-01

    Full Text Available Lipopolysaccharide (LPS-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST, a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10 for seven days and then were LPS-challenged (i.p., 5 mg/kg. The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT, glutamic oxaloacetic transaminase (GOT, blood urea nitrogen (BUN, creatinine (CRE, hepatic malondialdehyde (MDA and glutathione peroxidase (GSH-Px, IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS, suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day. Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  9. Effect of imidacloprid on hepatotoxicity and nephrotoxicity in male albino mice

    Directory of Open Access Journals (Sweden)

    Yasir Arfat

    2014-01-01

    Full Text Available Imidacloprid (IC is a systemic insecticide related to the tobacco toxin nicotine. IC is a toxic substance frequently used into combat insects, rodents and plants pests and other creatures that can pose problems for agriculture. We, therefore, planned this study to assess risk factors, biochemical and histological alterations associated with hepatotoxicity and nephrotoxicity. Forty-eight adult male albino mice were divided into four groups of 12 animals each. All the animals were given standard synthetic pellet diet. One group served as control, and the other three were served as experimental groups. Decrease in the body weight of the high dose group was observed at 15 mg/kg/day, and no mortality occurred during the treatment period. High dose of imidacloprid caused a significant elevation of serum clinical chemistry parameters, serum glutamic oxaloacetic transaminase (SGOT, serum glutamic pyruvate kinase (SGPT, alkaline phosphatase (ALP and total bilirubin (TBIL. Histology of liver and kidney indicates hepatotoxicity and nephrotoxicity at a high dose of imidacloprid. Based on the morphological, biochemical and histopathological analysis, it is evident that imidacloprid induced toxicological effects at 15 mg/kg/day to mice. The results of the present study demonstrate that IC had significant effects on body weight, liver functions and kidney (p < 0.05 at a dose of 15 mg/kg body weight. IC treatment 5 and 10 mg/kg/day may be considered as no observed adverse effect level (NOAEL for mice. It was concluded that IC can cause hepatotoxicity and nephrotoxicity at a dose much lower than the LD50 (131 mg/kg body weight in mice.

  10. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity.

    Science.gov (United States)

    Chiu, Chun-Hung; Chang, Chun-Chao; Lin, Shiang-Ting; Chyau, Charng-Cherng; Peng, Robert Y

    2016-07-14

    Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  11. Antioxidant and anti-inflammatory role of zingerone in ethanol-induced hepatotoxicity.

    Science.gov (United States)

    Mani, Vijay; Arivalagan, Sivaranjani; Siddique, Aktarul Islam; Namasivayam, Nalini

    2016-10-01

    Alcoholic liver disease is a direct result of alcohol-induced hepatotoxicity coupled with impaired hepatic regenerative activity. Our aim of the study was to investigate the beneficial effect of zingerone on hepatic oxidative stress and inflammation induced by ethanol in experimental rats. Male albino Wistar rats were divided into four groups. Rats of groups 1 and 2 received isocaloric glucose and dimethyl sulfoxide (2 % DMSO). Hepatotoxicity was induced in groups 3 and 4 by supplementing 30 % ethanol post orally for 60 days. Rats of groups 2 and 4 received zingerone (20 mg/kg body weight in 2 % DMSO p.o) daily during the final 30 days of the experimental period. Ethanol alone administered rats showed significant increase in the plasma and tissue lipid peroxidation markers such as thiobarbituric acid reactive substances, lipid hydroperoxides, conjugated dienes, and a significant decrease in the activities of plasma and tissue enzymic and non-enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, vitamin C, and vitamin E. Moreover, the presence of mast cells and increase in the expressions of inflammatory markers such as NF-κB, COX-2, TNF-α, and IL-6 and decrease in the expression of Nrf2 in the liver was observed in ethanol-fed rats. Supplementation with zingerone to ethanol-fed rats reversed the changes induced by ethanol in the experimental rats. Thus, zingerone, through its antioxidant and anti-inflammatory effects, may represent a therapeutic option to protect against ethanol-induced hepatotoxicity.

  12. The role of infliximab on paracetamol-induced hepatotoxicity in rats.

    Science.gov (United States)

    Ferah, Irmak; Halici, Zekai; Bayir, Yasin; Demirci, Elif; Unal, Bunyami; Cadirci, Elif

    2013-06-01

    Paracetamol 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. Infliximab is tumor necrosis factor alpha (TNF-α) inhibitor agent, which has been developed as a therapeutic agent for TNF-α-mediated disease. It acts by binding and neutralizing TNF. The aim of our study was to evaluate the hepatoprotective activity of infliximab on paracetamol-induced hepatotoxicity and to understand the relationship between the TNF-α and paracetamol-induced liver injury. Fifty-six rats were divided into eight groups as each composed of seven rats: (1) intact, (2) 7 mg/kg infliximab, (3) 140 mg/kg NAC, (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 3 mg/kg infliximab, (7) 2 g/kg paracetamol + 5 mg/kg infliximab and (8) 2 g/kg paracetamol + 7 mg/kg infliximab groups. Liver function tests including lipid peroxidation levels were analyzed and histopathological changes of liver were also observed. There were statistically significant increases in the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), levels of TNF-α and malondialdehyde (MDA) and decreases in the activity of superoxide dismutase (SOD) and level of glutathione (GSH) in the group treated with paracetamol. Infliximab administration dramatically reduced serum ALT, AST and TNF-α level. Also, it restored GSH, SOD and decreased MDA levels in liver. Liver histopathological examination showed that infliximab administration antagonized paracetamol-induced liver pathological damage. The results of present study suggest that infliximab has significant hepatoprotective activity on paracetamol-induced hepatotoxicity.

  13. Effects of platelet-rich plasma on liver regeneration in CCl4-induced hepatotoxicity model.

    Science.gov (United States)

    Mafi, Afsaneh; Dehghani, Farzaneh; Moghadam, Abbas; Noorafshan, Ali; Vojdani, Zahra; Talaei-Khozani, Tahereh

    2016-12-01

    Numerous bioactive growth factors and cytokines in platelet-rich plasma (PRP) have recently made it an attractive biomaterial for therapeutic purposes. These growth factors have the potential to regenerate the injured tissues. The aim of this study was to investigate the therapeutic effects of PRP in hepatotoxic animal model. Hepatotoxicity was induced in rats by oral administration of 4 mL/kg/week of CCl4 diluted 1:1 in corn oil for 10 weeks. To confirm the hepatotoxicity, 24 h after the last CCl4 administration, blood samples were collected via cardiac puncture to assess the serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein, and total bilirubin. Twenty-four hours after blood collection, the experimental animals received a single injection of PRP (1 mL) via the anterior mesenteric vein. One week later, all biochemical tests were performed again, and the rats were scarified and their livers were removed, prepared histologically, and stained. The stereological analyses were performed to evaluate the effects of PRP on histopathological features of CCl4-treated livers. The results were compared statistically with the corresponding control and CCl4+normal saline (NS)-treated animals. A significant decrease in the number and volume of hepatocytes (p = 0.01), and also a reduction in the volume of sinusoids (p = 0.001) and connective tissue (p = 0.04), were observed in the PRP-treated animals compared with the CCl4+NS-treated ones. Our findings demonstrated that application of PRP had beneficial effects on CCl4-induced fibrosis; however, it had detrimental effects on the total number of hepatocytes and the volume of hepatocytes and sinusoidal spaces.

  14. 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.

  15. A Systematic Strategy for Screening and Application of Specific Biomarkers in Hepatotoxicity Using Metabolomics Combined With ROC Curves and SVMs.

    Science.gov (United States)

    Li, Yubo; Wang, Lei; Ju, Liang; Deng, Haoyue; Zhang, Zhenzhu; Hou, Zhiguo; Xie, Jiabin; Wang, Yuming; Zhang, Yanjun

    2016-04-01

    Current studies that evaluate toxicity based on metabolomics have primarily focused on the screening of biomarkers while largely neglecting further verification and biomarker applications. For this reason, we used drug-induced hepatotoxicity as an example to establish a systematic strategy for screening specific biomarkers and applied these biomarkers to evaluate whether the drugs have potential hepatotoxicity toxicity. Carbon tetrachloride (5 ml/kg), acetaminophen (1500 mg/kg), and atorvastatin (5 mg/kg) are established as rat hepatotoxicity models. Fifteen common biomarkers were screened by multivariate statistical analysis and integration analysis-based metabolomics data. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the biomarkers. We obtained 10 specific biomarker candidates with an area under the curve greater than 0.7. Then, a support vector machine model was established by extracting specific biomarker candidate data from the hepatotoxic drugs and nonhepatotoxic drugs; the accuracy of the model was 94.90% (92.86% sensitivity and 92.59% specificity) and the results demonstrated that those ten biomarkers are specific. 6 drugs were used to predict the hepatotoxicity by the support vector machines model; the prediction results were consistent with the biochemical and histopathological results, demonstrating that the model was reliable. Thus, this support vector machine model can be applied to discriminate the between the hepatic or nonhepatic toxicity of drugs. This approach not only presents a new strategy for screening-specific biomarkers with greater diagnostic significance but also provides a new evaluation pattern for hepatotoxicity, and it will be a highly useful tool in toxicity estimation and disease diagnoses.

  16. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  17. Evaluation of hepatotoxicity and clastogenicity of carbofuran in male Wistar rats.

    Science.gov (United States)

    Gbadegesin, Michael A; Owumi, Solomon E; Akinseye, Victor; Odunola, Oyeronke A

    2014-03-01

    Carbofuran based pesticides have gained wide usage in Nigeria recently. Consequently, animals and human populations are exposed to them in the environment. Information on in vivo toxicity of carbofuran in experimental models is scanty. The present study therefore examined the hepatotoxicity and clastogenic effects of carbofuran in rats. Male Wistar rats were exposed to carbofuran (p.o) at 0-5mg/kg bw for 5weeks. Carbofuran induced significant (prats. It therefore may constitute an environmental health risks in individuals so exposed.

  18. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

    Energy Technology Data Exchange (ETDEWEB)

    Brusko, C.S.; Marten, J.T. (Purdue University School of Pharmacy and Pharmacal Sciences, Lafayette, IN (United States))

    1991-12-01

    Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.16 references.

  19. Evaluation of Prophylactic and Therapeutic Effects of Silymarin on Diazepam-Induced Hepatotoxicity in Cats

    OpenAIRE

    Bahman Mosallanejad; Reza Avizeh; Hossien Najafzadeh

    2011-01-01

    Problem statement: Diazepam is commonly administered for seizure control and appetite stimulant in cats. Cats may develop acute fatal hepatic necrosis after receiving oral diazepam for several days. The aim of this study was to detect the protective action of silymarin on diazepam-induced hepatotoxicity in cats. Approach: About 25 healthy cats were randomly allotted to five equal groups. Animals in Group A were given diazepam (repeated dose 2.5 mg kg-1, p.o. q 12 h for 4 days); Group B consis...

  20. Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

    Institute of Scientific and Technical Information of China (English)

    Lily Dare; Jennifer Hewett; Joseph Kartaik Lim

    2008-01-01

    Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxiciLy, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the seLLing of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements,and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted.

  1. Interaction between nitric oxide synthase and cyclooxygenase in the development of acetaminophen-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Meltem Kolgazi

    2015-03-01

    Results: AG and KET prevented the increase in liver malondialdehyde levels due to APAP toxicity. Decreased liver glutathione in APAP group was prevented by all treatments except NIM. Stimulated liver myeloperoxidase activity in APAP group was attenuated by all treatments except INDO and NIM. Elevation of liver chemiluminescence, nuclear factor (NF- and #61547;B expression and serum alanine transferase level due to APAP overdose were also suppressed by all treatments. Conclusions: NOS and COX pathways interact in the development of hepatotoxicity due to APAP overdose. [J Exp Integr Med 2015; 5(1.000: 16-22

  2. Amiodarone-induced exudative bullous lesion and hepatotoxicity in a patient with ventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Ahmet Karakurt

    2015-09-01

    Full Text Available Amiodarone is a potent, iodine rich, highly lipophilic class III antiarrhythmic drug widely used for the management of both supraventricular and ventricular arrhythmias. It tends to concentrate in tissues including fat, lung, liver cornea and skin. Several side effects have been reported in patients taking amiodarone. The mechanisms of amiodarone-induced side effects are poorly understood. Accumulation of amiodarone in tissues and organs has been suggested as a possible mechanism. The most frequent dermatologic side effects are photosensitivity, skin discoloration and erythema. This article presents the case of a patient who developed amiodarone-induced bullous skin lesions and hepatotoxicity.

  3. 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.

  4. Sida rhombifolia ssp. retusa seed extract inhibits DEN induced murine hepatic preneoplasia and carbon tetrachloride hepatotoxicity.

    Science.gov (United States)

    Poojari, Radhika; Gupta, Sanjay; Maru, Girish; Khade, Bharat; Bhagwat, Sanjay

    2009-01-01

    Sida rhombifolia ssp. retusa is a well established drug in the Ayurvedic system of medicine used for antirheumatism and antiasthmatism. Inhibitory effects of S. rhombifolia ssp. retusa seed extract on DEN induced hepatocellular preneoplastic foci and carbon tetrachloride (CCl4) induced hepatotoxicity was investigated in rats. Rats received DEN, 1ppm/g b.w. in drinking water for 6 weeks or CCl(4), 0.7 ml/kg i.p. once a week for 4 weeks and seed extract 50 mg, 100 mg/kg b.w. orally prior, during and after exposure to DEN/CCl4 for 20 or 5 weeks, respectively. Treatment with seed extract significantly inhibited the increase in DEN/CCl(4) induced activities of pre-cancerous marker enzymes; gamma-glutamyl transpeptidase, glutathione-S-transferase, hepatotoxicity marker enzymes; glutamate pyruvate transaminase, glutamate oxaloacetate transaminase and alkaline phosphatase as well as lipid peroxidase. Depleted glutathione, protein and albumin levels were restored. Also, histopathological and transmission electron microscopic studies showed prevention of cellular degenerative changes. The chemopreventive and hepatoprotective potentials of seed extract are due to free radical scavenging activity and restoration of cellular structural integrity.

  5. Can hyperbaric oxygenation decrease doxorubicin hepatotoxicity and improve regeneration in the injured liver?

    Science.gov (United States)

    Firat, Ozgur; Kirdok, Ozgur; Makay, Ozer; Caliskan, Cemil; Yilmaz, Funda; Ilgezdi, Savas; Karabulut, Bulent; Coker, Ahmet; Zeytunlu, Murat

    2009-01-01

    Portal vein embolization is used in the treatment of hepatocellular cancer, with the purpose of enhancing resectability. However, regeneration is restricted due to hepatocellular injury following chemotherapeutics (e.g. doxorubicin). The aim of this study was to investigate whether hyperbaric oxygenation (HBO) can alleviate the hepatotoxicity of chemotherapy and improve regeneration in the injured liver. Rats were allocated to four experimental groups. Group I rats were subjected to right portal vein ligation (RPVL); rats in groups II and III were administered doxorubicin prior to RPVL, with group III rats being additionally exposed to HBO sessions postoperatively; group IV rats was sham-operated. All rats were sacrificed on postoperative day 7, and liver injury was assessed by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Protein synthetic ability was determined based albumin levels and liver regeneration by the mitotic index (MI). The AST and ALT values of group II rats were significantly higher than those of group I, but not those of group III. Rats treated with doxorubicin and HBO (groups II and III) showed slightly but not significant differences in albumin levels than those subjected to only RPVL or sham-operated. The MI was significantly increased in groups I, II, and III, with the MI of group III rats significantly higher than those of group I rats. Based on our results, we conclude that HBO treatment has the potential to diminish doxorubicin-related hepatotoxicity and improve regeneration in the injured liver.

  6. 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.

  7. Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats.

    Science.gov (United States)

    Cuce, G; Canbaz, H T; Sozen, M E; Yerlikaya, F H; Kalkan, S

    2017-01-01

    Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.

  8. Hematological, antioxidant and protective performance of Usnea longissima on chemical induced hepatotoxicity in experimental animals

    Directory of Open Access Journals (Sweden)

    Pritt Verma

    2017-05-01

    Full Text Available Objective: To investigated the hematological, antioxidant and protective performance of Usnea longissima (U. longissima on CCl4 induced hepatotoxicity in experimental animals. Methods: Hepatotoxicity was induced by CCl4 (1 mL/kg body weigt 1:1 CCl4 i.p., ethanolic U. longissima extracts at a doses (200 and 400 mg/kg body weigt were administered to and compared with Silymarin (25 mg/kg body weigt and hematological, antioxidant and enzymatic, non-enzymatic parameters were assessed through the liver functions test. All the observation was also supplemented with histopathological examination of liver sections. Results: Phytochemical investigation showed that ethanolic extract contains poly phenolic compounds tannins, flavonoids, alkaloids and saponins and acute toxicity study shows that ethanolic extract was safe up to 2 000 mg/kg body weight. The toxicant induced a rise in the plasma enzyme levels of ALT, AST, ALP and total bilirubin level. This increased level was significantly decreased by the extract at 400 mg/kg body weight than 200 mg/kg body weight. The animals were prevented (partly or fully which was showed in the histopathological changes using ethonolic U. longissima extract. Conclusions: The outcome of this study reveals that, there is a powerful antioxidant and hepatoprotective activity of U. longissima. It is believed that the present constituents are responsible for courting the hepatic disease and alternative components have the power to act as free radical scavenging properties.

  9. Ameliorative Influence of Green Tea Extract on Copper Nanoparticle-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Ibrahim, Marwa A.; Khalaf, A. A.; Galal, Mona K.; Ogaly, Hanan A.; H. M. Hassan, Azza

    2015-09-01

    The potential toxicity of copper nanoparticles (CNPs) to the human health and environment remains a critical issue. In the present study, we investigated the protective influence of an aqueous extract of green tea leaves (GTE) against CNPs-induced (20-30 nm) hepatotoxicity. Four different groups of rats were used: group I was the control, group II received CNPs (40 mg/kg BW), group III received CNPs plus GTE, and group IV received GTE alone. We highlighted the hepatoprotective effect of GTE against CNPs toxicity through monitoring the alteration of liver enzyme activity, antioxidant defense mechanism, histopathological alterations, and DNA damage evaluation. The rats that were given CNPs only had a highly significant elevation in liver enzymes, alteration in oxidant-antioxidant balance, and severe pathological changes. In addition, we detected a significant elevation of DNA fragmentation percentage, marked DNA laddering, and significance over expression of both caspase-3 and Bax proteins. The findings for group III clarify the efficacy of GTE as a hepatoprotectant on CNPs through improving the liver enzyme activity, antioxidant status, as well as suppressing DNA fragmentation and the expression of the caspase-3 and Bax proteins. In conclusion, GTE was proved to be a potential hepatoprotective additive as it significantly ameliorates the hepatotoxicity and apoptosis induced by CNPs.

  10. Hepatotoxic effects of polidocanol in a model of autologously perfused porcine livers.

    Science.gov (United States)

    Grosse-Siestrup, Christian; Unger, Volker; Pfeffer, Jeanette; Dinh, Q Thai; Nagel, Stefan; Springer, Jochen; Witt, Christian; Wussow, Anke; Groneberg, David A

    2004-12-01

    Polidocanol is an effective sclerosing agent that consists of 95% hydroxypolyethoxydodecane and 5% ethyl alcohol and is known to have a low risk of complications. However, since the compound has been proposed for the local treatment of liver diseases, the potential for topical hepatic side effects should be examined. Therefore, the new model of normothermic-hemoperfused isolated porcine slaughterhouse livers was used to examine polidocanol-hepatotoxicity encompassing the advantages of slaughterhouse organs to reduce animal experiments and autologous blood as an optimal perfusate. Polidocanol was administered via the hepatic artery and portal vein and the effects of the sclerosant on organ function parameters were compared with those in an untreated control group. In contrast to the untreated control organs, significant differences were found in the polidocanol group for parameters such as alanine aminotransferase or organ weight after perfusion. The most striking differences were found for hepatic bile flow, which dropped in the polidocanol group to 0.24+/-0.02 ml/min per 1000 g after administration of the compound compared with 3.80+/-1.08 ml/min per 1000 g in the control group. In summary, the present observations indicate a risk of hepatotoxic effects of polidocanol. Clinicians should be aware of this problem and the use of polidocanol for intrahepatic sclerosing should be restricted to specialized centers.

  11. Hepatoprotective effect of Rosa canina fruit extract against carbon tetrachloride induced hepatotoxicity in rat

    Directory of Open Access Journals (Sweden)

    Heibatollah Sadeghi

    2016-03-01

    Full Text Available Objective: The present study was conducted to investigate the hepatoprotective activity of hydro-ethanolic fruit extract of Rosa canina (R. canina against carbon tetrachloride (CCl4-induced hepatotoxicity in rats. Methods: Male Wistar albino rats were randomly divided into six groups of 8 animals of each, including control, toxic (CCl4, R. canina 250, 500, and 750 mg/kg + CCl4 and R. canina 750 mg/kg alone. R. canina (p.o., daily and CCl4 (1 ml/kg twice a week, 50% v/v in olive oil, i.p. were administered to animals for six weeks. Serum analysis was performed to assay the levels of aspartate aminotransferase (AST, alanine amino transaminase (ALT, alkaline phosphatase (ALP, albumin (ALB, total protein (TP and malondialdehyde (MDA. Biochemical observations were also supplemented with histopathological examination (haematoxylin and eosin staining of liver section.Results: Hepatotoxicity was evidenced by considerable increase in serum levels of AST, ALT, ALP, and lipid peroxidation (MDA and decrease in levels of ALB and TP. Injection of CCL4 also induced congestion in central vein, and lymphocyte infiltration. Treatment with hydro-alcoholic fruit extract of R. canina at doses of 500 and 750 mg/kg significantly reduced CCl4-elevated levels of ALT, AST, ALP and MDA (p

  12. Chelidonium majus 30C and 200C in induced hepato-toxicity in rats.

    Science.gov (United States)

    Banerjee, Antara; Pathak, Surajit; Biswas, Surjyo Jyoti; Roy-Karmakar, Susanta; Boujedaini, Naoual; Belon, Philippe; Khuda-Bukhsh, Anisur Rahman

    2010-07-01

    Homeopathy is a popular form of complementary and alternative medicine and is used to treat for certain liver ailments. To analyze the efficacy of homeopathic Chelidonium majus (Chel) 30C and 200C in amelioration of experimentally induced hepato-toxicity in rats. Rats were randomized into six sub-groups: negative control; negative control+EtOH; positive control; positive control+EtOH group; Chel 30; Chel 200. Rats were sacrificed at day 30, 60, 90 and 120; various toxicity biomarkers and pathological parameters were evaluated. Gelatin zymography for determination of metalloproteinases activity and Western blot of p53 and Bcl-2 proteins were also employed. All analyses were observer blind. Chronic feeding of p-dimethyl amino azo benzene (p-DAB) and phenobarbital (PB) elevated the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), triglyceride, cholesterol, creatinine and bilirubin and lowered the levels of glutathione (GSH), glucose-6-phosphate dehydrogenase (G-6-PD), catalase and HDL-cholesterol. There were statistically significant modulations of these parameters in the treated animals, compared to positive controls. In both treated groups, there was downregulation of metalloproteinases, p53 and Bcl-2 proteins compared to over-expression in the positive control groups. Both the potencies of Chel exhibited anti-tumor and anti-oxidative stress potential against artificially induced hepatic tumors and hepato-toxicity in rats. More studies are warranted. 2010 Elsevier Ltd. All rights reserved.

  13. Chelidonium majus is not hepatotoxic in Wistar rats, in a 4 weeks feeding experiment.

    Science.gov (United States)

    Mazzanti, Gabriela; Di Sotto, Antonella; Franchitto, Antonio; Mammola, Caterina Loredana; Mariani, Paola; Mastrangelo, Sabina; Menniti-Ippolito, Francesca; Vitalone, Annabella

    2009-12-10

    Aerial parts of Chelidonium majus L. (Papaveraceae family) are traditionally used in the treatment of gallstones and dyspepsia, however several cases of hepatotoxicity are reported. In this work we evaluated the effects on liver function of a C. majus extract, obtained from the herbal material responsible for one case of hepatotoxicity. Experiments were performed in Wistar rats, after oral administration of doses corresponding to 1.5 and 3g/(kg day) of herbal drug, for 2 or 4 weeks. Blood samples were collected to perform biochemical analysis, whereas liver samples were used for histomorphological and immunohistochemical examination along with the determination of oxidative stress parameters. No significant modification in animal body weight, food consumption, enzyme activities, hepatic histomorphology and MDA formation, at either time or dosage level. Conversely, C. majus induced a slight but significant decrease of GSH levels and SOD activity, especially at the high dose. Our study suggests that C. majus, at doses about 50 and 100 times higher than those generally used in humans, does not alter hepatic function. However, the reduction in GSH levels and SOD activity suggests particular attention in use of C. majus or its preparations in situations (pharmacological treatments, physio-pathological conditions, etc.) that can compromise liver function.

  14. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    Science.gov (United States)

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  15. Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity.

    Science.gov (United States)

    Chang, Shih-Yu; Voellinger, Jenna L; Van Ness, Kirk P; Chapron, Brian; Shaffer, Rachel M; Neumann, Thomas; White, Collin C; Kavanagh, Terrance J; Kelly, Edward J; Eaton, David L

    2017-04-01

    The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc.) that can utilize primary liver cells from multiple species (e.g., rat and human). Compared to conventional monolayer cell culture, which typically survives for 5-7days or less, primary rat or human hepatocytes in an MPS exhibited higher viability and improved hepatic functions, such as albumin production, expression of hepatocyte marker HNF4α and canaliculi structure, for up to 14days. Additionally, induction of Cytochrome P450 (CYP) 1A and 3A4 in cryopreserved human hepatocytes was observed in the MPS. The acute cytotoxicity of the potent hepatotoxic and hepatocarcinogen, aflatoxin B1, was evaluated in human hepatocytes cultured in an MPS, demonstrating the utility of this model for acute hepatotoxicity assessment. These results indicate that MPS-cultured hepatocytes provide a promising approach for evaluating chemical toxicity in vitro. Copyright © 2017. Published by Elsevier Ltd.

  16. The pericarp extract of Prunus persica attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in mice.

    Science.gov (United States)

    Lee, Chang Ki; Park, Kwang-Kyun; Hwang, Jae-Kwan; Lee, Sang Kook; Chung, Won-Yoon

    2008-06-01

    The fruit of Prunus persica L. (peach) is one of the common fruits. Its seed is well known as a traditional medicine (Persicae Semen) in Japan, China, and other Asian countries. However, the biological activities of P. persica fruit except its seed are poorly understood. This study was aimed at evaluating the protective effect of the pericarp extract of P. persica (PPE) against cisplatin-induced acute toxicity in mice. PPE (500 mg/kg, p.o.) showed a significant protection against the acute nephrotoxicity and hepatotoxicity induced by a single administration of cisplatin (45 mg/kg, i.p.) over a 16-hour period in mice. Its protective effect was evaluated by serum and tissue biochemical parameters. The pretreatment with PPE for 7 days prevented the cisplatin-induced decrease in the kidney and liver weights as a percentage of the total body weight. PPE significantly inhibited both the cisplatin-induced elevation in serum blood urea nitrogen and creatinine levels caused by kidney damage and the cisplatin-induced increase in serum alanine aminotransferase and aspartate aminotransferase levels by the liver damage. In addition, the administration of PPE caused recovery of the cisplatin-mediated changes in levels of serum nitric oxide and tissue lipid peroxidation, and reduced glutathione content returned to control levels. These results suggest that PPE protects against cisplatin-induced nephrotoxicity and hepatotoxicity by reducing cisplatin-induced oxidative stress in mice.

  17. The chronic hepatotoxicity assessment of the herbal formula Zishen Yutai pill.

    Science.gov (United States)

    Xing, Xiaoyan; Deng, Xuehong; Shi, Jinjin; Zhang, Meishuang; Sun, Guibo; Tang, Shimin; Huang, Qiuling; Sun, Xiaobo

    2017-02-01

    Zishen Yutai pill (ZYP) is an oriental herbal formula, while hepatotoxicity assessment of ZYP was rarely evaluated. Therefore, our aim is to re-evaluate its hepatotoxicity in both normal and carbon tetrachloride (CCl4) induced chronic liver injury rats. In the normal model, two doses of ZYP (1.575 and 9.450 g kg(-1) d(-1); i.e. 1 × , 6 × clinical doses) were given orally to rats for 24 weeks. In the chronic liver injury model, 10% CCl4 was administered to rats abdominally twice a week at a dose of 5 mL kg(-1) for 12 consecutive weeks. Administration time started from 4 weeks after the beginning of CCl4 treatment. Toxicological parameters included mortality, body weight, food consumption, clinical signs, biochemical parameters, gross observation, organ weight, necropsy findings and histopathology were monitored. In the normal model, we found no any mortality or abnormality in clinical signs, relative liver weight, biochemical parameters and histopathology in ZYP treatment groups. In the chronic liver injury model, liver damage related parameter such as ALT was elevated at the high dose of ZYP treatment in contrast to the CCl4-treated group (P rats and 9.450 g kg(-1) d(-1) ZYP in the injury rats.

  18. Effect of fenugreek seed extract on adriamycin-induced hepatotoxicity and oxidative stress in albino rats.

    Science.gov (United States)

    Sakr, Saber A; Abo-El-Yazid, Samah M

    2012-11-01

    The purpose of this work was to evaluate the effect of aqueous extract of fenugreek seeds against hepatotoxicity induced in albino rats by the anticancer drug adriamycin (ADR). Animals were given single dose of ADR (10 mg/kg body weight) and were killed after 2 and 4 weeks. Liver of ADR-treated animals showed histopathological and biochemical alterations. The histopathological changes include hepatic tissue impairment, cytoplasmic vacuolization of the hepatocytes, congestion of blood vessels, leucocytic infiltrations and fatty infiltration. Moreover, the expression of proliferating cell nuclear antigen was increased in ADR-treated rats. The liver enzymes, aspartate aminotransferase (ALT) and alanine aminotransferase (AST) were increased in the sera of treated rats. Moreover, ADR significantly increased the concentration of malondialdehyde (MDA) and decreased the activities of superoxide dismutase (SOD) and catalase (CAT) in hepatic tissue. Treating animals with ADR and aqueous extract of fenugreek (0.4 g/kg body weight) seeds led to an improvement in histological and biochemical alterations induced by ADR. The biochemical results showed that AST and ALT appeared normal together with reduction in the level of MDA (lipid peroxidation marker) and increase in SOD and CAT activities. It was concluded from this study that the aqueous extract fenugreek seeds has a beneficial impact on ADR-induced hepatotoxicity due to its antioxidant effect in albino rats.

  19. An antibody of TNF-alpha did not prevent thioacetamide-induced hepatotoxicity in rats.

    Science.gov (United States)

    Demirel, Ulvi; Harputluoglu, Murat M M; Seckin, Yuksel; Ciralik, Harun; Temel, Ismail; Ozyalin, Fatma; Otlu, Baris; Yilmaz, Bilgic; Dincturk, Mehmet Sarp; Aladag, Hulya

    2011-07-01

    Tumor necrosis factor (TNF)-α antibodies have been shown to reduce liver damage in different models. We investigated the effects of infliximab (a TNF-α antibody) on liver damage in thioacetamide (TAA)-induced hepatotoxicity in rats. Group 1 (n = 8) was the control group. In group 2 (n = 8), the TAA group, the rats received 300 mg/kg intraperitoneal (ip) TAA daily for 2 days. In group 3 (n = 8), the TAA + Infliximab (INF) group, infliximab (5 mg/kg ip daily) was administered 48 hours before the first dose of TAA daily for 2 days and was maintained for 4 consecutive days. In group 4 (n = 8), the INF group, the rats received only ip infliximab (5 mg/kg) daily. Livers were excised for histopathological and biochemical tests (thiobarbituric-acid-reactive substances [TBARS], and myeloperoxidase [MPO]). Serum ammonia, aspartate transaminase (AST), alanine transaminase (ALT), TNF-α, liver TBARS and MPO levels, and liver necrosis and inflammation scores in the TAA group were significantly higher than in the control and INF groups (all p induced hepatotoxicity, and infliximab does not improve oxidative liver damage.

  20. Hepatoprotective potential of ethanolic extract of Aquilaria agallocha leaves against paracetamol induced hepatotoxicity in SD rats.

    Science.gov (United States)

    Alam, Janey; Mujahid, Md; Badruddeen; Jahan, Yasmeen; Bagga, Paramdeep; Rahman, Md Azizur

    2017-01-01

    Many traditional systems of medicines employ herbal drugs for the hepatoprotection. Aim of the study was designed to evaluate the hepatoprotective potential of 'ethanolic extract of Aquilaria agallocha ( Chen Xiang) leaves' (AAE) against paracetamol (PCM) induced hepatotoxicity in SD rats. Group I animals were treated with 1% CMC for 8 days. Group II, III, IV and V animals were first treated with '1% CMC' 1 ml/kg/day, AAE 200 mg/kg/day, AAE 400 mg/kg/day and silymarin 100 mg/kg/day respectively for 7 days and then, orally administered with PCM 3 g/kg b. wt. on 8th day in a single dose. 24 h after the last dosing by PCM, the blood was obtained through the retro-orbital plexus under light anesthesia and the animals were sacrificed. Hepatoprotective potential was assessed by various biochemical parameters such as ALT, AST, ALP, LDH, bilirubin, cholesterol, TP and ALB. Group IV rats showed significant (p rats. Hepatoprotective potential of AAE 400 mg/kg/day was comparable to that of standard drug silymarin 100 mg/kg/day. Results of the study were well supported by the histopathological observations. This study confirms that AAE possesses hepatoprotective potential comparable to that of standard drug silymarin as it exhibited comparable protective potential against PCM induced hepatotoxicity in SD rats.

  1. Syzygium Cumini (L. Seeds Extract Ameliorates Cisplatin Induced Hepatotoxicity in Male Wistar Rats

    Directory of Open Access Journals (Sweden)

    R.Maheswari

    2015-02-01

    Full Text Available The discovery of cisplatin, cis-[Pt(II(NH(3(2Cl(2] ([PtCl2(NH32] or CDDP, was a corner stone which triggered the interest in platinum(II-and other metal-containing compounds as potential anticancer drugs. Cisplatin, is one of the most potent chemotherapy drugs widely used for cancer treatment. In our present study, an attempt has been made to study the effect of Cisplatin on biochemical and histopathological parameters and ameliorating effects of the Syzygium cumini (L. aqueous seeds extract or Eugena Jambolana in male wistar rats. Adult male wistar rats were divided into four different groups. Group I Served as vehicle treated normal saline (Control, Group II Rats received single intra-peritoneal (Ip injection of cisplatin (7mg/kg bw, Group III received Syzygium cumini (L. aqueous seeds extract 400mg/kg/bw orally for 7 days beginning one day prior to cisplatin (CP injection. Group IV Rats received alone Syzygium cumini (L. aqueous seeds extract (400mg/kg bw treated. Cisplatin exposure leads to adverse effects on hematological, hepatotoxic parameters including Erythrocytes (RBCs. Cisplatin induction leads to reduction in the levels of Enzymic and Non-Enzymic antioxidants levels. However, on treatment with Syzygium cumini (L. aqueous seeds extract normalized the levels of all the biochemical and hematological parameters. These findings highlight the efficacy of Syzygium cumini (L. aqueous seeds extract as protective effects Cisplatin induced hepatotoxicity.

  2. Protective effect of Etlingera elatior (torch ginger) extract on lead acetate--induced hepatotoxicity in rats.

    Science.gov (United States)

    Haleagrahara, Nagaraja; Jackie, Tan; Chakravarthi, Srikumar; Rao, Mallikarjuna; Kulur, Anupama

    2010-10-01

    Lead is known to disrupt the biological systems by altering the molecular interactions, cell signaling, and cellular function. Exposure to even low levels of lead may have potential hazardous effects on brain, liver, kidneys and testes. The efficacy of Etlingera elatior (torch ginger) to protect hepatotoxicity induced by lead acetate was evaluated experimentally in male Sprague - Dawley rats. Rats were exposed to lead acetate in drinking water (500 ppm) for 21 days and the effects of concurrent treatment with extract of E. elatior on hepatic lipid hydroperoxides (LPO), protein carbonyl content (PCC), total antioxidants (TA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione S- Transferase (GST) levels and histopathological changes in liver were evaluated. There was a significant decrease in TA and other antioxidant enzymes (p induced changes in hepatic architecture. E. elatior has also reduced the blood lead levels (BLL). Thus, there has been extensive biochemical and structural alterations indicative of liver toxicity with exposure to lead and E. elatior treatment significantly reduced these oxidative damage. Our results suggest that E. elatior has a powerful antioxidant effect against lead-induced hepatotoxicity.

  3. Protective effect of Pisonia aculeata on thioacetamide induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Anbarasu C; Rajkapoor B; Bhat KS; John Giridharan; A Arul Amuthan; Satish K

    2012-01-01

    Objective:To evaluate the protective effect of Pisonia aculeata (P. aculeata) on thioacetamide induced hepatotoxicity in rats. Methods:Male Wistar rats were administered 250 or 500 mg/kg p.o. of P. aculeata extract for 21 days and simultaneously administered thioacetamide (TAA) 50 mg/kg bw s.c. 1 h after the respective assigned treatments every 72 h. At the end of all experimental methods, all the animals were sacrificed by cervical decapitation. Blood samples were collected. Serum was separated and analyzed for various biochemical parameters. Results: TAA induced a significant rise in aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin, gamma glutamate transpeptidase (GGTP), lipid peroxidase (LPO) with a reduction of total protein, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione S-transferase (GST). Treatment of rats with different doses of plant extract (250 and 500 mg/kg) significantly (P<0.001) altered serum marker enzymes and antioxidant levels to near normal against TAA treated rats. The activity of the extract at a dose of 300 mg/kg was comparable to the standard drug, silymarin (50 mg/kg, p.o.). Conclusions:It can be concluded that P. aculeata extract possesses a remarkable hepatoprotective and antioxidant activity against TAA induced hepatotoxicity. More research is required to derive an optimal therapeutic dose.

  4. Effects of selenium on chromium (VI)-induced hepatotoxicity in adult rats.

    Science.gov (United States)

    Soudani, Nejla; Ben Amara, Ibtissem; Sefi, Mediha; Boudawara, Tahia; Zeghal, Najiba

    2011-09-01

    Chromium, a major environmental pollutant, is known for its wide toxic manifestations. The present experiment pertains to the protective role of selenium (Se) against K(2)Cr(2)O(7)-induced hepatotoxicity. Female Wistar rats were divided into four groups of six each: group I served as controls which received standard diet; group II received in drinking water K(2)Cr(2)O(7) alone (700 ppm); group III received both K(2)Cr(2)O(7) and Se (0.5 Na(2)SeO(3) mg/kg of diet); group IV received Se (0.5 mg/kg of diet) for 3 weeks. Exposure of rats to chromium promoted oxidative stress with an increase in malondialdehyde (MDA) and a decrease in glutathione (GSH) levels. A decrease in glutathione peroxidase (GPx) and an increase in superoxide dismutase (SOD) and catalase (CAT) activities were observed. Se supplementation to the diet of group III improved all the parameters cited above. Yet, plasma transaminases (AST and ALT), lactate dehydrogenase (LDH) activities, cholesterol, triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) levels increased, while high density lipoprotein-cholesterol (HDL-C) decreased. Co-administration of Se to the diet of group III restored hepatic markers to near-normal values. The biochemical results confirmed the histopathological findings. Therefore, our investigation revealed that Se was effective in preventing K(2)Cr(2)O(7)-induced hepatotoxicity.

  5. Therapeutic effects of Cassia angustifolia in a cadmium induced hepatotoxicity assay conducted in male albino rats

    Directory of Open Access Journals (Sweden)

    Muhammad Tahir Haidry

    2016-06-01

    Full Text Available The present study aims to investigate the therapeutic effects of Senna plant (Cassia angustifolia L. in a cadmium induced hepatotoxicity assay by evaluating the activity of alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and total protein (TP in the albino rats’ serum. A total of 30 white albino rats were taken and divided into three groups; each group comprising ten rats. The group A was taken as a control group; group B was given cadmium chloride concentration of 5 mg/kg (body weight for 42 days; and group C was given cadmium chloride 5 mg/kg body weight for first 21 days and then extract of C. angustifolia 100 mg/kg (body weight was given for remaining 21 days. The analysis were performed twice i.e., on 21st day and 42nd day. Results illustrated that the concentration of cadmium was significantly elevated (P<0.05 at the levels of serum biochemical markers namely ALT, AST, ALP which lowered the protein levels in albino rats. Moreover, treatment with the standard extracts of C. angustifolia observed to reverse the effects of the cadmium significantly (P<0.05. It is concluded that the C. angustifolia had hepatoprotective effects and therapeutic potential against the cadmium induced hepatotoxicity in albino rats.

  6. Hepatoprotective potential of ethanolic extract of Caesalpenia crista leaves against paracetamol induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Garima Mishra

    2015-01-01

    Full Text Available Objective: To investigate the hepatoprotective activity of ethanolic extract of leaves of Caesalpenia crista (C. crista against paracetamol induced hepatotoxicity in rats. Methods: Paracetamol (2 g/kg body weight was used to induce hepatotoxicity in albino rats. Ethanolic extract of leaves of C. crista was administered at the dose levels of 200 and 400 mg/kg body weight orally for 7 d. Silymarin (100 mg/kg was used as standard drug. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, serum alkaline phosphatase, bilirubin (total and direct, and triglycerides content. Histopathological study of rat liver was also done. Results: Administration of ethanolic extract at doses 200 mg/kg and 400 mg/kg body weight exhibited significant reduction in elevated level of serum marker enzymes, bilirubin (total and direct and triglycerides when compared to positive control group. Conclusions: It is concluded that the ethanolic extract of C. crista leaves seems to justify the promising hepatoprotective effect on paracetamol induced liver damage in rats.

  7. Hypericum perforatum-induced hepatotoxicity with possible association with copaiba (Copaifera langsdorffii Desf):case report.

    Science.gov (United States)

    Agollo, Marjorie Costa; Miszputen, Sender Jankiel; Diament, Jayme

    2014-09-01

    We report a case of liver damage in an elderly patient after the use of herbal products of Hypericum perforatum and copaiba (Copaifera langsdorffii Desf). Hepatotoxicity related to Hypericum perforatum is anecdotally known, but for copaiba, widely used as anti-inflammatory, there is just experimental data in the national literature. This report aimed to draw attention to the possible toxic effects of this association as well as to the clinical recovery of the patient after discontinuing their use. There is a tendency to suspect of the action of drugs to justify a non-viral acute liver injury, because of the large number of drugs responsible for hepatotoxicity. There are experiments and clinical reports in the literature describing some herbal products, including Hypericum perforatum, as the causative agents of this aggression, and are considered innocuous and used with no restrictions. We must remember that adverse reactions also occur with these substances; hence, they should be investigated when collecting the patient´s history, for leading to severe liver failure.

  8. Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide.

    Science.gov (United States)

    Ansar, S; Iqbal, M

    2016-03-01

    Garlic contains diallylsulfide (DAS) and other structurally related compounds that are widely believed to be active agents in preventing cancer. This study shows the effect of DAS (a phenolic antioxidant used in foods, cosmetics, and pharmaceutical products) on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats. Male albino rats of Wistar strain weighing 125-150 g were given a single dose of Fe-NTA (9 mg kg(-1) body weight, intraperitoneally) after 1 week of treatment with 100 and 200 mg kg(-1) DAS in corn oil respectively administered through the gavage. Fe-NTA administration led to 2.5-fold increase in the values of both alanine transaminase and aspartate aminotransferase, respectively, and 3.2-fold increase in the activity of lactate dehydrogenase, microsomal lipid peroxidation to approximately 2.0-fold compared to saline-treated control. The activities of glutathione (GSH) and other antioxidant enzymes decreased to a range of 2.2-2.5-fold. These changes were reversed significantly (p induced tissue injury and hepatotoxicity in rats.

  9. The role of glutathione detoxification pathway in MCLR-induced hepatotoxicity in SD rats.

    Science.gov (United States)

    Li, Shangchun; Chen, Jun; Xie, Ping; Guo, Xiaochun; Fan, Huihui; Yu, Dezhao; Zeng, Cheng; Chen, Liang

    2015-12-01

    In the present study, we investigated the role of glutathione (GSH) and its related enzymes in Sprague Dawley (SD) rats subjected to microcystin-leucine-arginine (MCLR)-induced hepatotoxicity. SD rats were intraperitoneally (i.p.) injected with MCLR after pretreating with or without buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GSH synthesis. The depletion of GSH with BSO enhanced MCLR-induced oxidative stress, resulting in more severe liver damage and higher MCLR accumulation. Similarly, the contents of malondialdehyde (MDA), total GSH (T-GSH), oxidized GSH (GSSG) and GSH were significantly enhanced in BSO pretreated rats following MCLR treatment. The study showed that the transcription of GSH-related enzymes such as glutathione-S-transferase (GST), γ-glutamylcysteine synthetase (γ-GCS), glutathione reductase (GR) varied in different ways (expect for glutathione peroxidase (GPx), whose gene expression was induced in all treated groups) with or without BSO pretreatment before MCLR exposure, suggesting an adaptative response of GSH-related enzymes at transcription level to combat enhancement of oxidative stress induced by MCLR when pretreated with BSO. These data suggested the tissues with low GSH concentration are highly vulnerable to MCLR toxicity and GSH was critical for the detoxification in MCLR-induced hepatotoxicity in vivo.

  10. Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitis and hepatotoxicity in rats.

    Science.gov (United States)

    Farombi, Ebenezer O; Adedara, Isaac A; Awoyemi, Omolola V; Njoku, Chinonye R; Micah, Gabriel O; Esogwa, Cynthia U; Owumi, Solomon E; Olopade, James O

    2016-02-01

    The present study investigated the antioxidant and anti-inflammatory effects of dietary protocatechuic acid (PCA), a simple hydrophilic phenolic compound commonly found in many edible vegetables, on dextran sulphate sodium (DSS)-induced ulcerative colitis and its associated hepatotoxicity in rats. PCA was administered orally at 10 mg kg(-1) to dextran sulphate sodium exposed rats for five days. The result revealed that administration of PCA significantly (p rats. Furthermore, PCA prevented the increase in the plasma levels of pro-inflammatory cytokines, markers of liver toxicity and markedly suppressed the DSS-mediated elevation in colonic nitric oxide concentration and myeloperoxidase activity in the treated rats. Administration of PCA significantly protected against colonic and hepatic oxidative damage by increasing the antioxidant status and concomitantly decreased hydrogen peroxide and lipid peroxidation levels in the DSS-treated rats. Moreover, histological examinations confirmed PCA chemoprotection against colon and liver damage. Immunohistochemical analysis showed that PCA significantly inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression in the colon of DSS-treated rats. In conclusion, the effective chemoprotective role of PCA in colitis and the associated hepatotoxicity is related to its intrinsic anti-inflammatory and anti-oxidative properties.

  11. The protective effects of vitamin C on hepatotoxicity induced by radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Ki Jung; Park, Sung Kwang; Cho, Heung Lae [Pusan Paik Hospital, Inje University, Busan (Korea, Republic of); Kang, Ki Mun; Chai, Gyu Young; Chung, Duck Wha [Gyungsang National University, Jinju (Korea, Republic of); Kang, Jin Soon [Jinju International University, Jinju (Korea, Republic of)

    2004-12-15

    This study was carried out to determine the protective effects of vitamin C on the hepatotoxicity induced by radiation. The Spraque Dawley rats were randomly divided into 3 groups; the control group, the radiation exposed group, and the radiation and vitamin C-treated group. SOD activity catalase, malondialdehyde and liver enzymes were analyzed to assess the antioxidant effects of vitamin C. The increased level of malondialdehyde and the decreased catalase activity that were induced by radiation were improved after vitamin C but were was no statistical significance among three groups. The superoxide dismutase activity of the liver was increased by vitamin C, but there were no statistically significant differences between the vitamin C-treated group and the non vitamin C-treated group. The level of liver enzymes in sera such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehyrogenase and alkaline phosphatase were remarkably elevated by radiation. The levels of those enzymes were decreased in the vitamin C-treated group and statistical significance was noted for the GPT level ({rho} < 0.01). On the electromicrographic findings, the hepatic cell destruction was considerably decreased in the vitamin C-treated group. Vitamin C is thought to be an effective antioxidant against the hepatotoxicity induced by radiation.

  12. Influence of Moxifloxacin on Hepatic Redox Status and Plasma Biomarkers of Hepatotoxicity and Nephrotoxicity in Rat

    Directory of Open Access Journals (Sweden)

    Ayokanmi Ore

    2015-01-01

    Full Text Available Moxifloxacin is a broad spectrum fluoroquinolone antibacterial agent. We examined the hepatic redox status and plasma biomarkers of nephrotoxicity and hepatotoxicity in rat following administration of moxifloxacin (MXF. Twenty-four Wistar rats, 180–200 g, were randomized into four groups (I–IV. Animals in group I (control received 1 mL of distilled water, while animals in groups II, III, and IV received 1 mL each of MXF equivalent to 4 mg/kg b.w., 8 mg/kg b.w., and 16 mg/kg b.w., respectively. After seven days, plasma urea, bilirubin, and creatinine were significantly (P<0.05 elevated in the MXF-treated animals. Activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were significantly increased in the plasma of MXF-treated animals compared to control. Also plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides increased significantly in the MXF-treated groups relative to control. Moreover, MXF triggered a significant decrease in hepatic catalase, superoxide dismutase, and glutathione-S transferase activities. Likewise, MXF caused a decrease in the hepatic levels of glutathione and vitamin C. A significant increase in hepatic MDA content was also observed in the MXF-treated animals relative to control. Overall, our data suggest that the half-therapeutic, therapeutic, and twice the therapeutic dose of MXF induced nephrotoxicity, hepatotoxicity, and altered hepatic redox balance in rats.

  13. Prophylactic and therapeutic effects of taurine against aluminum-induced acute hepatotoxicity in mice.

    Science.gov (United States)

    El-Sayed, Wael M; Al-Kahtani, Mohamed A; Abdel-Moneim, Ashraf M

    2011-08-30

    Aluminum is a well known neurotoxin and a possible candidate of hepatotoxins to humans. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. In the present study, Aluminum (AlCl(3)) intoxication (a single injection of 25mg Al(3+)/kg, i.p.) for 24h in mice resulted in elevations in serum alanine aminotransferase activity and serum tumor necrosis factor and hepatic malondialdehyde levels. Aluminum reduced the activities of glutathione peroxidase, glutathione S-transferase, quinone oxidoreductase, and catalase in liver. In addition, Al caused hepatic hemorrhage, cellular degeneration as well as necrosis of hepatocytes. Ultrastructure examination showed swelling of mitochondria, derangement of rough endoplasmic reticulum cisternae and pleomorphic nuclei with abnormal chromatin distribution. Taurine, a sulfur-containing amino acid was administered to mice daily for 5 days before (at 100mg/kg, i.p.) or 2h after (a single dose of 1g/kg, i.p.) aluminum administration. Treating mice with taurine at either dosing regimens, pre- or post-aluminum administration alleviated aluminum oxidative damaging effects. The rate of recovery was better when taurine was administered prior to Al. Taurine had anaphylactic and therapeutic activity against hepatotoxicity induced by aluminum in mice.

  14. Hepatoprotective potential of ethanolic extract of Caesalpenia crista leaves against paracetamol induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Garima Mishra; Ratan Lal Khosa; Pradeep Singh; Keshri Kishor Jha

    2015-01-01

    Objective:To investigate the hepatoprotective activity of ethanolic extract of leaves of Caesalpenia crista (C. crista) against paracetamol induced hepatotoxicity in rats. Methods:Paracetamol (2 g/kg body weight) was used to induce hepatotoxicity in albino rats. Ethanolic extract of leaves of C. crista was administered at the dose levels of 200 and 400 mg/kg body weight orally for 7 d. Silymarin (100 mg/kg) was used as standard drug. The hepatoprotective effect of ethanolic extract was evaluated by assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, serum alkaline phosphatase, bilirubin (total and direct), and triglycerides content. Histopathological study of rat liver was also done. Results:Administration of ethanolic extract at doses 200 mg/kg and 400 mg/kg body weight exhibited significant reduction in elevated level of serum marker enzymes, bilirubin (total and direct) and triglycerides when compared to positive control group. Conclusions:It is concluded that the ethanolic extract of C. crista leaves seems to justify the promising hepatoprotective effect on paracetamol induced liver damage in rats.

  15. 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.

  16. Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: was causality adequately ascertained?

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-06-01

    Spontaneous reports of primarily assumed hepatotoxicity in connection with the use of Pelargonium sidoides (PS) have been interpreted by the Drug Commission of the German Medical Association (DCGMA) as showing some hepatotoxic potential of PS used to treat common cold and other respiratory tract infections. Causality for PS was assessed using the liver specific, structured, quantitative, and updated scale of the Council for International Organizations of Medical Sciences (CIOMS). In none of the 15 cases was there a highly probable or probable causality for PS. Analysis revealed confounding factors such as numerous final diagnoses unrelated to PS and poor data quality in virtually all cases. In only a minority of the cases were data provided to consider even common other diseases of the liver. For instance, biliary tract imaging data were available in only 3 patients; data to exclude virus infections by hepatitis A-C were provided in 4 cases and by CMV and EBV in 1 case, whereas HSV and VZV virus infections remained unconsidered. Thus, convincing evidence is lacking that PS was a potential hepatotoxin in the analyzed cases.

  17. Therapeutic Effects of Cassia angustifolia in a Cadmium Induced Hepatotoxicity Assay Conducted in Male Albino Rats

    Directory of Open Access Journals (Sweden)

    Muhammad Tahir Haidry

    2016-04-01

    Full Text Available The present study aims to investigate the therapeutic effects of Senna plant (Cassia angustifolia L. in a cadmium-induced hepatotoxicity assay by evaluating the activity of alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and total protein (TP in the albino rats’ serum. A total of 30 white albino rats were taken and divided into three groups; each group comprising ten rats. The group A was taken as a control group; group B was given cadmium chloride concentration of 5 mg/kg (body weight for 42 days; and group C was given cadmium chloride 5 mg/kg body weight for first 21 days and then extract of C. angustifolia 100 mg/kg (body weight was given for remaining 21 days. The analysis were performed twice i.e., on 21stst day and 42nd day. Results illustrated that the concentration of cadmium was significantly elevated (P<0.05 at the levels of serum biochemical markers namely ALT, AST, ALP which lowered the protein levels in albino rats. Moreover, treatment with the standard extracts of C. angustifolia observed to reverse the effects of the cadmium significantly (P<0.05. It is concluded that the C. angustifolia had hepatoprotective effects and therapeutic potential against the cadmium-induced hepatotoxicity in albino rats.

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

    Science.gov (United States)

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

    2015-12-01

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

  19. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin.

    Science.gov (United States)

    Lari, Parisa; Abnous, Khalil; Imenshahidi, Mohsen; Rashedinia, Marzieh; Razavi, Marjan; Hosseinzadeh, Hossein

    2015-04-01

    Diazinon (DZN) is one of the most widely used insecticides in agricultural pest control. Previous studies have shown that DZN may induce hepatotoxicity. Reactive oxygen species and apoptosis pathways are involved in the toxicity of DZN. Crocin, a constituent of saffron, has hepatoprotective effects due to its antioxidant activity. In this study, we examined the effects of subacute DZN exposure and ameliorating effect of crocin on lipid peroxidation and pathological changes in rat liver. Moreover, protein levels of activated and total caspases-3 and -9 and Bax/Bcl-2 ratio were measured. Five groups of rats were used in the experiment. Corn oil (control), DZN (15 mg/kg per day, orally) and crocin (12.5, 25 and 50 mg/kg per day, intraperitoneally in combination with DZN) were given to male Wistar rats (n = 6) for 4 weeks. The level of malondialdehyde (MDA) increased significantly in DZN group compared with the control group (p liver after oral exposure to DZN was observed. DZN also induced apoptosis through activation of caspases-9 and -3 and increasing Bax/Bcl-2 ratio. Crocin attenuated the activation of caspases and reduced the Bax/Bcl-2 ratio. It is concluded that subacute exposure to DZN induces oxidative stress-mediated apoptosis and crocin may reduce DZN-induced hepatotoxicity.

  20. 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.

  1. Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

    Science.gov (United States)

    El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

    2016-01-01

    The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.

  2. Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity : An Analysis of Spontaneous Report Data from the WHO Database

    NARCIS (Netherlands)

    Jessurun, Naomi; van Puijenbroek, Eugene

    2015-01-01

    BACKGROUND: Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the

  3. Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity and oxidative stress in rats

    Institute of Scientific and Technical Information of China (English)

    Adedayo O Ademiluyi; Ganiyu Oboh; Tosin R Owoloye; Oluwaseun J Agbebi

    2013-01-01

    To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. Methods: Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body weight) for 3 d. The liver and plasma were studied for hepatotoxicity and antioxidant indices. Results: Gentamycin induces hepatic damage as revealed by significant (P<0.05) elevation of liver damage marker enzymes (aspartate transaminase and alanine aminotransferase) and reduction in plasma albumin level. Gentamycin also caused a significant (P<0.05) alteration in plasma and liver enzymatic (catalase, glutathione and super oxygen dehydrogenises) and non-enzymatic (glutathione and vitamin C) antioxidant indices with concomitant increase in the malondialdehyde content; however, there was a significant (P<0.05) restoration of the antioxidant status coupled with significant (P<0.05) decrease in the tissues’ malondialdehyde content, following consumption of diets containing garlic. Conclusions: These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  4. DILI (drug induced liver injury in a 9-month-old infant: a rare case of phenobarbital-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Anna Paola Pinna

    2013-04-01

    Full Text Available Phenobarbital is one of the most commonly prescribed antiepileptic drugs in childhood, but it can rarely cause serious adverse effects, such as hepatotoxicity that includes a broad clinical spectrum (from isolate hypertransaminasemia to acute liver failure. We describe a case of DILI in a 9-month-old infant caused by chronic therapy with phenobarbital.

  5. Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

    Science.gov (United States)

    Okwa, Iniviefien B; Akindele, Abidemi J; Agbaje, Esther O; Oshinuga, Oladoyin T; Anunobi, Chidozie C; Adeyemi, Olufunmilayo O

    2013-01-01

    Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

  6. D-galactosamine/lipopolysaccharide-induced hepatotoxicity downregulates sirtuin 1 in rat liver: role of sirtuin 1 modulation in hepatoprotection.

    Science.gov (United States)

    Kemelo, M K; Wojnarová, L; Kutinová Canová, N; Farghali, H

    2014-01-01

    D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

  7. Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Boligon, Aline A; Athayde, Margareth L

    2014-12-01

    This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (Pinduced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

  8. Comparative Proteomic Analysis Shows an Elevation of Mdh1 Associated with Hepatotoxicity Induced by Copper Nanoparticle in Rats

    Institute of Scientific and Technical Information of China (English)

    DONG Shu-wei; GAO Zhao-hui; SHEN Xiao-yun; XUE Hui-wen; LI Xia

    2014-01-01

    Copper nanoparticle is a new material widely used in biological medicine, animal husbandry and industrial areas, but its potential toxicity to human health and environment remains unclear. In order to study the hepatotoxic mechanisms of nanoparticles copper, two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of lfight mass spectrometry (MALDI/TOF MS) of proteomics technology were used to isolate and identify the differentially expressed proteins from liver, which associated with hepatotoxicity induced by copper nanoparticle in rats. In this study, we have screened 15 kinds of proteins related with hepatotoxicity, of which spot8212 was identiifed as Malate dehydrogenase (Mdh1). The mRNA expression trend of Mdh1 was consistent with the result of 2-DE by RT-PCR validation. Bioinformatics analysis showed that Mdh1 was stable and no signal peptides, subcellular location was in endoplasmic reticulum;it contained many functional sites such as malate dehydrogenase activity signal sites 155LTRLDHNRAKSQI167; α helixes and random coils were the two main elements. Homologous analysis demonstrated high homologous of Mdh1 in rats with mouse and human, and the phylogenetic tree of Mdh1 was constructed. The result indicated that copper nanoparticle could regulate up the Mdh1 protein expression so as to compensate the energy deifcit. Energy metabolic disturbance may be a pathway for copper nanoparticle particles to exert the hepatotoxic effects in rats.

  9. Xanthine oxidase inhibition by allopurinol increases in vitro pyrazinamide-induced hepatotoxicity in HepG2 cells.

    NARCIS (Netherlands)

    Tostmann, A.; Aarnoutse, R.E.; Peters, W.H.M.; Richard, P.N.; Boeree, M.J.

    2010-01-01

    Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the mechanism of pyrazinamide-induced hepatotoxicity. We inhibited xanthine oxidase in HepG2 cells by using a nontoxic concentration of allopurinol, a well-known xanthine-oxidase inhibitor. This increased in

  10. Use of the HepaRG Cell Line to Assess Potential Human Hepatotoxicity of ToxCast™ Chemicals

    Science.gov (United States)

    The HepaRG cell line is a promising model system for predicting human hepatotoxicity in part because of the greater capacity to metabolize chemicals than other cell models. We hypothesized that this cell line would be a relevant model for toxicity testing of industrial chemicals....

  11. Cancer incidence among waiters

    DEFF Research Database (Denmark)

    Reijula, Jere; Kjaerheim, Kristina; Lynge, Elsebeth

    2015-01-01

    INCIDENCE IN SOME CANCER SITES CAN LIKELY BE EXPLAINED BY HIGHER ALCOHOL CONSUMPTION, THE PREVALENCE OF SMOKING AND OCCUPATIONAL EXPOSURE TO TOBACCO SMOKE HOPEFULLY, THE INCIDENCE OF CANCER AMONG WAITERS WILL DECREASE IN THE FUTURE, DUE TO THE BANNING OF TOBACCO SMOKING IN RESTAURANTS AND BARS IN THE NORDIC...

  12. Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats.

    Directory of Open Access Journals (Sweden)

    Brijesh Kumar Singh

    Full Text Available Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(PH and GSH (56% and 74% respectively; P<0.001, increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c. It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05. A combination of camphene and geraniol (CG; 1:1, when pre-administered in rats (10 mg/kg BW, accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(PH and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore

  13. Crucial role of cytochrome P450 in hepatotoxicity induced by 2,3-dimethoxy-1,4-naphthoquinone in rats.

    Science.gov (United States)

    Ishihara, Yasuhiro; Ishii, Satomi; Sakai, Yufu; Yamamura, Nobue; Onishi, Yukiko; Shimamoto, Norio

    2011-03-01

    Quinone toxicity is induced by two principal mechanisms: arylation/alkylation and a redox cycle. We have previously shown that increases in intracellular levels of superoxide anion and cell death induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a redox cycling quinone, are enhanced by pretreatment of rat primary hepatocytes with cytochrome P450 inhibitors. This indicates a novel interaction of quinones with cytochrome P450, and is thus worthy of further investigation using an in vivo model. The aim of this study was to examine the effects of cytochrome P450 inhibitors on DMNQ-induced hepatotoxicity in rats. When DMNQ was administered intraperitoneally, the activities of serum alanine aminotransferase and aspartate aminotransferase were found to increase in a dose-dependent manner, indicating that hepatotoxicity was induced by treatment with DMNQ. Pretreatment with the cytochrome P450 inhibitors SKF-525A (SKF), cimetidine and ketoconazole potentiated the DMNQ-induced hepatotoxicity. The blood concentration of DMNQ was not affected by administration of SKF. Pretreatment with the antioxidant α-tocopherol almost completely attenuated the hepatotoxicity induced by DMNQ and by the combination of DMNQ with SKF. Levels of reduced glutathione in the liver were decreased and levels of oxidized glutathione were increased by treatment with DMNQ. These effects were potentiated by pretreatment with SKF. DMNQ-induced lipid peroxidation in the liver was also enhanced by pretreatment with SKF. Taken together, these results indicate that DMNQ-induced hepatotoxicity is augmented by inhibition of cytochrome P450 and that this augmentation is due to the enhancement of oxidative stress.

  14. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events

    Directory of Open Access Journals (Sweden)

    Rankin Elizabeth

    2008-04-01

    Full Text Available Abstract Background Spontaneous reporting systems for adverse drug reactions (ADRs are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients. Methods Serious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions. Results Ten cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients. Conclusion Serious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.

  15. 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.

  16. Dutch perfusion incident survey.

    Science.gov (United States)

    Groenenberg, Ingrid; Weerwind, Patrick W; Everts, Peter A M; Maessen, Jos G

    2010-09-01

    Cardiopulmonary bypass procedures remain complex, involving many potential risks. Therefore, a nationwide retrospective study was conducted to gain insight into the number of incidents and accidents in Dutch adult perfusion practice. An anonymous postal survey (85 questions about hardware, disposables, fluids and medication, air emboli, anticoagulation, practice, and safety measures) was sent to all Dutch perfusionists involved in adult cardiovascular perfusion during 2006 and 2007. To guarantee complete anonymity, respondents were asked to return the survey to a notary who discarded personal information. The net response rate was 72% and covered 23,500 perfusions. Individual respondents performed 240 ± 103 perfusions during the 2-year study period and had 13.8 ± 8.7 years of practical experience. The incident rate was 1 per 15.6 perfusions and the adverse event rate was 1 per 1,236 perfusions. The three most reported incidents were: (1) persistent inability to raise the activated coagulation time above 400s during perfusion (184 incidents); (2) an allergic or anaphylactic reaction to drugs, fluids, or blood products (114 incidents); and (3) clotting formation in the extracorporeal circuit (74 incidents). Furthermore, pre-bypass safety measures showed no statistically significant association with the reported incidents. In comparison with data from the recent literature, the reported number of incidents is high. Nevertheless, the adverse outcome rate is well matched to other published surveys. The relatively high response rate conveys the impression that the Dutch perfusionist is vigilant and willing to report incidents. Hence, a web-based Dutch perfusion incident registration system is recommended.

  17. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.

    Science.gov (United States)

    Tommonaro, Giuseppina; García-Font, Nuria; Vitale, Rosa Maria; Pejin, Boris; Iodice, Carmine; Cañadas, Sixta; Marco-Contelles, José; Oset-Gasque, María Jesús

    2016-10-21

    Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3'-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of

  18. Hepatotoxicity after liver irradiation in children and adolescents. Results from the RiSK

    Energy Technology Data Exchange (ETDEWEB)

    Roesler, Pascal; Christiansen, Hans [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); Kortmann, Rolf-Dieter [University of Leipzig, Department of Radiotherapy, Leipzig (Germany); Martini, Carmen [University Hospital of Freiburg, Department of Radiotherapy, Freiburg im Breisgau (Germany); Matuschek, Christiane [Heinrich-Heine University of Duesseldorf, Department of Radiotherapy, Medical Faculty, Duesseldorf (Germany); Meyer, Frank [Hospital Augsburg, Department of Radiotherapy, Augsburg (Germany); Ruebe, Christian [University Hospital of Homburg/Saar, Department of Radiotherapy, Homburg/Saar (Germany); Langer, Thorsten [University Hospital of Schleswig-Holstein, Department of Pediatrics, Pediatric Oncology, Campus Luebeck (Germany); Koch, Raphael [University of Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany); Eich, Hans Theodor; Willich, Normann [University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany); Steinmann, Diana [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany)

    2015-05-01

    The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose-volume effects and liver function in childhood and adolescence. Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the ''Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)'' using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria. Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1-18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1-4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume-dose correlations showed no statistically noticeable effect on acute or chronic toxicity. Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose-volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It

  19. Amelioration of carbon tetrachloride- and paracetamol-induced hepatotoxicity in rats by Ficus dalhousiae

    Directory of Open Access Journals (Sweden)

    Syed Safiullah Ghori

    2014-12-01

    Full Text Available The present study was undertaken to investigate hepatoprotective activity of Ficus dalhousiae leaves ethanolic extract based on its traditional claim. Paracetamol- and carbon tetrachloride-induced hepatotoxicity in albino Wistar rats, experimental models was used for the evaluation. Various biochemical parameters like SGPT, SGOT, serum albumin, alkaline phosphatase, total bilirubin, direct bilirubin and total protein were estimated. Oral treatment with the extract 250 and 500 mg/kg, significantly (p<0.01 altered all the serum marker levels to the normal in both the experimental models. The activity of the extract was comparable to that of standard drug, silymarin (25 mg/kg, p.o.. Histopathological observations also demonstrated protective effect of the test extract on liver anatomy. Overall results suggest that F. dalhousiae possesses in vivo hepatoprotective activity.

  20. Ameliorative effect of vitamin E on potassium dichromate-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Ali A. Shati

    2014-07-01

    There was a significant accumulation of Cr in the livers of the Cr group compared with the control group. In addition, exposure to K2Cr2O7 induced significant increases in the level of thiobarbituric-reactive substances (TBARS and significant decreases in glutathione (GSH content and superoxide dismutase (SOD activity in the Cr group compared with the control group. Moreover, livers of the Cr group showed major histological alterations, such as severe necrosis, increased lymphocytic infiltration, and a significant decrease in the DNA content. Oral vitamin E administration concomitant with K2Cr2O7 ameliorated all these changes and resulted in normal hepatic histological and cellular contents. In conclusion, oral vitamin E administration has a hepatoprotective role against K2Cr2O7-induced hepatotoxicity in rats.

  1. Metabolism of the hepatotoxic compound sophoraflavanone G in rat liver microsomes.

    Science.gov (United States)

    Chen, Ping; Zhang, Xiuwen; Huang, Taomin; Yu, Qianqian; Cheng, Nengneng

    2014-07-01

    Our study aimed at investigating the metabolic characteristics of sophoraflavanone G (SFG), one of the hepatotoxic constituents of Sophora flavescens, in rat liver microsomes (RLMs). SFG was metabolized to 3 phase I metabolites, di-hydroxylated SFG (M1), mono-hydroxylated SFG (M2), dehydrogenated product of mono-hydroxylated SFG (M3) and 3 SFG glucuronides (M4, M5, and M6) by RLMs. The formation kinetics of M2 conformed to biphasic kinetics in RLMs. The formation kinetics of M4 and M5 best-fitted the Hill equation kinetics. Chemical inhibition studies found that CYP1A2 and CYP2E1 were the major enzymes responsible for the formation of M2, and the formation of M4 and M5 may be catalyzed by multiple UGT1A isoforms.

  2. Hepatoprotective activity of methanolic extract of Mussaenda philippica (stems against anti-tubercular drugs induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Swarnalatha Reddy Dugasani

    2014-12-01

    Full Text Available The present study was designed to evaluate the hepatoprotective effect of methanolic extract of Mussaenda philippica against isoniazid and rifampicin induced hepatotoxicity in experimental rats. Six groups of six rat were selected for the study. Methanolic extract of Mussaendaphilippicaat a dose of 100, 200 and 400 mg/kg as well as silymarin (50 mg/kg were administered orally once daily for 14 d in isoniazid and rifampicin group. The serum levels of glutamic oxaloacetic transaminase (SGOT, glutamate pyruvate transaminase (SGPT, alkaline phosphatase, and bilirubin were estimated along with total protein. Histopathological analysis was carried out to assess injury to the liver. The altered biochemical parameters were significantly reverting back by the methanolic extract treatment. Histopathology also supported the biochemical variation. From this study it has been concluded that the methanolic extract of Mussaendaphilippicashows significant hepatoprotective activity.

  3. Attenuation of Carbon Tetrachloride-Induced Hepatotoxicity by Cow Urine Distillate in Rats

    Institute of Scientific and Technical Information of China (English)

    M PGURURAJA; A B JOSHI; HIMANSHU JOSHI; D SATHYANARAYANA; E V S SUBRAHMANYAM; K S CHANDRASHEKHAR

    2009-01-01

    Objectives To study the carbon tetrachloride-induced hepatoprotective activity in cow urine. Methods Effect of cow urine distillate on liver function was studied in vivo in rats intoxicated with carbon tetrachloride (CCl4). Hepatotoxicity was induced by a 1:1 (v/v) mixture of CCl4 in olive oil (5 mL/kg i.p). Protective effect of cow urine distillate (in three dose levels) and standard drug Silymarin (100 mg/kg, p.o) on liver function were studied in intoxicated rats. Parameters in the study included liver function tests and histological observations. Results The cow urine distillate decreased the levels of SGOT, SGPT, ALP, GGT, and total bilirubin in a dose-dependent manner (P<0.05) as sylimarin. Conclusion The observed protective effects of cow urine distillate on liver function might be due to the presence of antioxidants in cow urine.

  4. PROTECTIVE EFFECT OF Solanum Pubescens LINN ON CCL4 INDUCED HEPATOTOXICITY IN ALBINO RATS

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    M.Pushpalatha

    2012-01-01

    Full Text Available Ethanol extract of Solanum pubescens Linn was evaluated for hepato protective and antioxidant activities in rats. The plant extract (500mg/kg/day showed a remarkable hepatoprotective and antioxidant activity against Carbon tetrachloride (CCl4-induced hepatotoxicity as judged from the serum marker enzymes and antioxidant levels in liver tissues. CCl4 induced a significant rise in aspartate amino transferase (AST, alanine amino transferase (ALT, alkaline phosphatase (ALP, total bilirubin, LPO with a reduction of total protein, superoxide dismutase (SOD, catalase, and reduced glutathione (GSH. Treatment of rats with plant extract (500 mg/kg significantly (P<0.01 altered serum marker enzymes and antioxidant levels to near normal against CCl4 - treated rats. The activity of the extract at dose of 500 mg/kg was comparable to the standard drug, Silymarin (50 mg/kg, p.o.. Histopathological examination of the liver tissues supported the hepatoprotective activity of plant.

  5. Hepatoprotective and Antioxidant potential of Tephrosia Purprea in Paracetamol Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Shivshankar M. Gunjegaonkar

    2016-03-01

    Full Text Available The present study was designed to evaluate Hepatoprotective and antioxidant potential of Tephrosia Purprea whole plant aqueous extract in paracetamol intoxicated rats. 75mg/kg and 150mg/kg of aqueous extract were administered orally once a daily for seven days. Animals were challenged with paracetamol on 5th day of treatment protocol. Elevated serum levels of transaminases, alkaline phosphatase and bilirubin (direct and total were restored significantly by the extract. Silymarine (reference standard exhibited significant hepatoprotective activity against paracetamol induced hepatotoxicity. The biochemical parameters were supplemented with histopathological studies. In-vitro free radical scavenging activity was screened and results concluded that possible mechanism of hepatoprotective activity may be due to its free radical scavenging activity.

  6. Development of a Capillary Zone Electrophoretic Method for the Rapid Separation and Detection of Hepatotoxic Microcystins

    Energy Technology Data Exchange (ETDEWEB)

    Li, Paul C.H.; Hu, Shen; Lam, Paul K.S

    1999-01-01

    Analysis of trace amounts of various hepatotoxic microcystins in marine and freshwater samples is very important since these toxins, especially microcystin-LR, have been demonstrated to have tumour-promoting activity. In this study, instead of measuring the total amount of microcystins, we developed a capillary zone electrophoretic method for the separation and detection of individual toxin standards. No additives were used for enhancement of resolution. This technique is characterized by a high separation efficiency, short analysis time and small sample volume. In order to improve the detection sensitivity, a laser-induced fluorescence detector was used, and the labelling of microcystins was accomplished through a two-step procedure. First, the microcystin standards were converted into cysteine conjugates, followed by derivatization with Fluorescein 5-Isothiocyanate (FITC). After derivatization, the FITC-labelled microcystins were directly injected, separated and detected in 8 min. This method was shown to be a promising technique for sensitive and rapid analysis of individual microcystin toxins.

  7. Comparison of the phenolic component profiles of skullcap (Scutellaria lateriflora) and germander (Teucrium canadense and T. chamaedrys), a potentially hepatotoxic adulterant

    Science.gov (United States)

    Scutellaria laterifora, commonly known as skullcap, is used as an ingredient in numerous herbal products. However, it has been occasionally adulterated with Teucrium canadense and T. chamaedrys, commonly known as germander, which contain potentially hepatotoxic diterpenes. Analytical methodologie...

  8. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  9. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats

    Science.gov (United States)

    El-Hosseiny, L. S.; Alqurashy, N. N.; Sheweita, S. A.

    2016-01-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats’ liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes’ activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition. PMID:27493593

  10. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Hosseiny, L S; Alqurashy, N N; Sheweita, S A

    2016-06-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition.

  11. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease.

    Science.gov (United States)

    Cerda, Cristian; Bruguera, Miguel; Parés, Albert

    2013-08-28

    Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis. These molecules are well tolerated with scarce secondary effects. Very few cases of possible hepatotoxicity due to these substances have been described. The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease. A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology (mean age 59 years, 56.9% women) attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results. Twenty-three patients (15.2%) recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire. Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment; one of the cases simultaneously presented a skin rash attributed to the drug. Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate. The clinical spectrum is variable, and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity. The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

  12. Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats.

    Science.gov (United States)

    Cayır, Kerim; Karadeniz, Ali; Simşek, Nejdet; Yıldırım, Serap; Karakuş, Emre; Kara, Adem; Akkoyun, Hürrem Turan; Sengül, Emin

    2011-10-01

    Cisplatin (CDDP), one of the most active cytotoxic agents against cancer, has adverse side effects, such as nephrotoxicity and hepatotoxicity. The present study was designed to investigate the potential protective effect of pomegranate seed extract (PSE) against oxidative stress caused by CDDP injury of the kidneys and liver by measuring tissue biochemical and antioxidant variables and immunohistochemically testing caspase-3-positive cells. Twenty-four Sprague-Dawley rats were divided into 4 groups: control; CDDP: injected intraperitoneally with CDDP (7 mg/kg body weight, single dose); PSE: treated for 15 consecutive days by gavage with PSE (300 mg/kg per day); and PSE+CDDP: treated by gavage with PSE 15 days after a single injection of CDDP. The degree of protection against CDDP injury afforded by PSE was evaluated by determining the levels of malondialdehyde as a measure of lipid peroxidation. The levels of glutathione and activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase were estimated from liver and kidney homogenates; the liver and kidney were also histologically examined. PSE elicited a significant protective effect toward liver and kidney by decreasing the level of lipid peroxidation; elevating the levels of glutathione S-transferase; and increasing the activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase. These biochemical observations were supported by immunohistochemical findings and suggested that PSE significantly attenuated nephrotoxicity and hepatotoxicity by the way of its antioxidant, radical-scavenging, and antiapoptotic effects. This PSE extract could be used as a dietary supplement in patients receiving chemotherapy medications.

  13. Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats.

    Science.gov (United States)

    Khan, Somaira; Beigh, Saba; Chaudhari, Bhushan P; Sharma, Shikha; Aliul Hasan Abdi, Sayed; Ahmad, Shahzad; Ahmad, Firoz; Parvez, Suhel; Raisuddin, Sheikh

    2015-10-09

    Bisphenol A (BPA), an estrogenic and endocrine disrupting agent, is widely used in manufacturing of polycarbonate plastics and epoxy resins. BPA and other endocrine disrupting chemicals (EDCs) act via multiple mechanisms including interference with mitochondrial functions. Mitochondria are the hub of cellular energy pool and hence are the target of many EDCs. We studied perturbation of activities of mitochondrial enzymes by BPA and its possible role in hepatotoxicity in Wistar rats. Rats were exposed to BPA (150 mg/kg, 250 mg/kg, 500 mg/kg per os, for 14 days) and activities of enzymes of mitochondrial electron transport chain (ETC) were measured. Besides, other biochemical parameters such as superoxide generation, protein oxidation, and lipid peroxidation (LPO) were also measured. Our results indicated a significant decrease in the activities of enzymes of mitochondrial ETC complexes, i.e., complex I, II, III, IV, and V along with significant increase in LPO and protein oxidation. Additionally, a significant increase in mitochondrial superoxide generation was also observed. All these findings could be attributed to enhanced oxidative stress, decrease in reduced glutathione level, and decrease in the activity of superoxide dismutase in rat liver mitochondria isolated from BPA-treated rats. BPA treatment also caused a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase indicating its potential hepatotoxicity. Furthermore, histopathological findings revealed marked edema formation, hepatocellular degeneration, and necrosis of liver tissue in BPA-exposed rats. In conclusion, this study provides an evidence of impaired mitochondrial bioenergetics and liver toxicity after high-dose BPA exposure in rats. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

  14. Protective effect of Livactine against CCl4 and paracetamol induced hepatotoxicity in adult Wistar rats

    Directory of Open Access Journals (Sweden)

    Candasamy Mayuren

    2010-10-01

    Full Text Available Background: Liver disease has become one of the serious health problems as it is exposed to many kinds of xenobiotics and therapeutic agents. Moreover the rapidly growing morbidity and mortality from liver disease are attributable to the increasing number of chemical compounds and environmental pollution. Unfortunately, so far, in the modern era of medicine there is no specific treatment to counter the menacing impact of these dreaded diseases. Many polyherbal formulations are used widely to treat these disorders. Livactine is a polyherbal formulation and is claimed to be useful in jaundice and biliary dysfunctions. Most of these formulations do not have standard and approved reports stating their pharmacological action or therapeutic efficacy. Therefore, there is a need for experimental confirmation of the pharmacological effects of this formulation. The rationale behind the selection of carbon tetrachloride is due to its free radical mechanism based liver injury, and paracetamol is consumed widely by the human population and it is also a potential liver hazard. Aim: To evaluate the anti-hepatotoxic activity of Livactine against carbon tetrachloride & paracetamol induced toxicity in rats. Material and Methods: Albino rats of Wistar strain were used to evaluate the hepatoprotective activity of Livactine against carbon tetrachloride & paracetamol induced toxicity. Liver damage was assessed by estimating various biochemical parameters such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, acid phosphatase, total bilirubin, and total protein. The results of the rats treated with Livactine were compared with that of Liv-52.Results: Livactine showed significant dose dependent hepatoprotective effect by reducing elevated serum enzyme levels when compared to that of Liv-52.Conclusion: Our findings confirm that the formulation was found to be effective pharmacologically at

  15. Protective effect of Livactine against CCl4 and paracetamol induced hepatotoxicity in adult Wistar rats

    Directory of Open Access Journals (Sweden)

    Candasamy Mayuren.

    2010-01-01

    Full Text Available Background : Liver disease has become one of the serious health problems as it is exposed to many kinds of xenobiotics and therapeutic agents. Moreover the rapidly growing morbidity and mortality from liver disease are attributable to the increasing number of chemical compounds and environmental pollution. Unfortunately, so far, in the modern era of medicine there is no specific treatment to counter the menacing impact of these dreaded diseases. Many polyherbal formulations are used widely to treat these disorders. Livactine is a polyherbal formulation and is claimed to be useful in jaundice and biliary dysfunctions. Most of these formulations do not have standard and approved reports stating their pharmacological action or therapeutic efficacy. Therefore, there is a need for experimental confirmation of the pharmacological effects of this formulation. The rationale behind the selection of carbon tetrachloride is due to its free radical mechanism based liver injury, and paracetamol is consumed widely by the human population and it is also a potential liver hazard. Aim: To evaluate the anti-hepatotoxic activity of Livactine against carbon tetrachloride & paracetamol induced toxicity in rats. Material and Methods: Albino rats of Wistar strain were used to evaluate the hepatoprotective activity of Livactine against carbon tetrachloride & paracetamol induced toxicity. Liver damage was assessed by estimating various biochemical parameters such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, acid phosphatase, total bilirubin, and total protein. The results of the rats treated with Livactine were compared with that of Liv-52. Results: Livactine showed significant dose dependent hepatoprotective effect by reducing elevated serum enzyme levels when compared to that of Liv-52. Conclusion: Our findings confirm that the formulation was found to be effective pharmacologically

  16. Saponins (Ginsenosides) from the Leaves of Panax quinquefolius Ameliorated Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Xu, Xing-Yue; Hu, Jun-Nan; Liu, Zhi; Zhang, Rui; He, Yu-Fang; Hou, Wei; Wang, Zhi-Qing; Yang, Ge; Li, Wei

    2017-05-10

    Acetaminophen (APAP) overdose is one of the most common inducements of drug-induced liver injury (DILI) in the world. The main purpose of this paper was to investigate the liver protection activity of saponins (ginsenosides) from the leaves of Panax quinquefolius (PQS) against APAP-induced hepatotoxicity, and the involved mechanisms were demonstrated for the first time. Mice were pretreated with PQS (150 and 300 mg/kg) by oral gavage for 7 days before being treated with 250 mg/kg APAP. Severe liver injury was exerted at 24 h post-APAP, and hepatotoxicity was assessed. Our results showed that pretreatment with PQS significantly decreased the serum alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β) levels in a dose-dependent manner as compared to the APAP administration. Meanwhile, compared with that in the APAP group, PQS decreased hepatic malondialdehyde (MDA) contents and 4-hydroxynonenal (4-HNE) expression and restored reduced glutathione (GSH) content and superoxide dismutase (SOD) activity in livers of mice. PQS inhibited the overexpression of pro-inflammatory factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the liver tissues. Furthermore, Western blotting analysis revealed that PQS pretreatment inhibited the activation of apoptotic signaling pathways via increase of Bcl-2 and decrease of Bax and caspase-3 protein expression levels. Liver histopathological observation provided further evidence that PQS pretreatment significantly inhibited APAP-induced hepatocyte necrosis, inflammatory cell infiltration, and congestion. Biological indicators of nitrative stress such as 3-nitrotyrosine (3-NT) were inhibited after PQS pretreatment, compared to the APAP group. The present study clearly demonstrates that PQS exerts a protective effect against APAP-induced hepatic injury because of its antioxidant, anti-apoptotic, and anti-inflammatory activities. The findings from

  17. Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity.

    Science.gov (United States)

    Du, Kuo; Farhood, Anwar; Jaeschke, Hartmut

    2017-02-01

    Acetaminophen (APAP) hepatotoxicity is characterized by an extensive mitochondrial oxidant stress. However, its importance as a drug target has not been clarified. To investigate this, fasted C57BL/6J mice were treated with 300 mg/kg APAP and the mitochondria-targeted antioxidant Mito-Tempo (MT) was given 1.5 h later. APAP caused severe liver injury in mice, as indicated by the increase in plasma ALT activities and centrilobular necrosis. MT dose-dependently reduced the injury. Importantly, MT did not affect APAP-protein adducts formation, glutathione depletion or c-jun N-terminal kinase activation and its mitochondrial translocation. In contrast, hepatic glutathione disulfide and peroxynitrite formation were dose-dependently reduced by MT, indicating its effective mitochondrial oxidant stress scavenging capacity. Consequently, mitochondrial translocation of Bax and release of mitochondrial intermembrane proteins such as apoptosis-inducing factor were prevented, and nuclear DNA fragmentation was eliminated. To demonstrate the importance of mitochondria-specific antioxidant property of MT, we compared its efficacy with Tempo, which has the same pharmacological mode of action as MT but lacks the mitochondria targeting moiety. In contrast to the dramatic protection by MT, the same molar dose of Tempo did not significantly reduce APAP hepatotoxicity. In contrast, even a 3 h post-treatment with MT reduced 70 % of the injury, and the combination of MT with N-acetylcysteine (NAC) provided superior protection than NAC alone. We conclude that MT protects against APAP overdose in mice by attenuating the mitochondrial oxidant stress and preventing peroxynitrite formation and the subsequent mitochondrial dysfunction. MT is a promising therapeutic agent for APAP overdose patients.

  18. The effect of fluorine substitution on the hepatotoxicity and metabolism of paracetamol in the mouse.

    Science.gov (United States)

    Barnard, S; Kelly, D F; Storr, R C; Park, B K

    1993-09-01

    The widely used analgesic paracetamol (P) produces fulminant hepatocellular necrosis in humans when taken in overdose. The toxicity is mediated by drug oxidation and depletion of hepatic glutathione. We have, therefore, explored the effects of fluorine substitution on the hepatotoxicity of P in female CD1 mice. 3-Fluoro-4-hydroxyacetanilide (1FPO), 3,5-difluoro-4-hydroxyacetanilide (2FPO), 2,6-difluoro-4-hydroxyacetanilide (2FPN) and 2,3,5,6-tetrafluoro-4-hydroxyacetanilide (4FP) were synthesized, characterized and investigated for their potential to cause hepatotoxicity in the mouse. Introduction of fluorine into P increases the oxidation potential of the drug. The oxidation potentials of paracetamol and its fluorinated analogues were measured by cyclic voltametry and found to increase in the order P < 1FPO < 2FPO < 2FPN < 4FP. Serum transaminase (ALT) and hepatic glutathione were measured 24 and 6 hr, respectively, after administration of a single dose (2.65 mmol/kg) of each compound to female CD1 mice. There was significant elevation of ALT in mice given P, 1FPO and 2FPO, but not in those which received either 2FPN or 4FP. Hepatic glutathione was reduced significantly by administration of P and IFP, but not after administration of 2FPO, 2FPN or 4FP. Accordingly, glucuronide and sulphate conjugates, but not thioether metabolites, were detected in urine after administration of 14C-labelled 2FPO, 2FPN and 4FP. These data indicate that introduction of fluorine into the 2 and 6 positions increases the oxidation potential of paracetamol which in turn reduces the propensity of the molecule to undergo oxidative bioactivation, and thereby reduces the in vivo toxicity of the molecule.

  19. Protective Effect of Propolis in Proteinuria, Crystaluria, Nephrotoxicity and Hepatotoxicity Induced by Ethylene Glycol Ingestion.

    Science.gov (United States)

    El Menyiy, Nawal; Al Waili, Noori; Bakour, Meryem; Al-Waili, Hamza; Lyoussi, Badiaa

    2016-10-01

    Propolis is a natural honeybee product with wide biological activities and potential therapeutic properties. The aim of the study is to evaluate the protective effect of propolis extract on nephrotoxicity and hepatotoxicity induced by ethylene glycol in rats. Five groups of rats were used. Group 1 received drinking water, group 2 received 0.75% ethylene-glycol in drinking water, group 3 received 0.75% ethylene-glycol in drinking water along with cystone 500 mg/kg/body weight (bw) daily, group 4 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 100 mg/kg/bw daily, and group 5 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 250 mg/kg/bw daily. The treatment continued for a total of 30 d. Urinalyses for pH, crystals, protein, creatinine, uric acid and electrolytes, and renal and liver function tests were performed. Ethylene-glycol increased urinary pH, urinary volume, and urinary calcium, phosphorus, uric acid and protein excretion. It decreased creatinine clearance and magnesium and caused crystaluria. Treatment with propolis extract or cystone normalized the level of magnesium, creatinine, sodium, potassium and chloride. Propolis is more potent than cystone. Propolis extract alleviates urinary protein excretion and ameliorates the deterioration of liver and kidney function caused by ethylene glycol. Propolis extract has a potential protective effect against ethylene glycol induced hepatotoxicity and nephrotoxicity and has a potential to treat and prevent urinary calculus, crystaluria and proteinuria. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

  20. N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes.

    Science.gov (United States)

    Rodriguez, R J; Acosta, D

    1997-02-28

    Ketoconazole (KT) is an azole antifungal agent that has been associated with hepatotoxicity. The mechanism of its hepatotoxicity has not yet been resolved. It has been suggested that a reactive metabolite may be the cause of toxicity because the hepatic injury does not appear to be mediated through an immunoallergic mechanism. Several metabolites of KT have been reported in the literature of which the deacetylated metabolite, N-deacetyl ketoconazole (DAK), is the major metabolite which undergoes further metabolism by the flavin-containing monooxygenases (FMO) to form a potentially toxic dialdehyde. The objective of this study was to evaluate DAK's cytotoxicity and the role of FMO in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of the cytosolic enzyme, lactate dehydrogenase (LDH), into the medium and by assessing mitochondrial reduction of 3-(4,5-dimethythiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT). The cultures were exposed to various concentrations of DAK (20-160 microM) for 0.5-4 h. There was a significant increase (P DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively). The concentrations to observe 50% LDH leakage from the hepatocytes were 155, 133, 100, 70 microM DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively. Moreover, co-treatment with methimazole, a competitive substrate for FMO, produced a significant decrease (P DAK. Also, the toxicity was significantly (P DAK is a more potent cytotoxicant than its parent compound, KT, as reported previously by our laboratory (Rodriguez and Acosta, Toxicology, 96: 83-92, 1995) and its toxicity was expressed in a dose- and time-dependent manner. Furthermore, DAK's cytotoxicity was enhanced with n-octylamine and suppressed with methimazole, suggesting a role for FMO in the toxicity of the metabolite.

  1. Protective effects of combined β-caryophyllene and silymarin against ketoprofen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Kelany, Mohamed Elsayed; Abdallah, Mohamed Abdelmohsen

    2016-07-01

    Ketoprofen (Ket), widely utilized in treatment of many inflammatory disorders, is found to induce liver toxicity especially with overdose. This study aimed to evaluate the possible protective effects of concomitant β-caryophyllene (Cary) and silymarin (Sily) against Ket-induced hepatotoxicity in rats. Forty adult male albino rats were divided into 5 groups (each n = 8): the control group received distilled water for 6 weeks; the Ket-treated group received distilled water for 5 weeks and Ket in a dose of 8 mg·kg(-1)·day(-1) p.o. for the 6th week; the Cary + Ket treated group received Cary in a dose of 200 mg·kg(-1)·day(-1) orally for 6 weeks and Ket for the 6th week; the Sily + Ket treated group received Sily in the dose of 150 mg·kg(-1)·day(-1) for 6 weeks and Ket for the 6th week; and the Cary + Sily + Ket treated group received Sily and Cary for 6 weeks and Ket for the 6th week. At end of the experiment, serum ALT, AST, and albumin and liver total antioxidant capacity (t.TAC) and malondialdehyde (t.MDA) were measured in all rats. Ket increased serum ALT and AST and t.MDA and decreased t.TAC. Cary and Sily improved these changes. Combined Cary and Sily restored these liver changes to nearly normal. Combined Cary and Sily is hepatoprotective, with the ability to scavenge oxidants against Ket-induced hepatotoxicity in rats.

  2. Protective role of licochalcone B against ethanol-induced hepatotoxicity through regulation of Erk signaling

    Science.gov (United States)

    Gao, Xiao-peng; Qian, Dong-wei; Xie, Zhen; Hui, Hao

    2017-01-01

    Objective(s): Oxidative stress has been established as a key cause of alcohol-induced hepatotoxicity. Licochalcone B, an extract of licorice root, has shown antioxidative properties. This study was to investigate the effects and mechanisms of licochalcone B in ethanol-induced hepatic injury in an in vitro study. Materials and Methods: An in vitro model of Ethanol-induced cytotoxicity in BRL cells was used in this study. Cell injury was assessed using WST-1 assay and lactate dehydrogenase, alanine transaminase, and aspartate aminotransferase release assay. Cell apoptosis were quantified by flow cytometric analysis. The intracellular oxidative level was evaluated by reactive oxidative species, malondialdehyde and glutathione detection. Furthermore, the expression level of Erk, p-Erk, Nrf-2 were assessed using Western blot. Results: Treatment with ethanol induced marked cell injury and cell apoptosis in BRL cells. Licochalcone B significantly attenuated ethanol-induced cell injury, and inhibited cell apoptosis. Furthermore, licochalcone B significantly inhibited ethanol-induced intracellular oxidative level, upregulated the expression of p-Erk, and promoted nuclear localization of Nrf2. Additionally, this hepatoprotective role was significantly abolished by inhibition of Erk signaling. However, no apparent effects of Erk inhibition were observed on ethanol-induced hepatotoxicity. Conclusion: This study demonstrates that licochalcone B protects hepatocyte from alcohol-induced cell injury, and this hepatoprotective role might be attributable to apoptosis reduction, inhibition of oxidative stress, and upregulation of Erk–Nrf2. Therefore, licochalcone B might possess potential as a novel therapeutic drug candidate for alcohol-related liver disorders.

  3. Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lu, Yuan-Fu; Liu, Jie; Wu, Kai Connie; Qu, Qiang; Fan, Fang; Klaassen, Curtis D

    2014-01-01

    Oxidative stress and glutathione (GSH) depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO) mice were treated with microcystin (50 μg/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc). Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.

  4. Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.

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    Yuan-Fu Lu

    Full Text Available Oxidative stress and glutathione (GSH depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2 in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO mice were treated with microcystin (50 μg/kg, i.p.. Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc. Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.

  5. Red Seaweed (Hypnea Bryodies and Melanothamnus Somalensis) Extracts Counteracting Azoxymethane-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Ibrahim Waly, Mostafa; Al Alawi, Ahmed Ali; Al Marhoobi, Insaaf Mohammad; Rahman, Mohammad Shafiur

    2016-12-01

    Background: Azoxymethane (AOM) is a well-known colon cancer-inducing agent in experimental animals via mechanisms that include oxidative stress in rat colon and liver tissue. Few studies have investigated AOM-induced oxidative stress in rat liver tissue. Red seaweeds of the genera Hypnea Bryodies and Melanothamnus Somalensis are rich in polyphenolic compounds that may suppress cancer through antioxidant properties, yet limited research has been carried out to investigate their anti-carcinogenic and antioxidant influence against AOM-induced oxidative stress in rat liver. Objective: This study aims to determine protective effects of red seaweed (Hypnea Bryodies and Melanothamnus Somalensis) extracts against AOM-induced hepatotoxicity and oxidative stress. Materials and Methods: Sprague–Dawley rats received intraperitoneal injections of AOM, 15 mg/kg body weight, once a week for two consecutive weeks and then orally administered red seaweed (100 mg/kg body-weight) extracts for sixteen weeks. At the end of the experiment all animals were overnight fasted then sacrificed and blood and liver tissues were collected. Results: AOM treatment significantly decreased serum liver markers and induced hepatic oxidative stress as evidenced by increased liver tissue homogenate levels of nitric oxide and malondialdehyde, decreased total antioxidant capacity and glutathione, and inhibition of antioxidant enzymes (catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase and superoxide dismutase). Both red seaweed extracts abolished the AOM-associated oxidative stress and protected against liver injury as evidenced by increased serum levels of liver function markers. In addition, histological findings confirmed protective effects of the two red seaweed extracts against AOM-induced liver injury. Conclusion: Our findings indicate that red seaweed (Hypnea Bryodies and Melanothamnus Somalensis) extracts counteracted oxidative stress-induced hepatotoxicity in a

  6. Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats.

    Science.gov (United States)

    Orazizadeh, Mahmoud; Fakhredini, Fereshtesadat; Mansouri, Esrafil; Khorsandi, Layasadat

    2014-09-05

    Many recent studies demonstrate that most nanoparticles (NPs) have an adverse or toxic action on liver. The aim of this study was to investigate the hepatoprotective effect of glycyrrhizic acid (GA) against hepatic injury induced by titanium dioxide nanoparticles (NTiO2) in rats. Thirty-two Wistar rats were randomly divided into 4 groups. NTiO2-intoxicated rats received 300 mg/kg of NTiO2 for 14 days by gavage method. Protection group pretreated with GA for 7 days before NTiO2 administration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were detected as biomarkers in the blood to indicate hepatic injury. Product of lipid peroxidation (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were evaluated for oxidative stress in hepatic injury. Light microscopy for histopathological studies and TUNEL assay was also done. Administration of NTiO2 induced a significant elevation in plasma AST, ALT and ALP. In the liver, NTiO2 increased oxidative stress through the increase in lipid peroxidation and decrease in SOD and GPx enzymes. Histopathological studies showed that treatment with NTiO2 caused liver damage including centrilobular necrosis, which was accompanied by congestion and accumulation of inflammatory cells. Apoptotic index was also significantly increased in this group. Pretreatment of GA significantly decreased ALT, AST and ALP, attenuated the histopathology of hepatic injury, decreased apoptotic index, ameliorated oxidative stress in hepatic tissue, and increased the activities of SOD and GPx. These findings indicate that GA effectively protects against NTiO2-induced hepatotoxicity. GA has a potent protective effect against the NPs induced hepatotoxicity and might be clinically useful.

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

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    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.

  8. Magnetic Resonance Imaging for Rapid Screening for the Nephrotoxic and Hepatotoxic Effects of Microcystins

    Directory of Open Access Journals (Sweden)

    Dušan Šuput

    2013-08-01

    Full Text Available In vivo visualization of kidney and liver damage by Magnetic Resonance Imaging (MRI may offer an advantage when there is a need for a simple, non-invasive and rapid method for screening of the effects of potential nephrotoxic and hepatotoxic substances in chronic experiments. Here, we used MRI for monitoring chronic intoxication with microcystins (MCs in rat. Male adult Wistar rats were treated every other day for eight months, either with MC-LR (10 μg/kg i.p. or MC-YR (10 μg/kg i.p.. Control groups were treated with vehicle solutions. T1-weighted MR-images were acquired before and at the end of the eight months experimental period. Kidney injury induced by the MCs presented with the increased intensity of T1-weighted MR-signal of the kidneys and liver as compared to these organs from the control animals treated for eight months, either with the vehicle solution or with saline. The intensification of the T1-weighted MR-signal correlated with the increased volume density of heavily injured tubuli (R2 = 0.77, with heavily damaged glomeruli (R2 = 0.84 and with volume density of connective tissue (R2 = 0.72. The changes in the MR signal intensity probably reflect the presence of an abundant proteinaceous material within the dilated nephrons and proliferation of the connective tissue. T1-weighted MRI-is a valuable method for the in vivo screening of kidney and liver damage in rat models of intoxication with hepatotoxic and nephrotoxic agents, such as microcystins.

  9. Cassia angustifolia extract is not hepatotoxic in an in vitro and in vivo study.

    Science.gov (United States)

    Vitalone, A; Di Giacomo, S; Di Sotto, A; Franchitto, A; Mammola, C L; Mariani, P; Mastrangelo, S; Mazzanti, G

    2011-01-01

    Cassia angustifolia L. (senna) is traditionally used as a laxative. Its major components are sennosides that are responsible for the laxative effect. Senna is recommended for the short-term treatment of acute constipation. Nevertheless people use its preparations as self-medication, often for long periods, to treat chronic constipation thus exposing themselves to adverse reactions. Most reactions were associated with hepatotoxicity. The present study was aimed to evaluate the toxicity of a C. angustifolia leafextract (standardized at 60% of sennosides) on rat liver cells and the long-term effects on liver functions, in Wistar rats. Cytotoxicity was assessed in a buffalo normal rat liver cell line (BRL-3A) by the trypan blue assay and the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction test. In vivo effects were observed after oral administration of the extract for 4 or 8 weeks at doses of 12 and 58 mg/kg/day. At the end of treatment, animals were sacrificed, the postmortem examination was performed and serum was used for biochemical analysis. Liver samples were used for histomorphological and immunohistochemical examination along with the determination of oxidative stress parameters. In BRL-3A cells, the extract was cytotoxic at concentrations that appear largely higher than those attainable in humans. In Wistar rats, the extract did not induce any significant change in all of the parameters tested. In summary, the present study indicates a lack of hepatotoxicity of senna at doses higher than those generally used in humans. Copyright © 2011 S. Karger AG, Basel.

  10. Hospitalized pediatric antituberculosis drug induced hepatotoxicity: Experience of an Indonesian referral hospital

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    Heda Melinda Nataprawira

    2017-05-01

    Full Text Available Objective: To determine the characteristics and risk factors of pediatric antituberculosis drug induced hepatotoxicity (ADIH in Dr. Hasan Sadikin Hospital, a referral hospital in West Java, Indonesia. Methods: Medical records of hospitalized pediatric ADIH from October 2010 to October 2015 were reviewed retrospectively through computer-based search. Descriptive data were presented as percentage. Analytical case-control study on characteristics of ADIH was conducted using Chi-square and Mann Whitney test. Results: Fifty (3.5% out of 1 424 pediatric TB patients developed ADIH; 20 (40% were boys and 30 (60% girls. More than half were under 5 years old and 33 (66% were malnourished. ADIH occured in 29 (58% cases treated for pulmonary TB, 15 (30% for extrapulmonary TB and 6 (12% for both; 34 cases (68% occured during the intensive phase. We identified hepatic comorbidities including CMV infection [1 (2%] and typhoid [1 (2%], and other diseases treated by hepatotoxic drugs such as chemotherapeutic drugs, antiepileptics, and antiretroviral drugs [9 (18%]. Case-control analysis of 50 ADIH cases and 100 TB controls without ADIH showed that the correlation between gender, age, type of TB, nutritional status and comorbidities to occurence of ADIH was statistically insignificant (P = 0.26, 0.765, 0.495, 0.534 9 and 0.336, respectively. Pediatric ADIH was treated using modified British Thoracic Society guidelines. Conclusions: Pediatric ADIH in our hospital is quite frequent, thus identifying risk factors and development of pediatric guideline is mandatory. Further study is needed to identify other risk factors such as genetic acetylator status.

  11. Hepatoprotective effect of Stachys pilifera ethanol extract in carbon tetrachloride-induce hepatotoxicity in rats.

    Science.gov (United States)

    Panahi Kokhdan, Esmaeel; Ahmadi, Kyomarth; Sadeghi, Heibatollah; Sadeghi, Hossein; Dadgary, Fahemeh; Danaei, Nazanin; Aghamaali, Mahmoud Reza

    2017-12-01

    Stachys pilifera Benth (Lamiaceae) has long been used to treat infectious diseases, respiratory and rheumatoid disorders in Iranian folk medicine. Antitumor and antioxidant activity of the plant have been reported. The study was designed to assess the hepatoprotective activity of ethanol extract of Stachys pilifera in carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. The rats were randomly divided into six equal groups (n = 7). Group I was treated with normal saline; Group II received CCl4 (1 mL/kg. i.p., twice a week) for 60 consecutive days; Groups III, IV and V were given CCl4 plus Stachys pilifera (100, 200 and 400 mg/kg/d,p.o.); Group VI received the extract (400 mg/kg/d, p.o.). Histopathological analysis and measurement of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), malondialdehyde (MDA), total protein (TP) and albumin (ALB) were performed. CCl4 caused a significant increase in the serum levels of AST, ALT, ALP and MDA as well as decreased ALB, and TP serum levels (p < 0.001). The extract (200 and 400 mg/kg/d) significantly normalized the CCl4-elevated levels of ALT, AST, ALP and MDA (p < 0.001). The extract (200 and 400 mg/kg/d) also increased the serum levels of TP compared to CCl4 group (p< 0.01). The extract (200 and 400 mg/kg/d) also decreased the histological injuries (inflammation and fatty degeneration) by CCl4. The results revealed that the Stachys pilifera extract could provide considerable protection against CCl4 hepatotoxicity in rats that may be related to its antioxidant properties.

  12. Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats.

    Science.gov (United States)

    Sawant, Sharmilee P; Dnyanmote, Ankur V; Shankar, Kartik; Limaye, Pallavi B; Latendresse, John R; Mehendale, Harihara M

    2004-02-01

    There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl(4) (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl(4) bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl(4) hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0-96 h) of CCl(4) (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and (14)CCl(4) covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl(4) administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl(4) hepatotoxicity is potentiated due to inhibited tissue repair.

  13. Large whale incident database

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Large whale stranding, death, ship strike and entanglement incidents are all recorded to monitor the health of each population and track anthropogenic factors that...

  14. Drug related critical incidents.

    Science.gov (United States)

    Khan, F A; Hoda, M Q

    2005-01-01

    Drug related incidents are a common form of reported medical errors. This paper reviews the critical incidents related to drug errors reported from the main operating theatre suite in a teaching hospital in a developing country from January 1997 to December 2002. Each report was evaluated individually by two reviewers using a structured process. During this period, 44 874 anaesthetics were administered; 768 critical incidents were reported, 165 (21%) of which were related to drug errors. Underdosage, side-effect/drug reaction and syringe swap were the most common. A total of 76% were classified as preventable; 56% due to human error and 19% due to system error. High risk incidents accounted for 10% of all drug errors and most of these were related to the use of neuromuscular blocking drugs. This analysis has been found useful in addressing some issues about priorities.

  15. Police Incident Blotter (Archive)

    Data.gov (United States)

    Allegheny County / City of Pittsburgh / Western PA Regional Data Center — The Police Blotter Archive contains crime incident data after it has been validated and processed to meet Uniform Crime Reporting (UCR) standards, published on a...

  16. Incident Report - Legacy

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Incident Report is a mandatory post trip legal document observers fill out to report any enforcement related situations they have encountered on an observed trip...

  17. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Youssef Dgachi

    2016-05-01

    Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  18. Glutathione peroxidase 3 is a protective factor against acetaminophen-induced hepatotoxicity in vivo and in vitro

    Science.gov (United States)

    Kanno, Syu-Ichi; Tomizawa, Ayako; Yomogida, Shin; Hara, Akiyoshi

    2017-01-01

    Acetaminophen (APAP) is a widely available antipyretic and analgesic; however, overdose of the drug inflicts severe damage to the liver. It is well established that the hepatotoxicity of APAP is initiated by formation of a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which can be detoxified by conjugation with reduced glutathione (GSH), a typical antioxidant. We recently found that the blood mRNA expression level of glutathione peroxidase 3 (Gpx3), which catalyzes the oxidation of GSH, is associated with the extent of APAP-induced hepatotoxicity in mice. The present study was carried out to determine the in vivo and in vitro role of GPx3 in APAP-induced hepatotoxicity. In in vivo experiments, oral administration of APAP to mice induced liver injury. Such liver injury was greater in males than in females, although no gender difference in the plasma concentration of APAP was found. Female mice had a 2-fold higher expression of Gpx3 mRNA and higher plasma GPx activity than male mice. 17β-estradiol, a major female hormone, decreased APAP-induced hepatotoxicity and increased both the expression of blood Gpx3 mRNA and plasma GPx activity, suggesting that the cytoprotective action of this hormone is mediated by the increase in GPx3. To further clarify the role of GPx3 in APAP-induced hepatotoxicity, we evaluated the effect of a change in cellular GPx3 expression resulting from transfection of either siRNA-GPx3 or a GPx3 expression vector on NAPQI-induced cellular injury (as assessed by a tetrazolium assay) in in vitro experiments using heterogeneous cultured human cell lines (Huh-7 or K562). NAPQI-induced cell death was reduced by increased GPx3 and was enhanced by decreased GPx3. These results suggest that GPx3 is an important factor for inhibition of APAP-induced hepatotoxicity both in vivo and in vitro. To our knowledge, this is the first report to show a hepatoprotective role of cellular GPx3 against APAP-induced liver damage. PMID:28677736

  19. Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish

    Science.gov (United States)

    Liu, Chunsheng; Su, Guanyong; Giesy, John P.; Letcher, Robert J.; Li, Guangyu; Agrawal, Ira; Li, Jing; Yu, Liqin; Wang, Jianghua; Gong, Zhiyuan

    2016-01-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.

  20. Identification of urine tauro-β-muricholic acid as a promising biomarker in Polygoni Multiflori Radix-induced hepatotoxicity by targeted metabolomics of bile acids.

    Science.gov (United States)

    Zhao, Dong-Sheng; Jiang, Li-Long; Fan, Ya-Xi; Dong, Lei-Chi; Ma, Jiang; Dong, Xin; Xu, Xiao-Jun; Li, Ping; Li, Hui-Jun

    2017-02-24

    Polygoni Multiflori Radix (PMR) has been widely used as a tonic for centuries. However, hepatotoxicity cases linked to PMR have been frequently reported and appropriate biomarkers for clinical diagnosis are currently lacking. Here, an approach using UPLC-QqQ/MS-based targeted metabolomics of bile acids (BAs) complemented with biochemistry and histopathology was applied to characterize the development and recovery processes of PMR-induced hepatotoxicity in rats and to identify biomarkers. The expression of bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) were evaluated to investigate the underlying mechanism. Steatosis and inflammatory cell infiltration were observed in PMR-treated rats, which were accompanied by the elevation of serum biochemistry. The metabolic profiles of BAs were analyzed by Principal Component Analysis, hyodeoxycholic acid (HDCA) in serum and tauro-β-muricholic acid (TβMCA) in urine were identified as potential biomarkers for PMR-induced hepatotoxicity. The elevated expression of Bsep and decreased expression of Ntcp in the liver of PMRtreated rats indicated that hepatotoxicity was related to the disorders of BAs metabolism. Our study demonstrated that BAs may be used for clinical diagnosis of PMR-induced hepatotoxicity. Urine TβMCA was identified as a promising biomarker to facilitate the clinical monitoring of PMR-induced hepatotoxicity and may serve as potential therapeutic target.

  1. INCIDENCE OF AMPUTATION IN EMERGENCY

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    K. Rojaramani Kumbha

    2016-08-01

    Full Text Available Advanced Technology and early detection of disease by recent improvements in investigation modalities lead to decreased incidents of amputations while Road Traffic Accidents (RTA increase. Furthermore, it leads to variation and decreased morbidity, mortality and accidents (crush injuries, and better equipped and trained staff, specialist services, diabetic food, rehabilitation centres, and giving good support physically and psychologically for Amputated patients. OBJECTIVE To know incidence rates of Emergency Amputation who attended causality with advanced disease and severe Trauma. METHODOLOGY The study is done over a period of one year i.e. between June 2015 to June 2016 who attended causality with advanced and severe disease affecting the limbs either due to diabetes, trauma or vascular diseases. RESULTS During one-year period, total 6,371 patients attended for general surgery OP. In those, 187 patients needed emergency surgery which included both major and minor operations. Among those, 81 patients were amputated. CONCLUSION As per our available records and observation, even though there is increased literacy and access to advanced technology, there is still increased incidence of patients undergoing amputations due to diseases. Therefore, there is a need to improve awareness and importance of early detection of diabetes, hazards of smoking, and regular general health checkups for patients at root level. With that we can treat diabetes and/or any disease in time. So there must be awareness in peripheral health staff i.e. PHC, subcentres, and community health centres about early detection of disease which in turn improves the quality of life of the patient. Due to diabetes slight injury to the glucose laden tissue may cause chronic infection and ulcer formation.(1 The tumours are seen commonly in the age group of 20-40 years after bone fusion, bones affected commonly are those around the knee (lower end of knee, upper end of tibia. A lytic

  2. Serum proteomic study on early esophageal carcinoma and precancerous lesions and precancerous ;lesions in the high incidence area%高发区早期食管癌及癌前病变血清蛋白研究

    Institute of Scientific and Technical Information of China (English)

    陈仙梅; 袁丽; 郭硕; 于卫芳; 王士杰; 张立玮

    2014-01-01

    Objective This study was to screen protein biomarkers in serum of esophageal carcinoma and precancerous lesions subjects using Mass Spectrometry in high incidence area of China. Boosting decision tree was constructed to identify normal from EC and precancerous lesions, to screen significant biomarkers for early diagnosis and explore the function in progression of esophageal cancer. Methods We recruited 254 subjects, Including low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), advanced esophageal carcinoma (AEC) and normal control (NOR). All serum samples were pretreated with weak cation exchange (WCX) magnetic beads and tested by MALDI-TOF-MS, finally construction of boosting decision tree and blinded testing. Results There were 146 protein peaks were detected between the three parents groups compared with normal, the decision tree classification were constructed by 14 protein peaks, which contain 32721, 3403, 1772, 1071, 1414, 33312, 32023, 31043, 4662, 2245, 1307, 10013, 6868, 1234. This decision algorithm correctly classified 90.91%(30/33) of normal control, 100% (31/31) of LGIN, 89.66% (52/58) of HGIN, and 81.26% (26/32) of AEC.In the blinded testing, the decision algorithm correctly classified 95.652%(22/23) of normal control, 95.455%(21/22) of LGIN, 94.118%(32/34) of HGIN, and 95.238%(20/21) of AEC. The peaks of 32023, 1234 and 1307 were speculated zinc alpha2 glycoprotein, glycosyltransferase like protein LARGE2 fibrinogen alpha chain and fibrinogen alpha chain by ExPasy database retrieval, others were unknown. Conclusion The diagnostic pattern are established by differently protein peaks could accurately recognize the patients groups and normal controls application of MALDI-TOF MS with high sensitivity and specificity. We speculate that the occurrence of esophageal carcinoma began in the LGIN or much earlier, the patients that have cancer-related proteins in serum should be follow up.%目的:应用质谱技术构建

  3. Protective and curative effect of poly herbal formulation containing indigenous medicinal plants against various hepatotoxic agents in rats

    Institute of Scientific and Technical Information of China (English)

    Sunil Mistry; Kunduri Rajeswar Dutt; Sashi Bhusan Biswal; Jyotirmoyee Jena

    2012-01-01

    Objective: To evaluate the protective and curative potential of PHF, a polyherbal formulation, against two experimentally induced hepatotoxicity models in rats. Methods: Hepatoprotective activity of the PHF containing three indigenous medicinal plants extracts Coccinia indica, Sidacordata and Scoparia dulcis, was screened against CCl4 and paracetamol induced hepatotoxicity in rats. Result: Administration of hepatotoxins (CCl4 and paracetamol) shows significant morphological, biochemical and histopathological deteriorations in the liver of experimental animals. Pretreatment with PHF had significant protection against hepatic damage by maintaining the morphological parameters within normal range and normalizing the elevated levels of biochemical parameters (SGPT, SGOT, ALP and total bilirubin), which were evidently showed in histopathological study. Conclusions: The PHF has highly significant hepatoprotective effect at 100 and 200 mg/kg, p.o. on the liver of all the two experimental animal models. The liver protection due to combined action of all plant extracts along with their phytoconstituents.

  4. Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.

    Science.gov (United States)

    Silva, Tiago; Mohamed, Tarek; Shakeri, Arash; Rao, Praveen P N; Martínez-González, Loreto; Pérez, Daniel I; Martínez, Ana; Valente, Maria João; Garrido, Jorge; Uriarte, Eugenio; Serrão, Paula; Soares-da-Silva, Patrício; Remião, Fernando; Borges, Fernanda

    2016-08-25

    Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.

  5. Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer′s Disease Therapy

    Directory of Open Access Journals (Sweden)

    Houssem Boulebd

    2016-03-01

    Full Text Available Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-ylethan-1-one (4 is non-hepatotoxic (cell viability assay on HepG2 cells, a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM, and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound.

  6. Radiation incidents in dentistry

    Energy Technology Data Exchange (ETDEWEB)

    Lovelock, D.J. [Dental Hospital and School, Newcastle upon Tyne (United Kingdom). Dept. of Radiology

    1996-12-31

    Most dental practitioners act as their own radiographer and radiologist, unlike their medical colleagues. Virtually all dental surgeons have a dental X-ray machine for intraoral radiography available to them and 40% of dental practices have equipment for dental panoramic tomography. Because of the low energy of X-ray equipment used in dentistry, radiation incidents tend to be less serious than those associated with other aspects of patient care. Details of 47 known incidents are given. The advent of the 1985 and 1988 Ionising Radiation Regulations has made dental surgeons more aware of the hazards of radiation. These regulations, and general health and safety legislation, have led to a few dental surgeons facing legal action. Because of the publicity associated with these court cases, it is expected that there will be a decrease in radiation incidents arising from the practice of dentistry. (author).

  7. LUNG CANCER INCIDENCE IN OMSK REGION

    Directory of Open Access Journals (Sweden)

    V. K. Kosenok

    2016-01-01

    Full Text Available Lung cancer incidence in the Omsk region was studied. Advanced lung cancer was shown to be commonly detected in patients of the 30 to 49 age group. For this patient group, adenocarcinoma was the most common histological type of lung cancer. The highest incidence of lung cancer was observed in both men and women aged 45–47 years. Thus, to improve early detection of lung cancer, the optimal age for lung cancer screening should be in the age range of 40–50 years.

  8. Recording pressure ulcer risk assessment and incidence.

    Science.gov (United States)

    Plaskitt, Anne; Heywood, Nicola; Arrowsmith, Michaela

    2015-07-15

    This article reports on the introduction of an innovative computer-based system developed to record and report pressure ulcer risk and incidence at an acute NHS trust. The system was introduced to ensure that all patients have an early pressure ulcer risk assessment, which prompts staff to initiate appropriate management if a pressure ulcer is detected, thereby preventing further patient harm. Initial findings suggest that this electronic process has helped to improve the timeliness and accuracy of data on pressure ulcer risk and incidence. In addition, it has resulted in a reduced number of reported hospital-acquired pressure ulcers.

  9. Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

    OpenAIRE

    Ma, Lei-Lei; Wu, Zhi-tao; Wang, Le; Zhang, Xue-Feng; Wang, Jing; Chen, Chen; Ni, Xuan; Lin, Yun-fei; Cao, Yi-yi; Luan, Yang; Pan, Guo-yu

    2016-01-01

    Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro...

  10. Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients.

    Science.gov (United States)

    Duong Van Huyen, Jean-Paul; Batisse, Dominique; Heudes, Didier; Belair, Marie-France; Piketty, Christophe; Gonzalez-Canali, Gustavo; Weiss, Laurence; Kazatchkine, Michel D; Bruneval, Patrick

    2006-10-01

    Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.

  11. HEPATOPROTECTIVE ACTIVITY OF ETHANOLIC EXTRACT OF ALTHAEA OFFICINALIS LINN AGAINST CARBON TETRACHLORIDE INDUCED HEPATOTOXICITY ON ALBINO WISTAR RATS

    OpenAIRE

    Jabbar Zoobi; Ali Mohd.

    2011-01-01

    In Indian traditional system of medicine, herbal remedies are prescribed for the treatment of various diseases including liver diseases. The present study was aimed to investigate the hepatoprotective activity of the ethanolic extract of Althaea officinalis against Carbon tetrachloride induced hepatotoxicity in rats. Liver function were assessed by the determination of SGPT and SGOT studies. The serum biochemical analysis results suggested that the use of ethanolic extract of Althaea officina...

  12. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

    OpenAIRE

    Mohamed A Dkhil; Saleh Al-Quraishy; Aref, Ahmed M.; Othman, Mohamed S.; Kamal M. El-Deib; Ahmed E Abdel Moneim

    2013-01-01

    Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative...

  13. Chemical Diversity Investigation of Hepatotoxic Pyrrolizidine Alkaloids in Qianliguang (Senecio scandens and Related Species by UHPLC-QTOF-MS

    Directory of Open Access Journals (Sweden)

    Lin Zhu

    2015-04-01

    Full Text Available Objective: Qianliguang (Senecio scandens is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. The presence of hepatotoxic pyrrolizidine alkaloids (PAs has raised concerns about the safety of using Qianliguang and its products. The present study aims at investigation of different types of PAs present in Qianliguang collected from representative locations in China.

  14. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits

    Directory of Open Access Journals (Sweden)

    Maysaa B Zubairi

    2014-01-01

    Full Text Available Objectives: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Materials and Methods : Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally, group 3, 4,5 and 6 were treated at a dose in (mg/kg/day of the following: Carvedilol (10 mg, prazosin (0.5 mg, metoprolol (10 mg, and a combination of metoprolol (10 mg and prazosin (0.5 mg respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA and glutathione (GSH in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Results: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Conclusion : Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

  15. Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals.

    Science.gov (United States)

    Rodrigues, Robim M; De Kock, Joery; Branson, Steven; Vinken, Mathieu; Meganathan, Kesavan; Chaudhari, Umesh; Sachinidis, Agapios; Govaere, Olivier; Roskams, Tania; De Boe, Veerle; Vanhaecke, Tamara; Rogiers, Vera

    2014-01-01

    Human skin-derived precursors (hSKP) are postnatal stem cells with neural crest properties that reside in the dermis of human skin. These cells can be easily isolated from small (fore) skin segments and have the capacity to differentiate into multiple cell types. In this study, we show that upon exposure to hepatogenic growth factors and cytokines, hSKP acquire sufficient hepatic features that could make these cells suitable in vitro tools for hepatotoxicity screening of new chemical entities and already existing pharmaceutical compounds. Indeed, hepatic differentiated hSKP [hSKP-derived hepatic progenitor cells (hSKP-HPC)] express hepatic progenitor cell markers (EPCAM, NCAM2, PROM1) and adult hepatocyte markers (ALB), as well as key biotransformation enzymes (CYP1B1, FMO1, GSTA4, GSTM3) and influx and efflux drug transporters (ABCC4, ABCA1, SLC2A5). Using a toxicogenomics approach, we could demonstrate that hSKP-HPC respond to acetaminophen exposure in a comparable way to primary human hepatocytes in culture. The toxicological responses "liver damage", "liver proliferation", "liver necrosis" and "liver steatosis" were found to be significantly enriched in both in vitro models. Also genes associated with either cytotoxic responses or induction of apoptosis (BCL2L11, FOS, HMOX1, TIMP3, and AHR) were commonly upregulated and might represent future molecular biomarkers for hepatotoxicity. In conclusion, our data gives a first indication that hSKP-HPC might represent a suitable preclinical model for in vitro screening of hepatotoxicity. To the best of our knowledge, this is the first report in which human postnatal stem cells derived from skin are described as a potentially relevant cell source for in vitro hepatotoxicity testing of pharmaceutical compounds.

  16. Human Skin-Derived Stem Cells as a Novel Cell Source for In Vitro Hepatotoxicity Screening of Pharmaceuticals

    OpenAIRE

    Rodrigues, Robim M.; De Kock, Joery; Branson, Steven; Vinken, Mathieu; Meganathan, Kesavan; Chaudhari, Umesh; Sachinidis, Agapios; Govaere, Olivier; Roskams, Tania; De Boe, Veerle; Vanhaecke, Tamara; Rogiers, Vera

    2014-01-01

    Human skin-derived precursors (hSKP) are postnatal stem cells with neural crest properties that reside in the dermis of human skin. These cells can be easily isolated from small (fore) skin segments and have the capacity to differentiate into multiple cell types. In this study, we show that upon exposure to hepatogenic growth factors and cytokines, hSKP acquire sufficient hepatic features that could make these cells suitable in vitro tools for hepatotoxicity screening of new chemical entities...

  17. Protective Effect of Cornus mas Fruits Extract on Serum Biomarkers in CCl4-Induced Hepatotoxicity in Male Rats.

    Science.gov (United States)

    Alavian, Seyed Moayed; Banihabib, Nafiseh; Es Haghi, Masoud; Panahi, Farid

    2014-04-01

    Nowadays attention to use herbs such as cornelian cherry (Cornus mas) is increasing, which contains high levels of antioxidants and anthocyanins. Cornus mas fruits have been used for gastrointestinal and excretory disorders for many years in traditional medicine, also may improve liver and kidney functions, and have protective effects such as anti-allergic, antidiabetic, antibacterial, antimicrobial, antihistamine and antimalarial properties. The aim of this study was to investigate protective effects of Cornus mas fruits extract on serum biomarkers in CCl4-induced hepatotoxicity in male rats. Hepatotoxicity was induced by administration of carbon tetrachloride (1 mL/kg i.p.) in 1:1 dilution with olive oil. To evaluate the effect of Cornus mas fruits extract on disease progression, serum marker enzymes, serum total protein and albumin and liver lipid peroxidation were determined in CCl4-induced hepatotoxicity. Oral administration of Cornus mas fruits extract to rats for 14 days provided a significant (P mas fruit extract effect may be due to including some antioxidant components, which caused membrane stabilizing and normalization of fluctuated biochemical profiles induced by CCl4 exposure. Our results validated the traditional use of Cornus mas in the treatment of liver disorders.

  18. Dose-response effects of Elephantopus scaber methanolic extract on N-nitrosodiethylamine-induced hepatotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    A.Linza; P.J.Wills; P.N.Ansil; S.P.Prabha; A.Nitha; B.Latha; K.O.Sheeba; M.S.Latha

    2013-01-01

    AIM:A decoction of Elephantopus scaber (Asteraceae) root is used to treat liver disorders in Indian and Chinese traditional medicine.The study was designed to examine the dose response effects of E.scaber methanolic extract on rats exposed to N-nitrosodiethylamine (NDEA) induced hepatotoxicity (0.02% NDEA in water five days per week,per oral) in preventive and curative models.METHODS:In preventive groups,NDEA was administered for six weeks.Daily doses of E.scaber methanolic extract (200 and 100mg·kg-1) started one week before the onset of NDEA intoxication and continued for six weeks.In curative animals,NDEA was administered for six weeks followed by treatment with the methanolic n-hexane extract of E.scaber (200 and 100mg·kg-1) for ten days.RESULTS:E.scaber extract treatment significantly (P≤0.05) reduced the levels of AST,ALT,and MDA in both experimental groups.The extract also enhanced the antioxidant enzyme and protein levels in rats intoxicated with NDEA.Treatment with the extract dose dependently protected the liver from NDEA-induced hepatotoxicity with normal hepatocytes and uniform sinusoids,but in some areas showed degenerating hepatic cells in both treatment groups.CONCLUSION:E.scaber methanolic extract dose dependently prevented and reversed the hepatotoxicity induced by NDEA in both experimental models.

  19. REPEATED EXPOSURE OF SODIUM TELLURITE ON THE RAT LIVER AND ON THE POTENTIAL MECHANISMS OF THE METALLOID-INDUCED HEPATOTOXICITY.

    Science.gov (United States)

    Safhi, Mohammed M; Alam, Mohammad Firoz; Khuwaja, Gulrana; Islam, Farah; Hussain, Sohail; Fageeh, Mohsen Mohammed; Anwer, Tarique; Islam, Fakhrul

    2016-01-01

    Tellurium (Te) is a semiconductor and is frequently doped with copper, tin, gold or silver. It is also used to color glass and ceramics and is one of the primary ingredients in blasting caps. Little is known about Te biological activity but it is well known for toxicity to human and animals. It has inhibited the lipids profiles and oxidative stress in the brain of mice. Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays. The hepatotoxicity biomarkers [bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)] were elevated significantly and dose dependently in the serum of Te treated groups as compared to control group. The content of thiobarbituric reactive substances in Te treated groups was increased significantly and dose-dependently as compared to control group. Conversely, the content of glutathione and activities of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase) were decreased significantly in Te treated groups as compared to control group. No data of inorganic Te compounds on the liver toxicity of rats are available. The aim of the present study was to evaluate the hepatotoxicity of inorganic Te compound. In conclusion, Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats.

  20. Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

    Science.gov (United States)

    Sumedha, N C; Miltonprabu, S

    2015-05-01

    The present study investigates the possible ameliorative effects of diallyl trisulfide (DATS) against arsenic (As)-induced hepatotoxicity and oxidative stress in rats. The four experimental groups evaluated include: (1) vehicle control; (2) As (5 mg/kg/day); (3) DATS (80 mg/kg/day) + As; and (4) DATS. Induction of As in rats caused severe hepatotoxicity as evidenced by an elevation of serum aspartate aminotransferase and alanine aminotransferase activities and increased total bilirubin concentration, indicating hepatic function abnormalities. Histopathological examination revealed various structural changes in the liver, characterized by hepatocyte degeneration/necrosis, congestion, sinusoidal dilatation, vacuolation, and inflammatory cell infiltration. The significant decrease in reduced glutathione content, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and the significant increase in lipid peroxidation (thiobarbituric acid reactive substance) and protein oxidation (protein carbonyl) contents indicated that As-induced hepatotoxicity was mediated through oxidative stress. As intoxication also elevated the levels of Cas-3 and nitric oxide and increased the expression of nuclear factor-κB p65 in the liver. In contrast, DATS pretreatment significantly improved As-induced serum biochemical, immunohistochemical, and histopathological alterations reflecting hepatic dysfunction. These results may contribute to a better understanding of the hepatoprotective role of DATS, emphasizing the influence of this garlic trisulfide in the diet for human health, possibly preventing the hepatic injury associated with As intoxication, presumably due to its ability to inhibit lipid peroxidation, protein oxidation, and restoration of antioxidant status.

  1. Maintenance of high quality rat precision cut liver slices during culture to study hepatotoxic responses: Acetaminophen as a model compound.

    Science.gov (United States)

    Granitzny, Anne; Knebel, Jan; Schaudien, Dirk; Braun, Armin; Steinberg, Pablo; Dasenbrock, Clemens; Hansen, Tanja

    2017-08-01

    Precision cut liver slices (PCLiS) represent a promising tool in reflecting hepatotoxic responses. However, the culture of PCLiS varies considerably between laboratories, which can affect the performance of the liver slices and thus the experimental outcome. In this study, we describe an easily accessible culture method, which ensures optimal slice viability and functionality, in order to set the basis for reproducible and comparable PCLiS studies. The quality of the incubated rat PCLiS was assessed during a 24h culture period using ten readouts, which covered viability (lactate dehydrogenase-, aspartate transaminase- and glutamate dehydrogenase-leakage, ATP content) and functionality parameters (urea, albumin production) as well as histomorphology and other descriptive characteristics (protein content, wet weight, slice thickness). The present culture method resulted in high quality liver slices for 24h. Finally, PCLiS were exposed to increasing concentrations of acetaminophen to assess the suitability of the model for the detection of hepatotoxic responses. Six out of ten readouts revealed a toxic effect and showed an excellent mutual correlation. ATP, albumin and histomorphology measurements were identified as the most sensitive readouts. In conclusion, our results indicate that rat PCLiS are a valuable liver model for hepatotoxicity studies, particularly if they are cultured under optimal standardized conditions. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

    Directory of Open Access Journals (Sweden)

    Fanny Knöspel

    2016-04-01

    Full Text Available Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR, while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  3. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System.

    Science.gov (United States)

    Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

    2016-04-16

    Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  4. Noninvasive biomarkers for acute hepatotoxicity induced by 1,3-dichloro-2-propanol: hyperpolarized 13C dynamic MR spectroscopy.

    Science.gov (United States)

    Kim, Gwang-Won; Oh, Chang-Hyun; Kim, Jong-Choon; Yoon, Woong; Jeong, Yong-Yeon; Kim, Yun-Hyeon; Kim, Jae-Kyu; Park, Jin-Gyoon; Kang, Heoung-Keun; Jeong, Gwang-Woo

    2016-02-01

    The purpose of this study was to investigate the cellular metabolite change for acute hepatotoxicity induced by 1,3-dichloro-2-propanol (1,3-DCP) in rats and its correlations with the enzyme levels. In order to induce acute hepatotoxicity, a single subcutaneous injection of 1,3-DCP (80 mg/kg) was given to six male Sprague-Dawley rats. Hyperpolarized (13)C dynamic magnetic resonance spectroscopy (MRS) was performed on rat liver following injection of hyperpolarized [1-(13)C] pyruvate. The levels of serum aspartate am inotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) in the 1,3-DCP treated rats were significantly increased as compared with those in normal rats. In the dynamic (13)C MR spectra, the ratios of [1-(13)C] lactate to the total carbon and [1-(13)C] alanine to the total carbon in the 1,3-DCP treated rats were significantly increased, and there were positive correlations between cellular metabolic changes and enzyme levels. The levels of [1-(13)C] lactate and [1-(13)C] alanine are potentially considered as important biomarkers for the 1,3-DCP-induced acute hepatotoxicity.

  5. Upgrading HepG2 cells with adenoviral vectors that encode drug-metabolizing enzymes: application for drug hepatotoxicity testing.

    Science.gov (United States)

    Gómez-Lechón, M José; Tolosa, Laia; Donato, M Teresa

    2017-02-01

    Drug attrition rates due to hepatotoxicity are an important safety issue considered in drug development. The HepG2 hepatoma cell line is currently being used for drug-induced hepatotoxicity evaluations, but its expression of drug-metabolizing enzymes is poor compared with hepatocytes. Different approaches have been proposed to upgrade HepG2 cells for more reliable drug-induced liver injury predictions. Areas covered: We describe the advantages and limitations of HepG2 cells transduced with adenoviral vectors that encode drug-metabolizing enzymes for safety risk assessments of bioactivable compounds. Adenoviral transduction facilitates efficient and controlled delivery of multiple drug-metabolizing activities to HepG2 cells at comparable levels to primary human hepatocytes by generating an 'artificial hepatocyte'. Furthermore, adenoviral transduction enables the design of tailored cells expressing particular metabolic capacities. Expert opinion: Upgraded HepG2 cells that recreate known inter-individual variations in hepatic CYP and conjugating activities due to both genetic (e.g., polymorphisms) or environmental (e.g., induction, inhibition) factors seems a suitable model to identify bioactivable drug and conduct hepatotoxicity risk assessments. This strategy should enable the generation of customized cells by reproducing human pheno- and genotypic CYP variability to represent a valuable human hepatic cell model to develop new safer drugs and to improve existing predictive toxicity assays.

  6. Alpha-glucosidase inhibitors and hepatotoxicity in type 2 diabetes: a systematic review and meta-analysis

    Science.gov (United States)

    Zhang, Longhao; Chen, Qiyan; Li, Ling; Kwong, Joey S. W.; Jia, Pengli; Zhao, Pujing; Wang, Wen; Zhou, Xu; Zhang, Mingming; Sun, Xin

    2016-09-01

    Alpha-glucosidase inhibitors (AGIs) was reported to be associated with several rare adverse hepatic events, but with inconsistent results. We aimed to investigate the risk of hepatotoxicity associated with the use of AGIs in patients with type 2 diabetes mellitus (T2DM), and performed a systematic review and meta-analysis. Fourteen studies (n = 2881) were eligible, all of which were RCTs. Meta-analysis of data regarding elevation of more than 3-fold the upper limit of normal (ULN) of AST and ALT showed statistically significant differences between AGIs treatment versus control (OR 6.86, 95% CI 2.50 to 18.80; OR 6.48, 95% CI 2.40 to 17.49). Subgroup analyses of elevation of more than 1.8-fold ULN of AST and ALT by dose of AGIs showed differential effects on AST and ALT (AST: OR 0.38 vs 7.31, interaction P = 0.003 ALT: OR 0.32 vs 4.55, interaction p = 0.02). Meta-analysis showed that AGIs might increase the risk of hepatotoxicity, and higher dose appeared to be associated with higher risk of hepatotoxicity. However, the evidence is limited with surrogate measures (i.e. ALT and AST), and no clinically important adverse events were observed.

  7. Systematic Review of Risk Factors of Oral Ketoconazole Hepatotoxicity%酮康唑口服制剂致肝损害风险因素的系统评价

    Institute of Scientific and Technical Information of China (English)

    聂晓璐; 陶庆梅; 詹思延; 王丹; 吴桂芝; 程刚

    2012-01-01

    目的 了解国内外酮康唑口服制剂所致肝损害发生风险因素.方法 2011年11月利用酮康唑有关药品名称、口服制剂等作检索词检索PubMed、MEDLINE、中国生物医学文献数据库(CBM)、中国期刊全文专题数据库(CNKI)、中国科技期刊数据库(VIP)及万方数据库等多个数据库.对于符合纳入标准的文献,提取基本信息、方法学特征、干预措施和不良反应发生情况等信息.用固定效应模型对各个研究的结果进行meta分析.结果 纳入分析的文献共195篇.按照剂量和疗程分组分析,尚不能认为肝损害的发生率与剂量和服药时间有明显的关系;儿童肝损伤发生率为2.2%(95%CI:0.7%~6.6%),60岁以上老年人肝损伤发生率为14.0% (95%CI:4.9%~34.3%);使用酮康唑口服制剂治疗超出其规定说明书适应证用药时,肝损害的发生率较高,为5.5%(95%CI:4.3%~7.0%).结论 酮康唑口服制剂所致肝损害发生的可能风险因素是老年、超说明书适应证使用,未能明确其与剂量和服药时间的关系.%Objective To study risk factors of oral ketoconazole hepatotoxicity. Method Searching articles using relative terms about ketoconazole, oral treatment published on PubMed, Medline, CBM, CNKI, VIP, Wanfang and many other databases by Nov. 2011. Picking up the basic information, method features, interventions and adverse reactions when the studies were included, fixed models were used for the final results'meta analysis. Results The included studies were 195. Subgroup analyze according to dose and duration does not yet obviously indicate that the relation between incidence of liver damage and dose and time for medication; Children's incidence of liver injury was 2.2% (95% CI: 0.7%~6.6%), while that of elderly people over the age of 60 was 14.0%(95% CI: 4.9% -34.3%); Using oral ketoconazole for treatment beyond the provisions of the instructions got a higher incidence of liver

  8. Lightning incidents in Mongolia

    Directory of Open Access Journals (Sweden)

    Myagmar Doljinsuren

    2015-11-01

    Full Text Available This is one of the first studies that has been conducted in Mongolia on the distribution of lightning incidents. The study covers a 10-year period from 2004 to 2013. The country records a human death rate of 15.4 deaths per 10 million people per year, which is much higher than that of many countries with similar isokeraunic level. The reason may be the low-grown vegetation observed in most rural areas of Mongolia, a surface topography, typical to steppe climate. We suggest modifications to Gomes–Kadir equation for such countries, as it predicts a much lower annual death rate for Mongolia. The lightning incidents spread over the period from May to August with the peak of the number of incidents occurring in July. The worst lightning affected region in the country is the central part. Compared with impacts of other convective disasters such as squalls, thunderstorms and hail, lightning stands as the second highest in the number of incidents, human deaths and animal deaths. Economic losses due to lightning is only about 1% of the total losses due to the four extreme weather phenomena. However, unless precautionary measures are not promoted among the public, this figure of losses may significantly increase with time as the country is undergoing rapid industrialization at present.

  9. HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

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    Camilla Stephens

    Full Text Available BACKGROUND AND AIM: The genotype-phenotype interaction in drug-induced liver injury (DILI is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7 and B*1801 (P/Pc = 0.008/0.22, OR 2.9 were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0 was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019 and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2 and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15 were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07. CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

  10. 3,4-Methylenedioxypyrovalerone (MDPV): in vitro mechanisms of hepatotoxicity under normothermic and hyperthermic conditions.

    Science.gov (United States)

    Valente, Maria João; Araújo, Ana Margarida; Silva, Renata; Bastos, Maria de Lourdes; Carvalho, Félix; Guedes de Pinho, Paula; Carvalho, Márcia

    2016-08-01

    Synthetic cathinones have emerged in recreational drug markets as legal alternatives for classical amphetamines. Though currently banned in several countries, 3,4-methylenedioxypyrovalerone (MDPV) is one of the most commonly abused cathinone derivatives worldwide. We have recently reported the potential of MDPV to induce hepatocellular damage, but the underlying mechanisms responsible for such toxicity remain to be elucidated. Similar to amphetamines, a prominent toxic effect of acute intoxications by MDPV is hyperthermia. Therefore, the present in vitro study aimed to provide insights into cellular mechanisms involved in MDPV-induced hepatotoxicity and also evaluate the contribution of hyperthermia to the observed toxic effects. Primary cultures of rat hepatocytes were exposed to 0.2-1.6 mM MDPV for 48 h, at 37 or 40.5 °C, simulating the rise in body temperature that follows MDPV intake. Cell viability was measured through the MTT reduction and LDH leakage assays. Oxidative stress endpoints and cell death pathways were evaluated, namely the production of reactive oxygen and nitrogen species (ROS and RNS), intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione, adenosine triphosphate (ATP) and free calcium (Ca(2+)), as well as the activities of caspases 3, 8 and 9, and nuclear morphological changes with Hoechst 33342/PI double staining. At 37 °C, MDPV induced a concentration-dependent loss of cell viability that was accompanied by GSH depletion, as one of the first signs of toxicity, observed already at low concentrations of MDPV, with negligible changes on GSSG levels, followed by accumulation of ROS and RNS, depletion of ATP contents and increases in intracellular Ca(2+) concentrations. Additionally, activation of caspases 3, 8, and 9 and apoptotic nuclear morphological changes were found in primary rat hepatocytes exposed to MDPV, indicating that this cathinone derivative activates both intrinsic and extrinsic apoptotic death pathways. The

  11. HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate