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  Subjects -> ENVIRONMENTAL STUDIES (Total: 754 journals)
    - ENVIRONMENTAL STUDIES (681 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (41 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (681 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 378 Journals sorted alphabetically
Acta Ecologica Sinica     Open Access   (Followers: 8)
Acta Limnologica Brasiliensia     Open Access   (Followers: 2)
Acta Oecologica     Hybrid Journal   (Followers: 9)
Acta Regionalia et Environmentalica     Open Access  
Advances in Ecological Research     Full-text available via subscription   (Followers: 39)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 18)
Advances in Life Science and Technology     Open Access   (Followers: 14)
Aeolian Research     Hybrid Journal   (Followers: 5)
African Journal of Environmental Science and Technology     Open Access   (Followers: 2)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10)
Amazon's Research and Environmental Law     Open Access   (Followers: 1)
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Environmental Engineering     Open Access   (Followers: 16)
American Journal of Environmental Protection     Open Access   (Followers: 6)
American Journal of Environmental Sciences     Open Access   (Followers: 14)
American Journal of Microbiology     Open Access   (Followers: 13)
American Naturalist     Full-text available via subscription   (Followers: 61)
Annals of GIS     Hybrid Journal   (Followers: 19)
Annals of Warsaw University of Life Sciences - SGGW. Land Reclamation     Open Access  
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (Followers: 47)
Annual Review of Environment and Resources     Full-text available via subscription   (Followers: 15)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 26)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 11)
Applied and Environmental Soil Science     Open Access   (Followers: 14)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 15)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 28)
Aquatic Toxicology     Hybrid Journal   (Followers: 17)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 6)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 8)
Archives of Environmental Protection     Open Access   (Followers: 6)
Archives of Toxicology     Hybrid Journal   (Followers: 15)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 5)
Asian Journal of Rural Development     Open Access   (Followers: 7)
Asian Review of Environmental and Earth Sciences     Open Access   (Followers: 1)
Atas de Saúde Ambiental - ASA     Open Access  
ATBU Journal of Environmental Technology     Open Access   (Followers: 3)
Atmospheric and Climate Sciences     Open Access   (Followers: 25)
Atmospheric Environment     Hybrid Journal   (Followers: 59)
Austral Ecology     Hybrid Journal   (Followers: 12)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 9)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Avicenna Journal of Environmental Health Engineering     Open Access   (Followers: 2)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 9)
Basic and Applied Ecology     Hybrid Journal   (Followers: 16)
Behavioral Ecology     Hybrid Journal   (Followers: 47)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 33)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 26)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 5)
Bioremediation Journal     Hybrid Journal   (Followers: 5)
BioRisk     Open Access   (Followers: 3)
BMC Ecology     Open Access   (Followers: 17)
Boletín Semillas Ambientales     Open Access  
Boston College Environmental Affairs Law Review     Open Access   (Followers: 7)
Bothalia : African Biodiversity & Conservation     Open Access   (Followers: 1)
Built Environment     Full-text available via subscription   (Followers: 4)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 10)
Bulletin of the American Meteorological Society     Open Access   (Followers: 31)
Business, Peace and Sustainable Development     Full-text available via subscription   (Followers: 3)
Canadian Journal of Earth Sciences     Full-text available via subscription   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 39)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 13)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 20)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 11)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 12)
Chain Reaction     Full-text available via subscription   (Followers: 1)
Challenges in Sustainability     Open Access   (Followers: 1)
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 18)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 12)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 60)
Civil and Environmental Engineering     Open Access   (Followers: 7)
Civil And Environmental Engineering Reports     Open Access   (Followers: 4)
Civil and Environmental Research     Open Access   (Followers: 17)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 18)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 6)
Cleanroom Technology     Full-text available via subscription   (Followers: 1)
Climate Change Economics     Hybrid Journal   (Followers: 11)
Climate Policy     Hybrid Journal   (Followers: 28)
Coastal Engineering Journal     Hybrid Journal   (Followers: 3)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 11)
Computational Ecology and Software     Open Access   (Followers: 8)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 4)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 28)
Conservation Science     Open Access   (Followers: 15)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 6)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 12)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 21)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 6)
Current Environmental Health Reports     Hybrid Journal  
Current Forestry Reports     Hybrid Journal  
Current Opinion in Environmental Sustainability     Hybrid Journal   (Followers: 10)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 4)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 15)
Developments in Earth and Environmental Sciences     Full-text available via subscription   (Followers: 5)
Developments in Earth Surface Processes     Full-text available via subscription   (Followers: 3)
Developments in Environmental Modelling     Full-text available via subscription   (Followers: 7)
Developments in Environmental Science     Full-text available via subscription   (Followers: 6)
Developments in Integrated Environmental Assessment     Full-text available via subscription   (Followers: 6)
Disaster Prevention and Management     Hybrid Journal   (Followers: 18)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 12)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 7)
E3S Web of Conferences     Open Access  
Earth Interactions     Full-text available via subscription   (Followers: 11)
Earth Science Informatics     Hybrid Journal   (Followers: 4)
Earth System Science Data (ESSD)     Open Access   (Followers: 7)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 6)
Earthquake Science     Hybrid Journal   (Followers: 9)
EchoGéo     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 10)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 3)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 129)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecological Complexity     Hybrid Journal   (Followers: 8)
Ecological Indicators     Hybrid Journal   (Followers: 16)
Ecological Informatics     Hybrid Journal   (Followers: 5)
Ecological Management & Restoration     Hybrid Journal   (Followers: 15)
Ecological Modelling     Hybrid Journal   (Followers: 97)
Ecological Monographs     Full-text available via subscription   (Followers: 30)
Ecological Processes     Open Access   (Followers: 6)
Ecological Questions     Open Access   (Followers: 7)
Ecological Research     Hybrid Journal   (Followers: 9)
Ecological Restoration     Full-text available via subscription   (Followers: 23)
Ecologist, The     Full-text available via subscription   (Followers: 26)
Ecology     Full-text available via subscription   (Followers: 253)
Ecology and Evolution     Open Access   (Followers: 51)
Ecology Letters     Hybrid Journal   (Followers: 160)
Economics and Policy of Energy and the Environment     Full-text available via subscription   (Followers: 8)
Économie rurale     Open Access   (Followers: 1)
Ecoprint : An International Journal of Ecology     Open Access   (Followers: 2)
Ecopsychology     Hybrid Journal   (Followers: 6)
Ecosphere     Hybrid Journal   (Followers: 3)
Ecosystem Services     Hybrid Journal   (Followers: 6)
Ecosystems     Hybrid Journal   (Followers: 25)
Ecotoxicology     Hybrid Journal   (Followers: 11)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 7)
Ecozon@ : European Journal of Literature, Culture and Environment     Open Access   (Followers: 4)
Ekologija     Open Access  
Electronic Green Journal     Open Access   (Followers: 6)
Elementa : Science of the Anthropocene     Open Access   (Followers: 1)
Empowering Sustainability International Journal     Open Access   (Followers: 1)
Energy & Environmental Science     Full-text available via subscription   (Followers: 21)
Energy and Environment Focus     Free   (Followers: 6)
Energy and Environment Research     Open Access   (Followers: 11)
Energy and Environmental Engineering     Open Access   (Followers: 6)
Engenharia Sanitaria e Ambiental     Open Access  
Envigogika     Open Access  
Environment and Behavior     Hybrid Journal   (Followers: 18)
Environment and Ecology Research     Open Access   (Followers: 5)
Environment and Natural Resources Research     Open Access   (Followers: 11)
Environment and Planning A     Full-text available via subscription   (Followers: 41)
Environment and Planning B : Planning and Design     Full-text available via subscription   (Followers: 33)
Environment and Planning C : Government and Policy     Full-text available via subscription   (Followers: 31)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 41)
Environment and Pollution     Open Access   (Followers: 10)
Environment International     Hybrid Journal   (Followers: 11)
Environment of Care News     Full-text available via subscription   (Followers: 1)
Environment Systems & Decisions     Hybrid Journal   (Followers: 4)
Environment, Development and Sustainability     Hybrid Journal   (Followers: 30)
Environment, Space, Place     Full-text available via subscription   (Followers: 5)
Environment: Science and Policy for Sustainable Development     Hybrid Journal   (Followers: 44)
Environmental & Engineering Geoscience     Full-text available via subscription   (Followers: 3)
Environmental & Socio-economic Studies     Open Access  
Environmental and Climate Technologies     Open Access   (Followers: 3)
Environmental and Molecular Mutagenesis     Hybrid Journal   (Followers: 2)
Environmental Bioindicators     Hybrid Journal   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)
Environmental Claims Journal     Hybrid Journal   (Followers: 1)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 19)
Environmental Development     Hybrid Journal   (Followers: 3)
Environmental Education Research     Hybrid Journal   (Followers: 14)
Environmental Engineering Science     Hybrid Journal   (Followers: 9)
Environmental Ethics     Hybrid Journal   (Followers: 7)
Environmental Evidence     Open Access   (Followers: 1)
Environmental Fluid Mechanics     Hybrid Journal   (Followers: 3)
Environmental Forensics     Hybrid Journal   (Followers: 1)
Environmental Geosciences     Full-text available via subscription   (Followers: 3)
Environmental Geotechnics     Hybrid Journal   (Followers: 3)
Environmental Hazards     Hybrid Journal   (Followers: 2)
Environmental Health     Open Access   (Followers: 10)
Environmental Health Insights     Open Access   (Followers: 4)
Environmental Health Perspectives (EHP)     Open Access   (Followers: 15)
Environmental History     Hybrid Journal   (Followers: 23)
Environmental Impact Assessment Review     Hybrid Journal   (Followers: 21)
Environmental Innovation and Societal Transitions     Hybrid Journal   (Followers: 4)
Environmental Justice     Hybrid Journal   (Followers: 11)
Environmental Law Review     Full-text available via subscription   (Followers: 25)
Environmental Management     Hybrid Journal   (Followers: 45)

        1 2 3 4 | Last

Journal Cover Basic & Clinical Pharmacology & Toxicology
  [SJR: 0.539]   [H-I: 70]   [9 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7835 - ISSN (Online) 1742-7843
   Published by John Wiley and Sons Homepage  [1612 journals]
  • Is Chelation Therapy Efficient for the Treatment of Intravenous Metallic
           Mercury Intoxication'
    • Authors: Daniela Pelclova; Stepanka Vlckova, Ondrej Bezdicek, Manuela Vaneckova, Pavel Urban, Petr Ridzon, Pavel Diblik, Tomas Navratil, Pavlina Klusackova, Kamil Vlcek, Olga Benesova, Pavel Trestik, Jiri Homolka, Sergey Zakharov
      Abstract: The efficacy of treatment for intravenous elemental mercury intoxication has not been fully studied with regard to clinical outcomes, and treatment recommendations vary. We treated a 41-year-old man with a history of drug abuse and depression who attempted suicide using 1 mL (13.53 g) metallic Hg i.v. He was admitted to the hospital two months later for dyspnoea and thoracic pain and was diagnosed with pneumonia. Hg deposits were seen in the lungs and extra-pulmonary organs. His blood level (372 μg/L) exceeded the population level of 5 μg/L by more than 70-fold. Dimercaptopropane sulfonate sodium (DMPS) (600 mg/day orally) was administered for 14 days.One year later, the patient presented with dyspnoea on exertion, fatigue, depression and impaired sleep. His chest X-ray showed multiple opacities (size up to 2.8 cm), and psychological testing revealed a selective cognitive deficit in the area of visual attentiveness, flexibility, source memory and impairment of the motor speed of the dominant upper extremity. Mercury blood level was 158 μg/L and mercury urine output was 1380 μg/24 hr. DMPS (800 mg/day orally) was administered for 40 days; the patient eliminated up to 18 mg Hg/day. His Hg blood level and Hg urine output belong to the highest among reported cases. In spite of the therapy, the patient's blood Hg, complaints and psychological tests showed no improvement. This case report confirms that DMPS does not effectively remove intravenous deposits of metallic Hg.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-02T08:12:17.201349-05:
      DOI: 10.1111/bcpt.12725
       
  • Utilization of Stimulants and Atomoxetine for
           Attention-Deficit/Hyperactivity Disorder among 5.4 million Children Using
           Population-based Longitudinal Data
    • Authors: Kari Furu; Øystein Karlstad, Helga Zoega, Jaana E Martikainen, Shahram Bahmanyar, Helle Kieler, Anton Pottegård
      Abstract: Use of stimulants to treat Attention-deficit/hyperactivity disorder (ADHD) has increased over the past two decades and varies substantially between countries. The objective of this multinational population-based study was to examine utilization of ADHD drugs (stimulants and atomoxetine) including co-medication with other psychothropic drugs in the entire child population in the five Nordic countries. We included longitudinal data on dispensed ADHD drugs from five Nordic prescription registers during 2008-2012; which in 2012 comprised 48,296 individuals among 5.42 million inhabitants aged 0-17 years.Prevalence of filling ≥1 prescriptions of ADHD drugs during 2008-2012 among children aged 6-17 years increased during 2008-2012 from 5.9 to 11.2 and 19.4 to 31.0 per 1000 girls and boys, respectively. Prevalence by country showed that Iceland, Finland and Sweden had a steady increase during the study period, while in Norway the prevalence was quite stable and in Denmark it leveled off from 2010. Use in preschoolers (age 0-5 years) was rare. Iceland had much higher prevalence and incidence than the other Nordic countries. The incidence of ADHD drug use increased during the study period, from 4.0 to 4.9 and from 1.5 to 2.3 per 1000 boys and girls, respectively. The increasing number of new users leveled off somewhat after 2010. Co-medication with other psychotropic drugs was more common among girls (33.9%) than boys (27.0%) and was mainly melatonin, followed by antidepressants and antipsychotics.Overall prevalence of ADHD drug use increased among Nordic girls and boys aged 6-17 years, whereas the incidence increased slightly during 2008-2010 but leveled off through 2012. The substantial differences in ADHD drug use across the Nordic countries and high degree of co-medication with other psychotropic drugs underscore the importance of close monitoring of treatment for ADHD among children.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-02T07:55:25.51056-05:0
      DOI: 10.1111/bcpt.12724
       
  • Topical Antimycotics for Oral Candidiasis in Warfarin Users
    • Authors: Maja Hellfritzsch; Anton Pottegård, Andreas James Thestrup Pedersen, Alaa Burghle, Fatima Mouaanaki, Jesper Hallas, Erik Lerkevang Grove, Per Damkier
      Abstract: Treatment of oral candidiasis in warfarin users may be complicated by drug-drug interactions between warfarin and topically applied antimycotics. However, current knowledge of these putative drug-drug interactions is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential drug-drug interactions between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n≈7,400). We collected data on cohort members’ measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential drug-drug interactions were assessed by comparing INR values before and after initiation of an antimycotic drug.Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure.In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-30T05:22:04.303683-05:
      DOI: 10.1111/bcpt.12722
       
  • Salivary DNA Methylation Profiling: Aspects to Consider for Biomarker
           Identification
    • Authors: Sabine A.S. Langie; Matthieu Moisse, Ken Declerck, Gudrun Koppen, Lode Godderis, Wim Vanden Berghe, Stacy Drury, Patrick De Boever
      Abstract: Is it not more comfortable to spit saliva in a tube than to be pricked with a needle to draw blood to analyse your health and disease risk' A lot of patients, study participants and (parents of) young children undoubtedly prefer non-invasive and convenient procedures. Such procedures increase compliance rates especially for longitudinal prospective studies. Saliva is an attractive biofluid providing good quality DNA to study epigenetic mechanisms underlying disease across development. In this MiniReview, we will describe the different applications of saliva in the field of epigenetics, focusing on genome-wide methylation analysis. Advantages of the use of saliva and its comparability with blood will be discussed, as will the challenges in data processing and interpretation. Knowledge gaps will be identified and suggestions given on how to improve the analysis, making saliva ‘the’ biofluid of choice for future biomarker initiatives in many different epidemiological and public health studies.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-30T05:11:46.258715-05:
      DOI: 10.1111/bcpt.12721
       
  • ECG Alterations Associated with Psychotropic Drug Use and CACNA1C Gene
           Variants in Three Independent Samples
    • Authors: Chiara Fabbri; Giuseppe Boriani, Igor Diemberger, Maria Giulia Filippi, Gloria Ravegnini, Patrizia Hrelia, Alessandro Minarini, Diego Albani, Gianluigi Forloni, Sabrina Angelini, Alessandro Serretti
      Abstract: Several antipsychotics and antidepressants have been associated with QTc prolongation or other ECG alterations, but their impact is still debated and other risk factors are known to affect QTc.We investigated the effect of antidepressants and antipsychotics on QTc and other ECG intervals/waves in three samples. Two discovery samples (cross-sectional sample n=145 and prospective sample n=68, naturalistic treatment) and a replication prospective sample (CATIE, n=515, randomized treatment) were analysed. In both prospective samples, baseline/follow-up changes in ECG parameters were analysed in relation to the number of psychotropic drugs stratified according to their known cardiovascular risk. In the cross-sectional sample, ECG parameters were compared among drugs with different risk profile. The possible effect of single nucleotide polymorphisms (SNPs) in the CACNA1C gene on QTc was also investigated.There was no evidence of mean QTc prolongation or increased risk of clinically relevant QTc prolongation (≥ 20 ms) in association with psychotropic drugs stratified according to their known cardiovascular risk. The prescription of drugs with cardiovascular risk was less common in older individuals or individuals with cardiovascular co-morbidities. Other factors (gender, baseline QTc, renal function) affected QTc. rs1006737 and SNPs in linkage disequilibrium with it modulated QTc duration/changes in all samples. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples.A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not observed. A number of factors other than psychotropic drugs may influence QTc. CACNA1C rs1006737 may modulate QTc in patients treated with psychotropic drugs.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-28T09:20:24.10946-05:0
      DOI: 10.1111/bcpt.12720
       
  • Performance of the High-Dimensional Propensity Score in a Nordic Health
           Care Model
    • Authors: Jesper Hallas; Anton Pottegård
      Abstract: The high-dimensional propensity score (hdPS) is increasingly used as a tool to adjust for confounding in observational studies of drug effects. It was developed within very rich data sources, e.g., the American claims databases. Thus, it is unknown whether it can be applied in settings that provide little more than prescriptions and diagnoses from hospital contacts, as in the Nordic data sources. Our objective was to evaluate the performance of hdPS under such circumstances.As our model, we chose the association between use of selective cyclooxygenase-2 inhibitors (coxibs) and traditional NSAIDs (tNSAIDs) and the risk of upper GI bleeding. Using Danish health registries, we identified 110,285 incident users of coxibs and 575,980 incident users of tNSAIDs and followed them for 90 days with respect to the occurrence of serious upper GI bleeding. Data were analysed using Cox regression, estimating the coxib/tNSAID hazard ratio (HR). Values below 1.00 indicate a lower estimated hazard with coxibs. We build hdPS models with inclusion of up to 500 diagnosis and 500 prescription drug covariates.The crude HR was 1.76 (95% confidence interval (CI): 1.57 - 1.97), decreasing to 1.12 (1.00 - 1.26) and 0.99 (0.88 - 1.12) after adjustment for age and sex and eleven pre-selected confounders, respectively. A hdPS with inclusion of 500 most prevalent diagnoses and 500 most prevalent prescription drugs resulted in a HR of 0.89 (0.77 - 1.02). These estimates were consistently lower when the analysis was restricted to non-users of low-dose aspirin. The estimate based on 500 diagnoses alone was higher than an estimate based on 500 prescription drugs alone (0.99 versus 0.91).We conclude that hdPS does work within a Nordic setting, that prescription data are more effective than diagnosis data in achieving confounder adjustment, and that hdPS seems more effective than simple confounder adjustment by variables selected on the basis of clinical reasoning.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-27T04:55:38.192083-05:
      DOI: 10.1111/bcpt.12716
       
  • An Adductomic Approach to Identify Electrophiles In Vivo
    • Authors: Henrik Carlsson; Margareta Törnqvist
      Abstract: Humans are exposed to many reactive electrophiles, both formed endogenously and from exogenous exposures. Such compounds could react with cellular biomolecules and form stable reaction products, adducts, at nucleophilic sites in proteins and DNA, constituting a risk for toxic effects. Adductomic approaches aim to study the totality of adducts, to specific biomolecules, by mass spectrometric screening. This MiniReview focuses on the development and application of an adductomic approach for the screening of unknown adducts to N-terminal valine (Val) in hemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC-MS/MS). The approach is based on the FIRE procedure, a modified Edman procedure for the analysis of adducts to N-terminal Val in Hb by LC-MS/MS. In the first application of the approach, samples from 12 smokers/non-smokers were screened for Hb adducts, and 6 previously identified adducts and 20 unknown adducts were detected. To confirm the observation of the detected unknown adducts, targeted screenings were performed in larger sets of blood samples (n = 50–120) from human cohorts. The majority of the previously detected unknown adducts was found in all analysed samples, with large interindividual variations in adduct levels. For structural identification of unknown adducts, a strategy using adductome LC-MS/MS data was formulated and applied. Six identified adducts correspond to ethylation and the precursor electrophiles ethyl vinyl ketone, glyoxal, methylglyoxal, acrylic acid and 1-octen-3-one. The observation of these adducts in human blood motivate further studies to evaluate possible contributions to health risks, as well as their potential as biomarkers of exposure.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-27T04:55:33.279193-05:
      DOI: 10.1111/bcpt.12715
       
  • Small Molecule Inhibiting NF-kB Ameliorates Oxidative Stress and
           Suppresses Renal Inflammation in Early Stage of Alloxan-induced Diabetic
           Nephropathy in Rat
    • Authors: Manash P. Borgohain; Mangala Lakhar, Sahabuddin Ahmed, Liakat Chowdhury, Saurabh Kumar, Rajat Pant, Abhinav Choubey
      Abstract: Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Oxidative stress produced by prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. NF-kB-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and diabetic renal inflammatory pathway in rat induced by alloxan. Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body weight (b.w.) of alloxan. Treatment with piceatannol to diabetic rats was given in two doses, i.e. 30 and 50 mg/kg b.w. After 14 days of oral treatment, piceatannol significantly restored blood sugar level, glomerular filtration rate (GFR), serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase (SOD) and glutathione (GSH), and the elevated levels of melondialdehyde (MDA) and nitric oxide (NO). Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg and in terms of body weight gain, piceatannol failed to effect significantly. However, overall findings clearly demonstrated that piceatannol provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-26T04:07:40.65415-05:0
      DOI: 10.1111/bcpt.12718
       
  • Vascular Toxicity Risk Assessment of MC18 and MC70, Novel Potential
           Diagnostic Tools for In Vivo PET Studies
    • Authors: Fabio Fusi; Miriam Durante, Claudia Sticozzi, Maria Frosini, Maria G. Perrone, Nicola A. Colabufo, Simona Saponara
      Abstract: The P-glicoprotein (P-gp) inhibitor MC18 has been recently proposed as a valuable PET tracer to measure P-gp expression in vivo.The aim of this study was to evaluate the toxic hazard towards the vasculature of MC18 along with the structurally related and more potent P-gp inhibitor MC70.Their effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of fresh and cultured rat aorta rings as well as on Cav1.2 channel current (ICa1.2) of A7r5 cells were studied.At concentrations >10 μM, MC18 and MC70 decreased cell viability causing evident morphological changes. In fresh rat aorta rings, both compounds (0.1-100 μM) antagonized phenylephrine-induced contraction in a concentration-dependent manner, with IC50 values in the range of 1.67 – 14.49 μM, whereas only MC18 caused a concentration-dependent decrease of the 60 mM K+ (K60)-induced responses. In rings cultured for 7 days with both compounds (1-10 μM), 10 μM MC70 significantly reduced, while 10 μM MC18 completely prevented the contractile response to both phenylephrine and K60. MC18 and MC70 (0.1-100 μM) inhibited ICa1.2 in a concentration-dependent manner with IC50 values of 16.81 and 32.13 μM, respectively.These findings demonstrate that MC18-induced vascular effects took place at concentrations that are at least three orders of magnitude higher than those (≤ 10 nM) allowing in vivo measurement of P-gp expression. Thus, MC18, and possibly MC70, can be considered promising PET tools for in vivo P-gp quantification.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-26T04:07:39.541726-05:
      DOI: 10.1111/bcpt.12719
       
  • Adverse Effect Profile of Topical Ocular Administration of Fingolimod for
           Treatment of Dry Eye Disease
    • Authors: Weibao Xiao; Li Sun, Nan Zhang, Wen Ye
      Abstract: Fingolimod is a promising prodrug in attenuating multiple sclerosis and prolonging survival of organ allograft, with many other protective effects. Its mechanism of action is related to the internalization of sphingosine 1-phosphate receptors (S1PRs). Our previous study indicated that fingolimod eyedrop was efficacious in inhibiting ocular inflammation in a dry eye disease (DED) model of Non-Obese Diabetic (NOD) mice. In the current study, we evaluated potential adverse effects of fingolimod eyedrop. Inbred 10-week-old BALB/C mice were randomly divided into four groups, fingolimod-treated groups at three different concentrations (0.01%, 0.1% and 0.5%) and a negative control group without intervention. Our results showed that, in the 0.5% fingolimod group, adverse effects such as photophobia, catacleisis and corneal oedema were observed after one week of treatment. One month later, corneal opacity, oedema and neovascularization persisted till the mice were euthanized two months later. In contrast, there was no significant abnormality in the negative control group, 0.01% and 0.1%fingolimod-treated groups. During a 2-month treatment period, we did not detect fingolimod, nor significant change of blood cells in peripheral blood, nor pathological changes in retina and systemic organs. Combined with our previous study and the current results, we recommend that an optimal range of safe and effective concentration of fingolimod as eyedrop is between 0.005% and 0.1%.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-26T04:07:38.583643-05:
      DOI: 10.1111/bcpt.12717
       
  • Impact of the Chronic Omega-3 Fatty Acids Supplementation in
           Hemiparkinsonism Model Induced by 6-Hydroxydopamine in Rats
    • Authors: Alexandre Sales Barros; Rafael Yuri Gouveia Crispim, Juliana Cavalcante Uchoa, Ricardo Basto Souza, Jonatas Cavalcante Lemos, Gerardo Cristino Filho, Mirna Marques Bezerra, Thales Fontenele Moraes Pinheiro, Silvânia Maria Mendes Vasconcelos, Danielle Silveira Macêdo, Glauce Socorro Barros Viana, Lissiana Magna Vasconcelos Aguiar
      Abstract: Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In the present study, the protective effect of ω-3 PUFAs administration on the 6-hydroxydopamine (6-OHDA) model of PD in rats was investigated. ω-3 PUFAs (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4th day, hemiparkinsonism was induced through intrastriatal injection of 6-OHDA. On the 25th day, the animals were submitted to behavioural analysis. On the 28th day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω-3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acids levels on the striatum from hemiparkinsonian rats, followed by reduction of the number of apomorphine-induced rotations and promotion of a partial locomotor recovery. In addition, ω-3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, the present study suggests that supplementation with ω-3 PUFAs prevents behavioural and neurochemical disturbances induced by 6-OHDA, presenting a potential neuroprotective action.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-24T10:00:30.274012-05:
      DOI: 10.1111/bcpt.12713
       
  • Pharmacovigilance Skills, Knowledge and Attitudes in our Future Doctors -
           A Nationwide Study in the Netherlands
    • Authors: Tim Schutte; Jelle Tichelaar, Michael O. Reumerman, Rike Eekeren, Robert Rissmann, Cornelis Kramers, Milan C. Richir, Eugène P van Puijenbroek, Michiel A van Agtmael,
      Abstract: Pharmacovigilance centres monitor the safety of drugs, based on adverse drug reactions (ADRs) reported by doctors, pharmacists and pharmaceutical companies. However, the underreporting of ADRs remains a major problem. Our aim was to investigate preparedness of future doctors for their role in pharmacovigilance, by assessing their pharmacovigilance awareness, skills and knowledge.The study was a nationwide e-survey among medical students (third to sixth year) of all eight medical schools in the Netherlands. The survey consisted of questions regarding pharmacovigilance awareness, skills and knowledge.Overall, 874 students provided informed consent and participated (response 12%). Almost all students (96%) intended to report serious ADRs in their future practice. Almost half (44%) of the students did not know where to report an ADR, and 78% did not know which items were necessary for a good-quality ADR report. While more than 78% of the students agreed that pharmacovigilance is an important topic in their medical education, only 26% found that their current curriculum covered pharmacovigilance adequately.Although ADR reporting is considered relevant and important among future doctors, many do not know where and what to report. This is highly undesirable and should have consequences for pharmacotherapy teaching.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-24T10:00:27.384821-05:
      DOI: 10.1111/bcpt.12712
       
  • Oil-Fortified Maize Porridge Increases Absorption of Lumefantrine in
           Children with Uncomplicated Falciparum Malaria
    • Authors: Norah Mwebaza; Markus Jerling, Lars L Gustafsson, Antero V Silva, Anton Pohanka, Celestino Obua, Paul Waako, Olof Beck, Manijeh Vafa Homann, Anna Färnert, Urban Hellgren
      Abstract: Artemether-lumefantrine (AL) is a first-line treatment for uncomplicated malaria. Absorption of lumefantrine (LUM) is fat-dependent, and in children intake is recommended with milk. We investigated whether oil-fortified maize porridge can be an alternative when milk is not available. In an open-label pharmacokinetic study, Ugandan children
      PubDate: 2016-11-24T10:00:25.13825-05:0
      DOI: 10.1111/bcpt.12714
       
  • Usefulness of transthoracic echocardiography parameters and brain
           natriuretic peptide as mortality predictors in hospitalized, acutely
           poisoned patients: a prospective observational study
    • Authors: Catalina Lionte; Victorita Sorodoc, Cristina Bologa, Cristina Tuchilus, Elisabeta Jaba
      Abstract: Acute poisonings represent a common cause of morbidity and mortality worldwide. The prognostic utility of the transthoracic echocardiography (TTE) parameters combined with brain natriuretic peptide (BNP) in acute poisoning with different xenobiotics, upon admission in the hospital was not evaluated. This prospective observational cohort study included 229 acutely poisoned non-diabetic adults, with a median age of 44 years (range 18-90 years), 50.7% women, with an in-hospital mortality rate of 8.7%. Univariate logistic regression analysis showed that age, the left ventricle kinetic abnormalities, the E wave deceleration time (EDT) and BNP correlated significantly with mortality in acutely poisoned patients. Multivariate logistic regression showed that only EDT [odds ratio (OR) 3.44, 95% confidence interval (CI) 1.54-7.69, p 0.003], BNP (OR 1.61, 95% CI 1.02-2.55, p 0.04), and age (OR 2.66, 95%CI 1.23-5.76, p 0.013) are predictive for mortality. The receiver operating characteristic (ROC) analysis proved EDT [area under the ROC curve (AUC), 0.85; CI, 0.76-0.94; p 0.001], BNP (AUC, 0.83; CI, 0.75-0.91; p 0.001) and age (AUC, 0.82; CI, 0.74-0.90; p 0.001) as indicators for fatalities. In hospitalized patients acutely intoxicated with undifferentiated poisons, EDT as a parameter of left ventricle diastolic function and BNP are useful to early predict mortality.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-24T09:55:25.769577-05:
      DOI: 10.1111/bcpt.12711
       
  • Decreased Activity and Genetic Polymorphisms of CYP2C19 in Behçet's
           Disease
    • Authors: Mustafa Tugrul Goktas; R. Ozgur Karaca, Said Kalkisim, Lokman Cevik, Levent Kilic, Ali Akdogan, Melih O. Babaoglu, Atilla Bozkurt, Leif Bertilsson, Umit Yasar
      Abstract: Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down-regulated due to inflammation. In the same Turkish BD patients, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5-hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms were made by using PCR-RFLP. The median lansoprazole/5-hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6-fold higher as compared to the healthy control group (p=0.001, 22.6 (1.3-26) and 8.8 (0.5-140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p=0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in 6 patients (p=0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-22T10:15:25.379909-05:
      DOI: 10.1111/bcpt.12710
       
  • Trends in Off-Label Prescribing of Sedatives, Hypnotics and
           Antidepressants among Children and Adolescents – A Danish, Nationwide
           Register-based Study
    • Authors: Eva Skovslund Nielsen; Lotte Rasmussen, Maja Hellfritzsch Poulsen, Per Hove Thomsen, Mette Nørgaard, Torben Laursen
      Abstract: In recent years, psychotropic drug use among children and adolescents in Europe and USA has increased. However, the majority of psychotropic drugs are not formally approved for use in children and adolescents, and consequently, use is often off-label.The objectives were to describe time trends in off-label prescribing rates and the most commonly used types of psychotropic drugs by age and gender in Danish children and adolescents.Using the Register of Medicinal Product Statistics, we identified all prescriptions for sedatives, hypnotics and antidepressants filled for children and adolescents in 2006-2012. Information on diagnoses was obtained from the Danish National Registry of Patients and allowed classification of prescriptions as either on- or off-label.We identified 186,831 prescriptions filled for 29,851 children and adolescents: 88.0% of these were classified as off-label. During 2006-2012, off-label rates for sedatives and hypnotics increased significantly, except for prescriptions for girls aged 15-17 years [range 24.1%-98.2% (girls), 31.9% to 99.0% (boys)]. In the same period, the number of registered melatonin prescriptions (all off-label) increased expansively.For antidepressants, we found decreasing trends in off-label rates over time [range 94.5%-65.6% (girls), 93.8%-71.2% (boys)].Off-label prescribing of psychotropic drugs to Danish children and adolescents is common. Off-label rates for sedatives and hypnotics increased in the period of 2006-2012, whereas off-label rates for antidepressants declined. Off-label rates might be underestimated and should be considered a conservative estimate.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-17T07:15:20.058228-05:
      DOI: 10.1111/bcpt.12706
       
  • Biodistribution of Carbon Nanotubes in Animal Models
    • Authors: Nicklas Raun Jacobsen; Peter Møller, Per Axel Clausen, Anne Thoustrup Saber, Christian Micheletti, Keld Alstrup Jensen, Håkan Wallin, Ulla Vogel
      Abstract: The many physical and chemical properties of carbon nanotubes (CNT) make it one of the most commercially attractive materials in the era of nanotechnology. Here, we review the recent publications on in vivo biodistribution of pristine and functionalized forms of single-walled and multi-walled CNT. Pristine CNT remains in the lung for months or even years following pulmonary deposition. If cleared, the majority of CNT move to the gastrointestinal (GI) tract via the mucociliary escalator. However, there appears to be no uptake of CNT from the GI tract, with a possible exception of the smallest functionalized SWCNT. Importantly, a significant fraction of CNT translocates from the alveolar space to the near pulmonary region including lymph nodes, sub-pleura and pleura (
      PubDate: 2016-11-16T09:46:16.608998-05:
      DOI: 10.1111/bcpt.12705
       
  • Activated Charcoal Hemoperfusion in the Treatment of Experimental
           Amitriptyline Poisoning in Pigs - The Effect on Amitriptyline Plasma
           Concentration and Hemodynamic Parameters
    • Authors: Tejs Jansen; Henrik Petersen, Cecilie M. Malskær, Charlotte Gabel-Jensen, Kim Dalhoff, Thomas Eriksen, Bo Belhage, Lotte C.G. Hoegberg
      Abstract: Coated activated charcoal hemoperfusion (CAC-HP) is a well-known treatment modality. Case reports have revealed conflicting results about the efficacy of CAC-HP in the treatment of amitriptyline (AT) poisoning, and no randomised clinical trials have been identified in the literature. This study aimed at quantifying the efficacy of modern CAC-HP as an adjunctive treatment of AT intoxication compared to standard care alone.Fourteen female Danish landrace pigs were randomized to either standard care or standard care plus 4 hr of CAC-HP. The pigs were anaesthetized and vital parameters were continuously recorded. Amitriptyline infusion (7.5 mg/kg) was completed in 20 min. Thirty minutes following AT infusion, activated charcoal was instilled orally in both groups. In the intervention group, CAC-HP was initiated 60 min. after AT infusion. Blood and urine samples were collected as were vital parameters at specific time intervals. The protocol was approved by the Danish Experimental Animal Expectorate and complied with the NIH guide for care and use of laboratory animals. Data were managed according to the ARRIVE guidelines.No statistical significant differences between intervention and control group were found when analysing for differences in AT levels in plasma at any time point. Furthermore, significant differences between the control and intervention group in regard to vital parameters could not be found either.In our animal model, the addition of CAC-HP did not improve the clearance of AT compared to standard treatment alone. We hypothesize that the effect of modern CAC-HP as a treatment modality in AT poisoned human patients may be inadequate.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-14T09:41:39.777124-05:
      DOI: 10.1111/bcpt.12704
       
  • ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a
           
    • Authors: André Ducati Luchessi; Marta Concheiro, Juliana Freitas Germano, Vivian Nogueira Silbiger, Raul Hernandes Bortolin, Angelines Cruz, Oscar Quintela, Maria Brion, Angel Carracedo, Andres Iñiguez, Marisol Bravo, Manuel López-Rivadulla, Rosario Dominguez Crespo Hirata, Amanda Guerra Moraes Rego Sousa, Mario Hiroyuki Hirata
      Abstract: Acetylsalicylic acid and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome (ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 (ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid (SA), and a carboxylic acid metabolite (CAM). Clopidogrel, CAM, and SA plasma concentrations were measured simultaneously by liquid chromatography tandem mass spectrometry (LCMS/MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392, and rs739923) and CYP2C19*2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression (r = 0.494, P < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers (P = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression (P = 0.017), rs757421 AA genotype (P = 0.001), blood collection time (BCT; P = 0.018), and clopidogrel dose (P = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19*2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-12T09:42:07.642381-05:
      DOI: 10.1111/bcpt.12703
       
  • Colchicine Increases Ventricular Vulnerability in an Experimental
           Whole-Heart Model
    • Authors: Gerrit Frommeyer; Julius Krawczyk, Dirk G. Dechering, Simon Kochhäuser, Patrick Leitz, Michael Fehr, Lars Eckardt
      Abstract: The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole-heart model.Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, colchicine was administered in 2 concentrations (1μM and 3μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose-dependent significant decrease of effective refractory period (ERP; 1μM: -19ms, 3μM: -22ms; p
      PubDate: 2016-11-11T06:45:21.275948-05:
      DOI: 10.1111/bcpt.12702
       
  • Extended Low-Dose Exposure to Saxitoxin Inhibits Neurite Outgrowth in
           Model Neuronal Cells
    • Authors: Katie O'Neill; Ian F. Musgrave, Andrew Humpage
      Abstract: The potent neurotoxin saxitoxin (STX) belongs to a group of structurally related analogues produced by both marine and freshwater phytoplankton. The toxins act by blocking voltage-gated sodium channels stopping the inflow of sodium ions and the generation of action potentials. Exposure from marine sources occurs as a result of consuming shellfish which have concentrated the toxins and freshwater exposure can occur from drinking water although there have been no acute poisonings from the latter source to date. Previously, the majority of research into this group of toxins, collectively known as the paralytic shellfish toxins, has focused on acute exposure resulting in paralytic shellfish poisoning. While acute exposure guidelines exist for both sources, there are no chronic exposure guidelines and there has been minimal research into this pattern of exposure despite the known role of electrical activity in neurogenesis. We aimed to investigate this pattern of exposure and its potential effects on neurodevelopment using model neuronal cells. PC12 and SH-SY5Y cells were exposed to STX (0.25-3μg/l) for seven days, after which time they were stained with TRITC-Phalloidin, to observe adverse morphological effects. Cells exposed to STX had a significant decrease (18 - 85%) in long axon-like projections, instead exhibiting a significant increase in shorter projections classified as filopodia (p
      PubDate: 2016-11-07T10:06:05.285805-05:
      DOI: 10.1111/bcpt.12701
       
  • A Novel Scale Linking Potency and Dosage to Estimate Anticholinergic
           Exposure in Older Adults: the Muscarinic Acetylcholinergic Receptor
           ANTagonist Exposure (MARANTE) Scale
    • Authors: Therese T. Klamer; Maarten Wauters, Majda Azermai, Carlos Durán, Thierry Christiaens, Monique Elseviers, Robert Vander Stichele
      Abstract: Quantification of the anticholinergic exposure insufficiently or imprecisely incorporates dosage information, leading to inaccurate estimations. The aim was to construct a novel scale, including potency and dosage for the quantification of the anticholinergic exposure in older adults. Potency information was retrieved from a previous systematic review. The dosage range for each drug was delineated in minimal, maintenance and maximal dosage for adults and older adults. Dosage information was collected from authorative sources and reviewed in an expert panel. The Muscarinic Acetylcholinergic Receptor ANTagonist Exposure (MARANTE) scale was tested for clinimetric properties using cohorts of community-dwelling older adults and nursing home residents. After 3 data collection rounds, data for the dosage ranges remained incomplete for 32 active substances. Remaining gaps were filled in, and 11 dosage adjustments were proposed during the expert panel meeting.We chose the values {0; 1; 2) for the categories of potency and {0; 0.5; 1; 1.5; 2) for the levels of dosage ranges, showing good clinimetric properties.Forty-one anticholinergic drugs were prescribed in the two cohorts. Most (61%) were low potency anticholinergics, used for depression (19%, e.g. citalopram).There were 31.8% (median MARANTE 1.5, IQR 1.5 – 2.5) and 37.6% (median 2, IQR 1.5 – 2.5) anticholinergic users in the community-dwelling cohort and nursing home cohort, respectively. The MARANTE scale combines potency with the dosage spectrum, to quantify the anticholinergic exposure in older adults. An open feedback systems on the list of anticholinergic and proposed anticholinergic potency and dosage values is advised.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-07T10:06:04.12749-05:0
      DOI: 10.1111/bcpt.12699
       
  • Acute Treatment with Lauric Acid Reduces Blood Pressure and Oxidative
           Stress in Spontaneously Hypertensive Rats
    • Authors: Naiane Ferraz Bandeira Alves; Thyago Moreira Queiroz, Rafael Almeida Travassos, Marciane Magnani, Valdir Andrade Braga
      Abstract: The effects of acute administration of lauric acid (LA), the most abundant medium chain fatty acid of coconut oil, on blood pressure, heart rate and oxidative stress were investigated in spontaneously hypertensive rats (SHR). Intravenous doses of LA reduced blood pressure in a dose-dependent fashion (1, 3, 4, 8 and 10 mg/kg) in both SHR and Wistar Kyoto rats. LA (10-8 to 3 x 10-3 M) induced vasorelaxation in isolated superior mesenteric artery rings of SHR in the presence (n = 7) or absence (n = 8) of functional endothelium [maximum effect (ME) = 104 ± 3 versus 103 ± 4 %]. After exposure to KCl (60 mM), LA also induced concentration-dependent vasorelaxation (n = 7) compared to that under Phe-induced contraction (ME = 113.5 + 5.1 versus 104.5 + 4.0 %). Furthermore, LA induced vasorelaxation in vessels contracted with S(−)-BayK8644 (200 nM), a L-type Ca2+ channel agonist (ME = 91.4 + 4.3 versus 104.5 + 4.0 %, n = 7). Lastly, LA (10-3 M) reduced NADPH-dependent superoxide accumulation in the heart (18 ± 1 versus 25 ± 1 MLU/min/μg protein, n = 4, P < 0.05) and kidney (82 ± 3 versus 99 ± 4 MLU/min/μg protein, n = 4, P < 0.05). Our data show that LA reduces blood pressure in normotensive and hypertensive rats. In SHR, this effect might involve Ca+2 channels in the resistance vessels and by its capability of reducing oxidative stress in heart and kidneys.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-07T10:05:59.123316-05:
      DOI: 10.1111/bcpt.12700
       
  • Towards a new paradigm in nano-genotoxicology: Facing complexity of
           nanomaterials cellular interactions and effects
    • Authors: Laetitia Gonzalez; Enrico Cundari, Luc Leyns, Micheline Kirsch-Volders
      Abstract: Changes in paradigm contribute to advances in research. The current paradigms for the evaluation of toxicity of chemicals refer to linear or curvilinear dose-response curves with or without threshold and to surface-dependent induction of oxidative damage for particles. The unique physico-chemical properties and biological/genotoxic activity of engineered nanomaterials (NMs) require the development of a new paradigm. Because of their unusual dosimetry and their multiple interactions at NM level (agglomeration/ aggregation) and at different cellular and extra-cellular levels, NMs are likely to have complex modes of action (multiple hits at multiple targets) leading to complex thresholded – non-thresholded dose-response curves. Understanding their cellular targets and their modes of action will contribute to the production of safe-by-design NMs. An integrative, cell-by-cell approach for genotoxic effects should be applied to tackle this emerging paradigm in nano-genotoxicology.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-04T03:46:13.06063-05:0
      DOI: 10.1111/bcpt.12698
       
  • LPS, but not Angiotensin ll, lnduces Direct Pro-lnflammatory Effects in
           Cultured Mouse Arteries and Human Endothelial and Vascular Smooth Muscle
           Cells
    • Authors: Emilie M. Outzen; Marina Zaki, Rahila Mehryar, Bahareh Abdolalizadeh, Waseem Sajid, Harrie C.M. Boonen, Anette Sams, Majid Sheykhzade
      Abstract: Angiotensin II (Ang II) might induce pro-inflammatory effects directly on the vascular wall independently of its hemodynamic effects. The aim of our study was to investigate the putative direct pro-inflammatory and vasomotor effects of Ang II and compare to those of LPS in mouse isolated mesenteric resistance-sized arteries (MRA) supported by experiments in cultured human primary endothelial and vascular smooth muscle cells. Results showed that 24-hr organ culture of mouse MRA with 10 nM Ang II had, unlike 100 ng/mL LPS, no effects on IL-6 or MCP-1 secretion, VCAM1 mRNA expression or endothelial function, while Ang II significantly decreased maximal vasomotor responses to phenylephrine. In support, 24-hr organ culture of mouse MRA significantly suppressed Agtr1a mRNA and augmented Tlr4 mRNA along with attenuated vasomotor responses to Ang II. Moreover, contrary to LPS and TNFα, Ang II and [Sar1]-Ang II had no concentration- or time-dependent effects on IL-6 and MCP-1 secretion in human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HASMC). AGTR1 or AGTR2 mRNA expression were undetectable in HUVEC, whereas HASMC expressed only AGTR1 mRNA. In summary, contrary to previous studies and the observed effects of LPS, we could not demonstrate direct vascular pro-inflammatory effects of Ang II ex vivo or in vitro. As indicated by our results, down-regulation or desensitization of AT1R during culture may explain our findings.This article is protected by copyright. All rights reserved
      PubDate: 2016-11-04T03:17:00.812249-05:
      DOI: 10.1111/bcpt.12697
       
  • Clinical Pharmacist-Provided Services In Iron Overloaded Beta-Thalassemia
           Major Children; A New Insight To Patient Care
    • Authors: Salma M. Bahnasawy; Lamia M. El Wakeel, Nagham El Beblawy, Manal El-Hamamsy
      Abstract: Iron overloaded β-thalassemia major (BTM) children have high risk of delayed sexual/physical maturation, liver/heart diseases and reduced life expectancy. The lifelong need to use iron chelators along with their unpleasant administration, side effects and lack of awareness regarding iron overload risks, all hamper BTM patient compliance to iron chelators. This study evaluated the impact of clinical pharmacist-provided services on the outcome of iron overloaded BTM children. Forty-eight BTM children were randomly assigned to either control group, who received standard medical care or intervention group, who received standard medical care plus clinical pharmacist-provided services. Services included detection of drug-related problems (DRPs) and their management, patient education regarding disease nature and iron chelators, as well as providing patient-tailored medication charts. After six months of study implementation, there was a highly significant difference between the control and intervention groups in serum ferritin (SF) (Mean: 3871 versus 2362, μg/l, p=0.0042), patient healthcare satisfaction (Median: 24.47 versus 90.29, p
      PubDate: 2016-10-31T23:01:02.275258-05:
      DOI: 10.1111/bcpt.12695
       
  • Crocin Attenuates Kindling Development and Associated Cognitive
           Impairments in Mice via Inhibiting Reactive Oxygen Species-Mediated NF-κB
           Activation
    • Authors: Arindam Ghosh Mazumder; Pallavi Sharma, Vikram Patial, Damanpreet Singh
      Abstract: Crocin is a pharmacologically active carotenoid pigment mainly present in the stigmas of Crocus sativus L. (Iridaceae). It has been well explored in experimental animal models of cognitive impairments, depression, anxiety and epilepsy. The present study was designed to understand the effect of crocin on pentylenetetrazol (PTZ)-induced kindling development and its associated cognitive deficit in mouse. Crocin treatment at 5, 10 and 20 mg/kg p.o. doses showed marked reduction in severity of PTZ-induced seizures. There was increase in novel object preference index and discrimination ratio in the crocin-treated groups in the novel object recognition test. Its treatment also increased percentage spontaneous alternations in T-maze test at all the tested doses. Histopathological examination by Nissl staining showed reduction in dark neurons in the hippocampal pyramidal layer of crocin-treated animals in contrast to vehicle control, indicating decrease in neuronal damage. Biochemical estimations showed significant increase in superoxide dismutase activity and reduced reactive oxygen species (ROS) in the hippocampus of crocin-treated animals. Immunohistochemistry results revealed attenuation in the levels of nuclear factor-κB (NF-κB) and phosphorylated-NF-κB in the hippocampal sections of crocin-treated animals. The results of the present study concluded that crocin treatment increased seizure threshold, thus inhibiting PTZ-induced kindling development and improving cognitive functions. The effect was found to be due to suppression of seizures-induced ROS generation and its linked NF-κB pathway associated neuronal damage.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-31T22:55:30.487812-05:
      DOI: 10.1111/bcpt.12694
       
  • Idarucizumab for Reversal of Dabigatran Prior to Acute Surgery: A
           Schematic Approach based on a Case Report
    • Authors: Lene Rosenberg; Gustav Gerstrøm, Mads Nybo
      Abstract: Dabigatran, an oral direct thrombin inhibitor, is frequently used in treatment of venous thromboembolism and prevention of stroke in non-valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment that reverses the dabigatran effect, was introduced to the market to be used in case of life-threatening bleeding or acute surgery/invasive procedures. Whether usage should be guided by measurement of plasma dabigatran and/or other coagulation parameters is, however, still uncertain.We here describe the use of idarucizumab prior to acute surgery in a patient on dabigatran and acetylsalicylic acid. In this case, the decision to use idarucizumab was based on the clinical manifestations and other routine coagulation parameters, as the plasma dabigatran concentration was not available prior to administration.Due to challenges with the plasma dabigatran analysis and taking the safety of idarucizumab into consideration, it could be questioned whether a dabigatran measurement in general is necessary in this setting. Based on this case, we suggest a scheduled approach when considering requesting a plasma dabigatran measurement prior to administration of idarucizumab.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-31T10:20:25.723143-05:
      DOI: 10.1111/bcpt.12696
       
  • DNA Damage Potential of Engine Emissions Measured In Vitro by Micronucleus
           Test in Human Bronchial Epithelial Cells
    • Authors: Tereza Cervena; Andrea Rossnerova, Jitka Sikorova, Vit Beranek, Michal Vojtisek-Lom, Miroslav Ciganek, Jan Topinka, Pavel Rossner
      Abstract: Internal combustion engine emissions belong among the major anthropogenic sources of air pollution in urban areas. According to the International Agency for Research on Cancer (IARC), there is sufficient evidence of the carcinogenicity of diesel exhaust in humans. Although alternative fuels, mainly biodiesel, have recently become popular, little is still known about the genotoxicity of emissions from these fuels. We analysed DNA damage expressed as the frequency of micronuclei (MN) in human bronchial epithelial cells (BEAS-2B), induced by extractable organic matter (EOM; tested concentrations: 1, 10 and 25 μg/ml) obtained from particle emissions from various blends of biodiesel with diesel fuels (including neat diesel fuel (B0), a blend of 70% B0 and 30% biodiesel (B30) and neat biodiesel (B100)). We also tested the effect of selected diesel exhaust organic/genotoxic components [benzo[a]pyrene (B[a]P): concentrations: 25, 100 and 200 μM; 1-nitropyrene (1-NP): concentrations: 1, 5 and 10 μM; 3-nitrobenzanthrone (3-NBA): concentrations: 1, 5 and 50 μM]. The cells were treated with the compounds for 28 hr and 48 hr. Our results showed that most of the tested compounds (except for the 25 μM B[a]P, 28-hr treatment) significantly increased MN frequency. The genotoxicity of EOMs from the engine emissions of diesel and biodiesel engines were comparable. Both nitro-PAHs compounds demonstrated higher genotoxic potential in comparison with B[a]P. Considering our results and due to increasing popularity of alternative fuels, it is prudent that the potential genotoxic effects of various fuels are investigated across engine technologies and operating conditions in a relevant model system.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-26T04:26:13.496524-05:
      DOI: 10.1111/bcpt.12693
       
  • Integrin Targeting and Toxicological Assessment of Peptide-Conjugated
           Liposome Delivery Systems to Activated Endothelial Cells
    • Authors: Ali Kermanizadeh; Klaus Villadsen, Ragnhild G. Østrem, Knud J. Jensen, Peter Møller, Steffen Loft
      Abstract: Utilisation of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines following exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-21T06:20:52.784785-05:
      DOI: 10.1111/bcpt.12692
       
  • Modelling Mutational Signatures of Human Carcinogens using Experimental
           Systems
    • Authors: Maria Zhivagui; Michael Korenjak, Jiri Zavadil
      Abstract: Mutation spectra in cancer genomes provide information on the disease aetiology and the causality underlying the evolution and progression of cancer. Genome-wide mutation patterns reflect the effects of mutagenic insults and can thus reveal past carcinogen-specific exposures and inform hypotheses on the causative factors for specific cancer types. In order to identify mutation profiles in human cancers, single genes studies were first employed, focusing mainly on the tumour suppressor gene TP53. Furthermore, experimental studies had been developed in model organisms. They allowed the characterization of the mutation patterns specific to known human carcinogens, such as polycyclic aromatic hydrocarbons or ultraviolet light. With the advent of massively parallel sequencing, mutation landscapes became generated on a large scale, in human primary tumours and in experimental models, enabling deeper investigations of the functional and structural impact of the mutations on the genome, including exposure-specific base-change fingerprints known as mutational signatures. These studies can now accelerate the identification of aetiological factors, contribute to carcinogen evaluation and classification, and ultimately inform cancer prevention measures.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-18T09:25:27.045174-05:
      DOI: 10.1111/bcpt.12690
       
  • Is Nickel Chloride really a Non-Genotoxic Carcinogen?
    • Authors: Leanne Stannard; Shareen H. Doak, Ann Doherty, Gareth J. Jenkins
      Abstract: Humans are exposed to carcinogens through air, water, food and tobacco smoke. Nickel chloride (NiCl2) is a toxic and carcinogenic environmental and occupational pollutant, which was previously classified as a non-genotoxic carcinogen, and thought to not directly alter the DNA. Non-genotoxic carcinogens like NiCl2 are difficult to detect in vitro, hence a heavy reliance on animal studies exists.NiCl2 has previously been classified as a non-genotoxic carcinogen (NGTC); however, after studying the effect of NiCl2 on many mechanistic endpoints, it has become clear that NiCl2 behaves more like a genotoxic carcinogen. The induction of reactive oxygen species (ROS) after treatment with NiCl2, along with positive micronuclei results from a preliminary 5-day chronic dose micronucleus study further support that NiCl2 has been misclassified as a NGTC. It is possible that NiCl2 causes indirect DNA damage by the production of ROS and requires a longer, chronic exposure, which is more similar to that of human exposure.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-17T04:15:35.155947-05:
      DOI: 10.1111/bcpt.12689
       
  • Lipid-soluble Cigarette Smoke Particles Induced Vascular Endothelin Type A
           Receptor Up-Regulation through Activation of ERK1/2 Signal Pathways
    • Authors: Yaping Zhang; Wei Zhang, Lars Edvinsson, Cang-Bao Xu
      Abstract: Abnormal contraction of vessels termed “vasospasm” is associated with various cardiovascular diseases. Smoking is a well-known risk factor that increases vasospasm. However, the molecular mechanisms by which smoking leads to vasospasm and cardiovascular disease are not fully understood. The present study was designed to examine if DMSO-extracted cigarette smoke particles (DSP) could induce up-regulation of vascular endothelin type A (ETA) receptors, and if ETA receptor is up-regulated through activation of extracellular regulated protein kinase 1 and 2 (ERK1/2) signal pathways. Mesenteric arterial segments from rats were cultured in the presence of DSP, water-extracted cigarette smoke particles (WSP), or equivalent concentration of nicotine for up to 24 hr. The results showed that DSP, but not WSP or nicotine, induced ETA receptor up-regulation with increased ETA receptor-mediated contraction (myograph, P
      PubDate: 2016-10-12T09:14:16.805361-05:
      DOI: 10.1111/bcpt.12688
       
  • Repression of MicroRNA-372 by Arsenic Sulfide Inhibits Prostate Cancer
           Cell Proliferation and Migration through Regulation of LATS2
    • Authors: Hongwen Cao; Yigeng Feng, Lei Chen
      Abstract: As the main component of realgar, arsenic sulfide (As4S4) contains anti-tumour activity by repressing cancer cell proliferation and migration in many tumours. However, the detailed mechanism of these processes is not clear yet. MicroRNAs (miRNAs) can function as tumour suppressor or oncogene based on their target mRNAs in different tumour tissues. Here, we found that As4S4 could repress the over-expression of microRNA-372 (miR-372) in two prostate cancer cell lines and its over-expression promoted cell proliferation and migration. LATS2 (large tumour suppressor kinase 2) was confirmed as a direct target of miR-372 using luciferase assays in these two prostate cancer cell lines. Down-regulation of LATS2 could promote prostate cancer cell proliferation and migration just as over-expression of miR-372 did and over-expression of LATS2 could reverse this effect of miR-372. The anti-tumour activity of As4S4 and the oncogenic function of miR-372 were further confirmed using a mouse xenograft model. Altogether, our data showed evidence that repressing the over-expression of miR-372 by As4S4 could inhibit prostate cancer cell proliferation and migration by targeting LATS2. Therefore, miR-372 may be a possible biomarker for the prediction of prostate cancer and As4S4 may have potential therapeutic function for prostate cancer.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-12T02:21:41.744584-05:
      DOI: 10.1111/bcpt.12687
       
  • Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in
           Asthmatic Children during Acute Exacerbation
    • Authors: Yang Quan-Jun; Zhang Jian-Ping, Zhang Jian-Hua, Han Yong-Long, Xin Bo, Zhang Jing-Xian, Dai Bona, Zhang Yuan, Guo Cheng
      Abstract: Inhaled budesonide and salbutamol represent the most important and frequently used drugs in asthmatic children during acute exacerbation. However, there is still no consensus about their resulting metabolic derangements; thus, the present study was conducted to determine the distinct metabolic profiles of these two drugs. A total of 69 children with asthma during acute exacerbation were included, and their serum and urine were investigated using high-resolution nuclear magnetic resonance (NMR). A metabolomics analysis was performed using a principal component analysis and orthogonal signal correction-partial least squares using SIMCA-P. The different metabolites were identified, and the distinct metabolic profiles were analysed using MetPA. A high-resolution NMR-based serum and urine metabolomics approach was established to study the overall metabolic changes after inhaled budesonide and salbutamol in asthmatic children during acute exacerbation. The perturbed metabolites included 22 different metabolites in the serum and 21 metabolites in the urine. Based on an integrated analysis, the changed metabolites included the following: increased 4-hydroxybutyrate, lactate, cis-aconitate, 5-hydroxyindoleacetate, taurine, trans-4-hydroxy-l-proline, tiglylglycine, 3-hydroxybutyrate, 3-methylhistidine, glucose, cis-aconitate, 2-deoxyinosine, and 2-aminoadipate; and decreased alanine, glycerol, arginine, glycylproline, 2-hydroxy-3-methylvalerate, creatine, citrulline, glutamate, asparagine, 2-hydroxyvalerate, citrate, homoserine, histamine, sn-glycero-3-phosphocholine, sarcosine, ornithine, creatinine, glycine, isoleucine, and trimethylamine N-oxide. The MetPA analysis revealed 7 involved metabolic pathways: arginine and proline metabolism; taurine and hypotaurine metabolism; glycine, serine and threonine metabolism; glyoxylate and dicarboxylate metabolism; methane metabolism; citrate cycle; and pyruvate metabolism.The perturbed metabolic profiles suggest potential metabolic reprogramming associated with a combination treatment of inhaled budesonide and salbutamol in asthmatic children.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-12T02:14:50.747196-05:
      DOI: 10.1111/bcpt.12686
       
  • HAS-BLED Predicts Warfarin Control in Australian Patients treated for Deep
           Vein Thrombosis
    • Authors: Kylie Mueller; Nijole Bernaitis, Tony Badrick, Shailendra Anoopkumar-Dukie
      Abstract: The HAS-BLED model is widely utilised to assess patients’ bleed risk prior to anticoagulant therapy including warfarin. Some of the variables assessed in the model are also known to influence warfarin control, commonly measured by time in therapeutic range (TTR). The aim of the study was to determine if the HAS-BLED risk tool is a good predictor of bleed risk and warfarin control in deep vein thrombosis (DVT) patients. Retrospective data were collected for DVT warfarin care patients at Sullivan Nicolaides Pathology. Data included age, medical history and concurrent drug therapy to calculate HAS-BLED scores. INR results were used to calculate TTR with the Rosendaal method and mean TTR used for analysis and comparison. The eligible 533 patients had a mean TTR of 78.3%. Categorisation according to HAS-BLED score resulted in 150 patients classified as low risk, 331 as moderate and 52 as high risk with a haemorrhagic incidence per patient of 0.08, 0.53, and 0.54, respectively. Patients in the low, moderate and high risk HAS-BLED categories had a mean TTR of 81%, 79% and 65%, respectively, with significant differences (p
      PubDate: 2016-10-08T09:35:26.622829-05:
      DOI: 10.1111/bcpt.12685
       
  • Long-term Use of Z-Hypnotics and Co-Medication with Benzodiazepines and
           Opioids
    • Authors: Solveig Sakshaug; Marte Handal, Vidar Hjellvik, Christian Berg, Åse Ripel, Ingebjørg Gustavsen, Jørg Mørland, Svetlana Skurtveit
      Abstract: Benzodiazepine-like drugs (z-hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z-hypnotics are recommended for short-term treatment not exceeding 4 weeks.We aimed to study the use of z-hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co-medication with benzodiazepines and opioids in long-term users.Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z-hypnotic use was defined as new fillings at least once in each of the four 365-day follow-up periods. Age groups 18-39, 40-64 and 65+ were analysed separately for men and women.In 2013, 354,571 (8.9%) of the population filled at least one prescription of z-hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z-hypnotics in 2009, 13,996 (16.8%) received z-hypnotics all four 365-day periods of follow-up. In these long-term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group.27.9% of the long-term recurrent users of z-hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co-medication increased with level of z-hypnotic treatment intensity.Overall, many z-hypnotics users had medicines dispensed for longer periods than recommended, and co-medications with drugs that may reinforce the central depressing and intoxicating effects were common.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-07T08:36:23.149855-05:
      DOI: 10.1111/bcpt.12684
       
  • Gene-Gene Interactions among PRKCA, NOS3 and BDKRB2 Polymorphisms Affect
           the Antihypertensive Effects of Enalapril
    • Authors: Gustavo H. Oliveira-Paula; Marcelo R. Luizon, Riccardo Lacchini, Vanessa Fontana, Pamela S. Silva, Celso Biagi, E. Tanus-Santos
      Abstract: Protein kinase C (PKC) signaling is critically involved in the control of blood pressure. Angiotensin-converting enzyme inhibitors (ACEi) affect PKC expression and activity, which are partially associated with thel responses to ACEi. We examined whether PRKCA (Protein Kinase C, Alpha) polymorphisms (rs887797 C>T, rs1010544 T>C, and rs16960228 G>A), or haplotypes, and gene-gene interactions within the ACEi pathway affect the antihypertensive responses in 104 hypertensive patients treated with enalapril as monotherapy. Patients were classified as poor responders (PR) or good responders (GR) to enalapril if their changes in mean arterial pressure were lower or higher than the median value, respectively. Multifactor dimensionality reduction was used to characterize interactions among PRKCA, NOS3 (Nitric Oxide Synthase 3) and BDKRB2 (Bradykinin Receptor B2) polymorphisms. The TC+CC genotypes for the rs1010544 polymorphism were more frequent in GR than in PR (P=0.037). Conversely, the GA+AA genotypes for the rs16960228 polymorphism, and the CTA haplotype, were more frequent in PR than in GR (P=0.040 and P=0.008, respectively). Moreover, the GG genotype for the PRKCA rs16960228 polymorphism was associated with PR or GR depending on the genotypes for the rs2070744 (NOS3) and rs1799722 (BDKRB2) polymorphisms (P=0.012). Our results suggest that PRKCA polymorphisms and gene-gene interactions within the ACEi pathway affect the antihypertensive responses to enalapril.This article is protected by copyright. All rights reserved.
      PubDate: 2016-10-01T09:45:36.957079-05:
      DOI: 10.1111/bcpt.12682
       
  • Clinical Pharmacology in Denmark in 2016 – 40 Years with the Danish
           Society of Clinical Pharmacology and 20 Years as a Medical Speciality
    • Authors: Kim Brøsen; Stig Ejdrup Andersen, Jeanett Borregaard, Hanne Rolighed Christensen, Palle Mark Christensen, Kim Peder Dalhoff, Per Damkier, Jesper Hallas, Jens Heisterberg, Niels Jessen, Gesche Jürgens, Jens Peter Konnerup Kampmann, Britt Elmedal Laursen, Torben Laursen, Lars Peter Nielsen, Birgitte Klindt Poulsen, Henrik Enghusen Poulsen, Ljubica Vukelic Andersen, Thomas Senderovitz, Jesper Sonne
      Abstract: The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the Society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish health care system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees in both hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutics drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital work closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, postmortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1,000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-29T08:20:59.232134-05:
      DOI: 10.1111/bcpt.12681
       
  • A Novel Model of P‐Glycoprotein Inhibitor Screening Using Human
           Small Intestinal Organoids
    • Authors: Junfang Zhao; Zhiyang Zeng, Jialiang Sun, Yuanjin Zhang, Dali Li, Xueli Zhang, Mingyao Liu, Xin Wang
      Abstract: P‐glycoprotein (P‐gp), an important efflux transporter in intestine, regulates the bioavailability of orally taken drugs. To develop an in vitro model that preferably mimics the physiological microenvironment of human intestine, we employed the three‐dimensionally (3D) cultured organoids from human normal small intestinal epithelium. It was observed that the intestinal crypts could efficiently form cystic organoid structure with the extension of culture time. Furthermore, the physiological express of ABCB1 was detected at both mRNA and protein levels in cultured organoids. Rhodamine 123 (Rh123), a typical substrate of P‐gp, was actively transported across 3D organoids and accumulated in the luminal space. This transport process was also inhibited by verapamil and mitotane. In summary, the above‐mentioned model based on human small intestinal 3D organoids is suitable to imitate the small intestinal epithelium and could be used as a novel in vitro model especially for P‐gp inhibitor screening.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-22T12:30:20.12345-05:0
      DOI: 10.1111/bcpt.12680
       
  • The Effects of L‐carnitine against Cyclophosphamide‐induced
           Injuries in Mouse Testis
    • Authors: Yuanchao Cao; Xinsheng Wang, Shenqian Li, Hongqiang Wang, Lei Yu, Peitao Wang
      Abstract: In order to explore the possibility of L‐carnitine (LC) as a protector of male fertility in chemotherapy, we observed the damage of cyclophosphamide (CTX) to Sertoli cells and the protective effect of LC on the testis Sertoli cells from such damage in this study. Healthy adult male mice were divided into three groups. Chemotherapy group were injected intraperitoneally with the CTX; Protective agent group were injected both LC and CTX; Control group mice were injected only with isochoric physiological saline; all once a day for 5 days. After 5 days, the mice were respectively killed at 24 hr after the last injection. The testis and epididymis were removed. Epididymis was for sperm analysis immediately, and immunohistochemistry, RT‐PCR and Western blot for the assessments of occludin, GDNF and TGF‐β3 mRNA and protein expression. The sperm analysis of epididymis showed that CTX can significantly decrease sperm count and motility; and administration of LC resulted in significant recovery of the sperm count and sperm motility. Compared with control group, the expressions of occludin and GDNF decreased and the expression of TGF‐β3 increased significantly (P
      PubDate: 2016-09-21T02:55:46.434466-05:
      DOI: 10.1111/bcpt.12679
       
  • Anabolic Effect of Insulin Therapy on the Bone: Osteoprotegerin and
           Osteocalcin Up-Regulation in Streptozotocin-Induced Diabetic Rats
    • Authors: Raul Hernandes Bortolin; Francisco Paulo Freire Neto, Carlos Alberto Arcaro Filho, João Felipe Bezerra, Flávio Santos da Silva, Marcela Abott Galvão Ururahy, Karla Simone da Costa Souza, Valeria Morgiana Gualberto Duarte Moreira Lima, André Ducati Luchessi, Francisco Pignataro Lima, Marcus Vinicius Lia Fook, Bartolomeu Jorge da Silva, Maria das Graças Almeida, Bento João Abreu, Luciana Augusto Rezende, Adriana Augusto Rezende
      Abstract: Type 1 diabetes mellitus (T1DM) is associated with several skeletal alterations, particularly in conditions of poor glycaemic control. Insulin therapy is the major conservative treatment for T1DM; however, the effects of this hormone on bone markers of T1DM rats are limited, and the regulatory mechanisms remain elusive. Therefore, the evaluation of molecular and non-molecular parameters in a chronic animal model of T1DM-induced bone loss, treated with and without insulin, may help in elucidating insulin mechanisms. Male Wistar rats were assigned into three groups: control, T1DM (T1DM rats induced with streptozotocin [STZ] at 40 mg/kg intravenously) and T1DM plus insulin therapy (T1DMI). After eight weeks, we evaluated serum biochemistry, tibia histomorphometric and biomechanical parameters, as well as the gene expression of the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and osteocalcin (OC) of femur mRNA. Compared with T1DM, the T1DMI group showed less bone loss, which was revealed by the increased trabecular width (TbWi, p < 0.001) and trabecular bone area (BAr, p < 0.01), reduced trabecular separation (TbSp, p < 0.01), and increased Young's modulus (p < 0.05). Moreover, molecular analyses indicated that the expression of OPG and OC was up-regulated (p < 0.001 and p < 0.05, respectively). In summary, the up-regulation of OPG and OC in the T1DMI group supports an anabolic effect of insulin, which was evidenced by the maintenance of bone architecture and flexibility. These results suggest that insulin therapy may prevent T1DM-induced bone loss via effects on bone formation.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-21T02:48:18.308334-05:
      DOI: 10.1111/bcpt.12672
       
  • Students and Doctors are Unaware of the Cost of Drugs they frequently
           prescribe
    • Authors: Tim Schutte; Jelle Tichelaar, Prabath Nanayakkara, Milan Richir, Michiel Agtmael
      Abstract: Given the increasing healthcare costs of an ageing population, there is growing interest in rational prescribing, which takes costs of medication into account. We aimed to gain insight into the attitude to and knowledge of medication costs of medical students and doctors in daily practice.This was a cross‐sectional electronic survey among medical students (bachelor/master) and doctors (consultants/registrars). Attitude to costs was evaluated using a cost‐consciousness scale. In open questions, the participants estimated the cost of commonly prescribed (generic/non‐generic) drugs (including separate pharmacy dispensing costs). They were asked where they could find information about drug costs.Overall, a reasonable cost‐consciousness was found. Students were less conscious of the cost than were doctors (15.56 SD 3.25 versus 17.81 SD 2.25; scale 0–24; p=0.001). In contrast to this consciousness, actual estimated drug costs were within a 25% margin for only 5.4% of generic and 13.7% of proprietary drugs (Wilcoxon signed‐ranks, p
      PubDate: 2016-09-17T09:30:57.461966-05:
      DOI: 10.1111/bcpt.12678
       
  • Quantitative Assessment of Food Effect on the Pharmacokinetics of
           Nano‐Crystallized Megestrol Acetate
    • Authors: Jinju Guk; Hankil Son, Dong Woo Chae, Kyungsoo Park
      Abstract: Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano‐crystallized megestrol acetate (NCMA), using a model‐based approach.Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr post‐dose. With the incorporation of body weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an AUC (area under concentration) and Cmax (maximum concentration) of NCMA close to those obtained with the fed dose.NCMA concentrations were best characterized by a two‐compartment model with first‐order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2‐fold, and decreased the absorption rate constant 0.58‐fold. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%.This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-17T09:30:56.522231-05:
      DOI: 10.1111/bcpt.12677
       
  • Proliferative Properties of 17β-aminoestrogens in MCF-7 Human Breast
           Cancer Cells
    • Authors: Cristina Lemini; María Estela Avila, Martha Medina, Carlos Sánchez, Alejandra Figueroa, Juana García-Mondragón, Arsenio Vargas-Vázquez, Alejandro Jiménez-Orozco
      Abstract: The 17β-aminoestrogens (AEs) prolame, butolame and pentolame are weakly oestrogenic in rodents and display anticoagulant properties in contrast to oestradiol (E2) which presents procoagulant effects, potentially thrombogenic. They possess anti-anxiety and anti-depressive properties, being good candidates for menopausal hormone therapy. Their capability to induce proliferation of MCF-7 human breast cancer cells, which proliferative rate depends on oestrogens, has not been explored; thus, the aim of this work was to characterize it. AEs proliferation properties were evaluated compared with E2 in MCF-7 carcinoma cell-line cultures using established methods. Receptor mediation on cell proliferation was studied by co-incubating them with the oestrogen receptor antagonists tamoxifen, ICI 182,780 and the selective antagonists MPP (ERα) and PHTPP (ERβ). E2 and AEs increased MCF-7 cell proliferation; their proliferative effect was between 1.5-2 and E2 = 3.6 compared to controls (0); their relative proliferative effect was 18-38% (E2 = 100%) with a relative proliferative potency of 4.5–8.9 (E2 = 100). The ERα antagonist MPP inhibited the MCF-7 cells proliferation induced by E2 and AEs; on the contrary, the ERβ antagonist PHTPP exacerbated the proliferative response, showing that the AEs proliferative activity was mainly ERα-mediated and apparently controlled by ERβ. Preliminary cytometric DNA flow analysis showed that AEs’ cell cycle S-phase-inducer property was lower than E2 following the proliferative order: E2 > butolame > prolame > pentolame, indicating pentolame with the weakest proliferative properties and being the safest of this series as a candidate for MHT.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-16T20:30:49.938188-05:
      DOI: 10.1111/bcpt.12674
       
  • Use of a Target‐Mediated Drug Disposition Model to Predict the Human
           Pharmacokinetics and Target Occupancy of GC1118, an Anti‐Epidermal
           Growth Factor Receptor Antibody
    • Authors: Wan‐Su Park; Seunghoon Han, Jongtae Lee, Taegon Hong, Jonghwa Won, Yangmi Lim, Kyuhyun Lee, Han Yeul Byun, Dong‐Seok Yim
      Abstract: GC1118 is an anti‐epidermal growth factor receptor (EGFR) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics (PK) of GC1118 were modelled in monkeys to predict human PK and receptor occupancy (RO) profiles. The serum concentrations of GC1118 and its comparator (cetuximab) were assessed in monkeys with a non‐compartmental analysis and a target‐mediated drug disposition (TMDD) model following intravenous infusion (3–25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis. The human cetuximab exposures were simulated by applying different exponents (0.7–1.0) for the EGFR synthesis rate in the allometric monkey PK model. Simulated Cmax and area under the curve values therein were compared with those previously reported in the literature to find the best exponent for the EGFR synthesis rate in human beings. The TMDD model appropriately described the monkey PK profile, which showed a decrease in clearance (CL; 1.2–0.4 mL/hr/kg) as the dose increased. The exponents for CL (0.75) and volume of distribution (Vd; 1.0) were used for the allometric scaling to predict human PK. The allometric coefficient for the EGFR synthesis rate chosen by the sensitivity analysis was 0.85 and the RO profiles that could not be measured experimentally were estimated based on the predicted concentrations of the total target and the drug‐target complex. Our monkey TMDD model successfully predicts human PK and RO profiles of GC1118 and can be used to determine the appropriate dose for a first‐in‐human study investigating this drug.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-16T20:30:44.378653-05:
      DOI: 10.1111/bcpt.12675
       
  • Penicillin G Treatment in Infective Endocarditis Patients – Does
           Standard Dosing Result in Therapeutic Plasma Concentrations'
    • Authors: Kristina Öbrink‐Hansen; Henrik Wiggers, Bo Martin Bibby, Tore Forsingdal Hardlei, Kaare Jensen, Marianne Kragh Thomsen, Birgitte Brock, Eskild Petersen
      Abstract: Penicillin G is frequently used to treat infective endocarditis (IE) caused by streptococci, penicillin‐susceptible staphylococci and enterococci. Appropriate antibiotic exposure is essential for survival and reduces the risk of complications and drug resistance development. We determined Penicillin G plasma concentrations [p‐penicillin] once weekly in 46 IE patients. The aim was to evaluate if Penicillin G 3g every 6 hr (q6h) resulted in therapeutic concentrations and to analyse potential factors that influence inter‐ and intra‐individual variability, using linear regression and a random coefficient model. [P‐penicillin] at 3 hr and at 6 hr was compared with the minimal inhibitory concentration (MIC) of the bacteria isolated from blood cultures to evaluate the following PK/PD targets: 50% fT>MIC and 100% fT>MIC.[P‐penicillin] varied notably between patients and was associated with age, weight, p‐creatinine and estimated creatinine clearance (eCLcr). Additionally, an increase in [p‐penicillin] during the treatment period showed strong correlation with age, a low eCLcr, a low weight and a low p‐albumin. Of the 46 patients, 96% had [p‐penicillin] that resulted in 50% fT>MIC, while 71% had [p‐penicillin] resulting in 100% fT>MIC. The majority of patients not achieving the 100% fT>MIC target were infected with enterococci. Streptococci and staphylococci isolated from blood cultures were highly susceptible to Penicillin G.Our results suggest that Penicillin G 3g q6h is suitable to treat IE caused by streptococci and penicillin‐susceptible staphylococci, but caution must be taken when the infection is caused by enterococci. When treating enterococci, therapeutic drug monitoring should be applied to optimize Penicillin G dosing and exposure.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-16T03:01:07.698435-05:
      DOI: 10.1111/bcpt.12661
       
  • Hepatocyte Concentrations of Indocyanin Green (ICG) Reflects Transfer
           Rates Across Membrane Transporters
    • Authors: Fabien Cusin; Liliana Fernandes Azevedo, Pierre Bonnaventure, Jules Desmeules, Youssef Daali, Catherine M. Pastor
      Abstract: Peroperative imaging with indocyanin green (ICG) is developing to increase safety in dissecting anatomical structures during hepatobiliary surgery. Images obtained with the fluorescence camera rely on concentrations measured in liver regions of interest. However, how ICG sinusoidal uptake and hepatocyte elimination rates generate ICG hepatocyte concentrations is largely unknown. To investigate such issue and better understand the role of membrane transporters in generating ICG hepatocyte concentrations, we perfused ICG in livers isolated from normal livers. Whether the well‐known transporter inhibitor rifampicin modifies hepatocyte ICG concentrations was also studied. The dye has a very high and constant extraction ratio (96%) into hepatocytes. This persistent high extraction ratio generates a huge uphill concentration gradient across the sinusoidal membrane: from 5 μM (sinusoids) to 1600 μM (liver). When inside hepatocytes, ICG has low hepatocyte elimination (7 nmol/min) and liver concentrations do not decrease much over time. Moreover, the tiny hepatocyte ICG efflux is mainly due to ICG return back to sinusoids (90%). Rifampicin slightly inhibits ICG uptake into hepatocytes and when inside hepatocytes blocks ICG efflux into bile canaliculi. In contrast, it increases ICG efflux back to sinusoids with significant decrease in ICG liver concentrations. Imaging with ICG in the peroperative period reflects the high hepatocyte concentrations and relies on the high extraction ratio across hepatocyte sinusoidal membrane. Although ICG concentrations are low in bile ducts, they are adequate for a good visualisation and avoid bile duct injury.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-14T03:55:35.805593-05:
      DOI: 10.1111/bcpt.12671
       
  • Effects of Di-Isononyl Phthalate on Neuropeptide Y Expression in
           Differentiating Human Neuronal Cells
    • Authors: Filip Rendel; Christina Fjæraa Alfredsson, Carl-Gustaf Bornehag, Birgitta E Sundström, Eewa Nånberg
      Abstract: Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian brain important for behavioural consequences of stress and energy metabolism. We have addressed possible effects of the phthalate DiNP on NPY expression in human SH-SY5Y cells, a neuronal in vitro differentiation model. Pico- to nanomolar doses of DiNP and its metabolite MiNP resulted in decreased NPY mRNA and peptide expression in retinoid-differentiated cells. Thus, dys-regulated NPY may be an adverse outcome for exposure to low doses of DiNP in human beings.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-13T23:51:01.438499-05:
      DOI: 10.1111/bcpt.12670
       
  • Neuroprotective Effects of Sulfated Agaran from Marine Alga Gracilaria
           cornea in Rat 6‐hydroxydopamine Parkinson's Disease Model: Behavioural,
           Neurochemical and Transcriptional Alterations
    • Authors: Ricardo Basto Souza; Annyta Fernandes Frota, Rayane Siqueira Sousa, Nayara Araújo Cezario, Tarcizio Brito Santos, Luziana Mara Frota Souza, Chistiane Oliveira Coura, Valdécio Silvano Monteiro, Gerardo Cristino Filho, Silvânia Maria Mendes Vasconcelos, Rodrigo Maranguape Silva da Cunha, Lissiana Magna Vasconcelos Aguiar, Norma Maria Barros Benevides
      Abstract: Parkinson's disease (PD) is a multifactorial disease associated with the degeneration of dopaminergic neurons and behavioural alterations. Natural bioactive compounds may provide new therapeutic alternatives for neurodegenerative disorders, such as PD. The sulfated polysaccharides isolated from marine algae are heterogenic molecules that show different biological activities. The red marine alga Gracilaria cornea has a sulfated polysaccharide (SA‐Gc) with structure and anti‐inflammatory and anti‐nociceptive activities reported in the literature. Therefore, this study aimed to evaluate the neuroprotective effects of SA‐Gc in rat model PD induced by 6‐hydroxydopamine (6‐OHDA). Firstly, we established the PD model in rats, induced by an intrastriatal injection (int.) of 6‐OHDA, followed by a single administration of SA‐Gc (15, 30 or 60 μg; int.). On the 14th day, behavioural tests were performed. After euthanasia, brain areas were dissected and used for neurochemical and/or transcriptional analyses. The results showed that SA‐Gc (60 μg, int.) promoted neuroprotective effects in vivo through reducing the oxidative/nitroactive stress and through alterations in the monoamine contents induced by 6‐OHDA. Furthermore, SA‐Gc modulated the transcription of neuroprotective and inflammatory genes, as well as returning behavioural activities and weight gain to normal conditions. Thus, the present study reports the neuroprotective effects of SA‐Gc against 6‐OHDA in rats.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-09T10:41:33.964784-05:
      DOI: 10.1111/bcpt.12669
       
  • Comparison of Pharmacokinetics and Tissue Distribution Kinetics of
           Roxithromycin and Expression of CYP 3A1 between Pregnant Mice and Foetuses
           
    • Authors: Yi Qin; Weizhe Xu, Lanjian Mo, Xiaorong Li, Beikang Ge, Jie Xiong, Lifang Gao, Pinxiang Xu, Ming Xue
      Abstract: The macrolide antibiotic, roxithromycin, is recommended for treating mycoplasma infection and has the potential to be administered to pregnant women who are susceptible to the infection. The current study compared the pharmacokinetic properties and tissue distribution of roxithromycin among pregnant mice and their foetuses. We also determined the level of CYP3A1, a major enzyme for roxithromycin metabolism, in liver microsomes and investigated the placental transport properties of roxithromycin. Biosamples were collected from female mice at gestational day 17 following a single intragastric administration of roxithromycin. A sensitive and specific lipid chromatography‐tandem mass spectroscopy method was developed to detect the drug concentration and to obtain kinetic data. The level of CYP3A1 was significantly lower in foetal liver compared with that in maternal liver according to western blot data, suggesting a decreased metabolism and prolonged half‐life of roxithromycin in the foetus. The tissue distributions of roxithromycin were similar between mother and foetus, indicating that the placental barrier did not block the transport of roxithromycin from mother to foetus. The current findings are consistent with the clinical efficacy of roxithromycin in both pregnant mothers and foetuses. Based on this study, it is feasible and reasonable to predict the transport properties of other lipophilic drugs during pregnancy.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-09T10:17:05.477677-05:
      DOI: 10.1111/bcpt.12668
       
  • Effects of Genetic Polymorphisms of Cytochrome P450 Enzymes and MDR1
           Transporter on Pantoprazole Metabolism and Helicobacter pylori Eradication
           
    • Authors: R O Karaca; S Kalkisim, A Altinbas, S Kilincalp, I Yuksel, M T Goktas, U Yasar, A Bozkurt, M O Babaoglu
      Abstract: Pantoprazole is a proton pump inhibitor that is commonly used in the treatment of peptic ulcer disease (PUD) and metabolized by cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4. Pantoprazole is a substrate for multidrug resistance protein 1 (MDR1). Single nucleotide polymorphisms (SNPs) in CYP2C19, CYP3A4 and MDR1 affect enzyme activity or gene expression of proteins and may alter plasma pantoprazole concentrations and treatment success in PUD. In this study, we aimed to investigate the association between genetic polymorphisms in CYP2C19, CYP3A4 and MDR1 and pharmacokinetics of pantoprazole and therapeutic outcomes in patients with either Helicobacter pylori associated [H.P.(+)]‐PUD or [H.P.(+)]‐gastritis. The plasma pantoprazole concentrations were determined by using an HPLC method at the third hour after a 40‐mg tablet of pantoprazole administration in 194 newly diagnosed patients with either [H.P.(+)]‐PUD or [H.P.(+)]‐gastritis. Genotyping was performed by using PCR‐RFLP and DNA sequencing. Among patients appearing for follow‐up examination (n=105), the eradication rate for H. pylori was 82.8% (n=87). The median pantoprazole plasma concentrations in poor metabolisers (PM), rapid metabolisers (RM) and ultra‐rapid metabolisers (URM) were 2.07; 1.69; 1.28 μg/ml, respectively (p=0.04). CYP3A4*1G and *22 polymorphisms did not affect plasma pantoprazole concentrations and H. pylori eradication rate. The MDR1 genetic polymorphisms did not affect plasma pantoprazole concentrations. MDR1 3435CC‐2677GG‐1236CC haplotype carriers had lower H. pylori eradication rate (60%) than the remaining subjects (84.9%) while the difference was not statistically significant (p=0.07).In conclusion, while CYP2C19 genetic polymorphisms significantly affected plasma pantoprazole concentrations, polymorphisms of CYP2C19, CYP3A4 and MDR1 did not affect H. pylori eradication rates.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-09T02:33:50.634897-05:
      DOI: 10.1111/bcpt.12667
       
  • Investigating Prevalence and Pattern of Long‐Term Cardiovascular
           Disorders in Sulfur Mustard‐exposed Victims and Determining Proper
           Biomarkers for Early Defining, Monitoring and Analysis of Patients’
           Feedback on Therapy
    • Authors: Behrad Darvishi; Yunes Panahi, Mostafa Ghanei, Leila Farahmand
      Abstract: Among the most readily existing chemical warfare agents, sulfur mustard (SM), also known as Mustard Gas, is the most commonly used agent owing to its ease of synthesis and stockpiling. Unprotected exposure mostly results in debilitation rather than lethal injuries, leaving an exposed victim incapacitated for days to even months. Although acute toxicity of sulfur mustard has been fairly established, the long‐term post‐exposure effects either chronic or short‐term but significant are still evolving. 30,000 Iranian victims of the Iran‐Iraq imposed war, have now – after 30 years ‐ formed the key population demonstrating long‐term effects from sulfur mustard exposure. Recent studies have shown that the prevalence of several long‐term cardiovascular disorders (CVDs) has significantly increased among SM‐exposed victims including Coronary Artery Disorders (CAD), Coronary Artery Ectasia (CAE), Congestive Heart Failure (CHF), myocardium abnormalities and so on. The more important point is the lack of a determinant biomarker for early screening, recognizing, treating, monitoring and estimating exposed victims’ response to applied therapy. Additionally, unidentified risk factors significantly decrease the chance of a successful therapy and result in undesired failure of a comprehensive therapeutic strategy. In this MiniReview, we examined the literature in detail to evaluate relevant reports considering long‐term cardiovascular complications of SM, detecting possible risk factors and determining possible preventing events.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-08T09:45:23.035-05:00
      DOI: 10.1111/bcpt.12666
       
  • Foetal Fentanyl Exposure and Ion Trapping after Intravenous and
           Transdermal Administration to the Ewe
    • Authors: Emma M Heikkinen; Kokki Hannu, Heikkinen Aki, Ranta Veli‐Pekka, Räsänen Juha, Voipio Hanna‐Marja, Kokki Merja
      Abstract: Opioids given to pregnant and parturient women are relatively freely transferred across the placenta. Spinal, epidural and intravenous fentanyl have been studied in pregnant women and neonates, but foetal safety of fentanyl dosing with transdermal patch during pregnancy and labour is not sufficiently studied. Foetal pH is physiologically lower than maternal pH, and thus, opioids, that are weak bases, are ionized and may cumulate to foetus. Foetal asphyxia may further worsen acidosis and ion trapping induced by low pH is assumed to increase the foetal exposure to opioids. Here, we show that no correlation between foetal acidosis and ion trapping of fentanyl could be found. In three experiments, 29 pregnant sheep were administered fentanyl with 2 μg/kg/h patch supplemented with IV‐boluses/infusion. Foetal exposure to fentanyl was extensive, median 0.34 ng/ml (quartiles 0.21, 0.42), yet drug accumulation to foetus was not observed, median of foetal‐maternal concentration (F/M) ‐ratio was 0.63 (0.43, 0.75) during the first hours after fentanyl administration. Low foetal pH and pH difference between ewe and the foetus did not correlate with fentanyl concentration in the foetus or F/M‐ratio. At steady state during the second patch worn foetal plasma fentanyl was low, 0.13 ng/ml, and the median of F/M‐ratio was 0.69. Our results demonstrate that drug accumulation to foetus caused by ion trapping seen with some weak base opioids may not be that significant with fentanyl. These results have a clinical relevance when fentanyl is dosed to pregnant woman and the foetus is acidemic.This article is protected by copyright. All rights reserved.
      PubDate: 2016-09-08T09:25:20.699523-05:
      DOI: 10.1111/bcpt.12665
       
  • Anti‐Inflammatory Effect of Erythropoietin in the TNBS‐induced
           Colitis
    • Authors: Vanessa Mateus; João Rocha, Paula Alves, Hélder Mota‐Filipe, Bruno Sepodes, Rui Manuel Amaro Pinto
      Abstract: Erythropoietin is a potent stimulator of erythroid progenitor cells, which is able to inhibit NF‐kB activation, due to its pleiotropic properties, thus promoting an anti‐inflammatory effect. Since inflammatory bowel disease is a chronic disease with reduced quality of life, and the current pharmacotherapy only induces or maintains the patient in remission, there is a crucial need of new pharmacological approaches. The main objective of this study was to evaluate the effect of erythropoietin in the TNBS‐induced colitis model in mice with a normal intestinal flora. Mice with TNBS‐induced colitis were treated with a daily dose of erythropoietin at 500 IU/kg bw/day and 1000 IU/Kg bw/day IP during 4 days. As to clinical symptoms/signs, erythropoietin attenuated the decreased body weight and reduced diarrhoea and edema of the anus registered in the non‐treated mice group in a dose‐dependent manner. The anti‐inflammatory properties of erythropoietin in the TNBS‐induced colitis were confirmed by suppression of pro‐inflammatory mediators, such as TNF‐α, IL‐1β and MPO, as well as a significant increase of the anti‐inflammatory cytokine, IL‐10, was promoted. These treated mice also presented a reduction of hemoglobin fecal and ALP, suggesting a beneficial effect of erythropoietin in the hemorrhagic focus and destruction of the enterocyte associated to the colon injury induced by TNBS, respectively. The histopathological score was reduced after treatment with erythropoietin, decreasing the severity and extension of the colitis. Furthermore, renal and hepatic biomarkers, as well as hematocrit concentration remained stabilized after treatment. In conclusion, erythropoietin reduces the inflammatory response associated with TNBS‐induced colitis in mice.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-31T09:50:33.834155-05:
      DOI: 10.1111/bcpt.12663
       
  • Treatment Changes among Users of Non‐Vitamin K Antagonist Oral
           Anticoagulants in Atrial Fibrillation
    • Authors: Maja Hellfritzsch; Steen Elkjær Husted, Erik Lerkevang Grove, Lotte Rasmussen, Birgitte Klindt Poulsen, Søren Paaske Johnsen, Jesper Hallas, Anton Pottegård
      Abstract: Patients with atrial fibrillation discontinuing anticoagulant therapy are left unprotected against ischaemic stroke. Further, switching between oral anticoagulants may be associated with a transiently increased risk of bleeding or thromboembolism. However, there is a paucity of real‐life data on pattern of switching and discontinuation of oral anticoagulants. To address this, we conducted a nationwide drug utilization study including all registered Danish atrial fibrillation patients initiating a non‐VKA oral anticoagulant (NOAC) between August 2011 and February 2016. We assessed changes in anticoagulant treatment, including switching between oral anticoagulants as well as discontinuation of NOACs, and explored patient characteristics predicting these changes.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-31T09:50:31.68339-05:0
      DOI: 10.1111/bcpt.12664
       
  • Oesophageal Obstruction from a Pharmacobezoar resulting in Death
    • Authors: Katrine E. Mortensen; Julie Munkholm, Kim Peder Dalhoff, Lotte Christine Groth Hoegberg
      Abstract: Formation of an intestinal pharmacobezoar is a rare condition. It may form after intake of various oral pharmaceutical preparations of drugs, both as a result of an acute overdose and through chronic use of therapeutic doses of a drug. We report a case with a patient presenting with an oesophageal pharmacobezoar and complete obstruction of the oesophagus and severe toxic symptoms and death related to oral ingestion of multiple drugs.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-27T02:20:20.895915-05:
      DOI: 10.1111/bcpt.12662
       
  • Pharmacological Value of Murine delayed‐type Hypersensitivity Arthritis;
           A Robust Mouse Model of Rheumatoid Arthritis in C57BL/6 Mice
    • Authors: Sara Marie Atkinson; Anneline Nansen
      Abstract: In this MiniReview, we summarise the body of knowledge on the delayed‐type hypersensitivity arthritis (DTHA) model, a recently developed arthritis model with 100% incidence, low variation and synchronised onset in C57BL/6 (B6) mice, and compare it to other murine arthritis models. It is desirable to have robust arthritis models in B6 mice, as many transgene strains are bred on this background. However, several of the most widely used mouse model of arthritis cannot be induced in B6 mice without the drawback of lower incidence, reduced severity and higher variation, if at all. DTHA is induced by modifying a classical methylated bovine serum albumin (mBSA)‐induced DTH response by administering a cocktail of anti‐type II collagen antibodies (anti‐CII) between immunisation and challenge. Arthritis affects one, pre‐defined paw in which acute inflammation and severe arthritis rapidly develops and peaks after 4‐7 days. Disease is self‐resolving over the course of around 3 weeks. Disease manifestations resemble those seen in other arthritis models and include bone erosion, cartilage destruction, oedema, pannus and new bone formation. Induction of DTHA is dependent on CD4+ T cells while B cells are dispensable. The DTHA model is set apart from other murine arthritis models in that it can be induced in B6 mice with 100% incidence and with high and consistent severity. This is the clearest advantage of the model, as the mechanisms of disease and clinical manifestations can be found in other arthritis models. The model holds potential for future modifications that may improve the lack of chronicity.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-24T06:36:40.226255-05:
      DOI: 10.1111/bcpt.12657
       
  • Toxicity of Atorvastatin on Pancreas Mitochondria: A justification for
           increased risk of Diabetes Mellitus
    • Authors: Melina Sadighara; Zahra Amirsheardost, Mohsen Minaiyan, Valiollah Hajhashemi, Parvaneh Naserzadeh, Ahmad Salimi, Enayatollah Seydi, Jalal Pourahmad
      Abstract: Statins (including atorvastatin) are a widely used class of drugs, and like all medications, they have a potential for adverse effects. Recently, it has been shown that statins also exert side effects on the pancreas. In vitro studies have suggested that this class of drugs induced a reduction in insulin secretion. Also, the use of statins is associated with a raised risk of diabetes mellitus (DM), but the mechanisms underlying statin‐induced diabetes poorly known. Literature data indicate that several statins are able to induce apoptosis signalling. This study was designed to examine the mechanism of atorvastatin on mitochondria obtained from rat pancreas. In our study, mitochondria were obtained from the pancreas and then exposed to atorvastatin and vehicle to investigate probable toxic effects. The results showed that atorvastatin (25, 50, 75, 100 and 125 μM) increased reactive oxygen species (ROS) production, mitochondrial swelling, collapse of mitochondrial membrane potential (MMP) and cytochrome c release, the orchestrating factor for mitochondria‐mediated apoptosis signalling. Atorvastatin also reduced the ATP levels. These results propose that the toxicity of atorvastatin on pancreas mitochondria is a key point for drug‐induced apoptotic cell loss in the pancreas and therefore a justification for increased risk of diabetes mellitus.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-24T06:25:23.63624-05:0
      DOI: 10.1111/bcpt.12656
       
  • The pan‐Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal
           Excitability by Direct Action on Striatal Neurons In Vivo
    • Authors: Henrik H. Hansen; Pia Weikop, Maria D. Mikkelsen, Frederik Rode, Jens D. Mikkelsen
      Abstract: Central Kv7 (KCNQ) channels are voltage‐dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan‐Kv7 channel opener retigabine. The effect of retigabine likely involves inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c‐Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c‐Fos positive neurons following a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2=Kv7.3=Kv7.5>>Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-23T21:05:31.201038-05:
      DOI: 10.1111/bcpt.12636
       
  • The Pharmacology & Toxicology of the “Holy Trinity”
    • Authors: Joseph T. Horsfall; Jon E. Sprague
      Abstract: Combining opioids with benzodiazepines and skeletal muscle relaxants (“The Holy Trinity”) has been reported to potentiate the “high”. Through unique interactions with co‐localized μ‐opioid and GABAA receptors, the combined use of these agents induce a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by μ1‐opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAAR to suppress respiration in the medullary respiratory centers. The skeletal muscle relaxant, carisoprodol appears to bind to a unique binding domain within the GABAAR to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-23T02:55:39.586497-05:
      DOI: 10.1111/bcpt.12655
       
  • Direct Inhibitory Effects of Carbon Monoxide on Six Venoms Containing
           Fibrinogenolytic Metalloproteinases
    • Authors: Vance G. Nielsen; Philip A. Losada
      Abstract: Since the introduction of antivenom administration over a century ago to treat venomous snake bite, it has been the most effective therapy for saving life and limb. However, this treatment is not always effective and not without potential life‐threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases by inhibiting these Zn+2‐dependent enzymes directly with carbon monoxide exposure. Assessment of the fibrinogenolytic effects of venoms collected from the Arizona Black rattlesnake, Northern Pacific rattlesnake, Western cottonmouth, Eastern cottonmouth, Broad‐banded copperhead and Southern copperhead on human plasmatic coagulation kinetics was performed with thrombelastography in vitro. Isolated exposure of all but one venom (Southern copperhead) to carbon monoxide significantly decreased the ability of the venoms to compromise coagulation. These results demonstrated that direct inhibition of transition metal containing venom enzymes by yet to be elucidated mechanisms (e.g., CO binding to Zn+2 or displacing Zn+2 from the catalytic site, CO binding to histidine residues) can in many instances significantly decrease fibrinogenolytic activity. This new paradigm of carbon monoxide‐based inhibition of the anticoagulant effects of snake venom metalloproteinases could potentially diminish hemostatic compromise in envenomed patients until antivenom can be administered.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-22T03:03:04.549312-05:
      DOI: 10.1111/bcpt.12654
       
  • Prophylactic Melatonin Attenuates Isoflurane‐induced Cognitive
           Impairment in Aged Rats through Hippocampal Melatonin Receptor 2 ‐ CREB
           Signalling
    • Authors: Yajie Liu; Cheng Ni, Zhengqian Li, Ning Yang, Yang Zhou, Xiaoying Rong, Min Qian, Dehua Chui, Xiangyang Guo
      Abstract: Melatonin exerts many physiological effects via melatonin receptors, among which the melatonin‐2 receptor (MT2) plays a critical role in circadian rhythm disorders, Alzheimer's disease and other neurological disorders. A melatonin replacement strategy has been tested previously, and MT2 was a critical target during the process. cAMP response element‐binding (CREB) is an essential transcription factor for memory formation, and could be involved in MT2 signalling. Therefore, the present study was designed to investigate the effects of prophylactic melatonin on inhaled anaesthetic isoflurane‐induced cognitive impairment, and to determine whether the protective effects of melatonin are dependent on MT2 and downstream CREB signalling in the hippocampus of aged rats. The results showed that prophylactic melatonin attenuated isoflurane‐induced decreases in plasma / hippocampal melatonin levels and cognitive impairment in aged rats. Furthermore, 4P‐PDOT, a selective MT2 antagonist, blocked the protective effects of melatonin on isoflurane‐induced decreases in both hippocampal MT2 expression and downstream CREB phosphorylation. And 4P‐PDOT blocked the attenuation of melatonin on isoflurane‐induced memory impairment. Collectively, the results suggest that the protective effects of prophylactic melatonin are dependent on hippocampal MT2‐CREB signalling, which could be a potential therapeutic target for anaesthetic‐induced cognitive impairment.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-12T00:55:28.060444-05:
      DOI: 10.1111/bcpt.12652
       
  • Apoptotic process induced by oxaliplatin in rat hippocampus causes memory
           impairment
    • Authors: Enrica Bianchi; Lorenzo Di Cesare Mannelli, Laura Micheli, Mersedez Farzad, Margherita Aglianò, Carla Ghelardini
      Abstract: Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus‐sensitive. Rodents, previously subjected to two‐week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose‐dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in hippocampus from OX rats co‐treated with copper sulfate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co‐administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-10T03:26:55.449099-05:
      DOI: 10.1111/bcpt.12629
       
  • Thermoresponsive polymers with LCST‐ or UCST‐type phase behaviour do
           not induce toxicity to human endothelial cells
    • Authors: Yuejia Ji; Mengxiang Zhu, Yu Gong, Haoyu Tang, Juan Li, Yi Cao
      Abstract: Thermoresponsive polymers have gained extensive attention as biomedical materials especially for targeted drug delivery systems. We have recently developed water‐soluble polypeptides based thermoresponsive polymers that exhibit lower critical solution temperature (LCST) or upper critical solution temperature (UCST) type phase behaviours. In this study, the toxicity of these polymers to human umbilical vein endothelial cells (HUVECs) was investigated to assess the safety and biocompatibility. Up to 100μg/ml thermoresponsive polymers did not induce cytotoxicity to HUVECs, showing as unaltered mitochondrial viability assessed as cell counting kit‐8 (CCK‐8) assay and membrane integrity assessed as lactate dehydrogenase (LDH) assay. Inflammatory response, assessed as the release of chemokines soluble monocyte chemotactic protein 1 (sMCP‐1) and interleukin‐8 (IL‐8) as well as cytokine IL‐6, was not significantly affected by the polymers. In addition, 1μM thapsigargin (TG), an endoplasmic reticulum (ER) stress inducer, significantly decreased mitochondrial viability, but did not affect membrane integrity or inflammatory response. The presence of thermoresponsive polymers with LCST‐ type phase behaviour did not further affect the effects of TG. In conclusion, the thermoresponsive polymers used in this study are not toxic to endothelial cells, and therefore could be further considered as safe materials for biomedical applications.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-05T06:31:04.893932-05:
      DOI: 10.1111/bcpt.12643
       
  • Geraniol Induces Anti‐nociceptive Effect in Mice Evaluated in
           Behavioural and Electrophysiological Models
    • Authors: Viviana La Rocca; Diogo Vilar Fonsêca, Kerly Shamyra Silva‐Alves, Francisco Walber Ferreira‐da‐Silva, Damião Pergentino Sousa, Priscila Laise Santos, Lucindo José Quintans‐Júnior, José Henrique Leal‐Cardoso, Reinaldo Nóbrega Almeida
      Abstract: Geraniol (GER) is a monoterpene alcohol with various biochemical and pharmacological properties present in the essential oil of more than 160 species of herbs, (especially the Cymbopogon genus). In this study, we evaluated the anti‐nociceptive activity of GER in behavioural and electrophysiological in vitro experimental models of nociception using male Swiss mice. GER (12.5, 25 or 50 mg/kg i.p. and 50 or 200 mg/kg p.o.) reduced the number of writhes induced by acetic acid. The opioid antagonist naloxone (5 mg/kg s.c.) administered in mice subsequently treated with GER (25 mg/kg i.p.) did not reverse such anti‐nociceptive activity, suggesting a non‐opioid pathway for the mechanism of action. GER (12.5, 25 and 50 mg/kg i.p.) reduced paw licking time in the second phase of the formalin test. Also, in the glutamate test, GER when administered 50 mg/kg i.p. reduced paw licking time, probably modulating glutamatergic neurotransmission. GER blocked reversibly components of the compound action potential (CAP) recorded in isolated sciatic nerve in a dependent manner for concentration and drug exposure time: 1 mM to 120 min. for the first component and 0.6 mM to 90 min. for the second component. The IC50 was calculated for the peak‐to‐peak amplitude (PPA) at 0.48 ± 0.04 mM. The conduction velocity was also reduced by exposure to GER starting from the concentration of 0.3 mM for both components of the CAP. In conclusion, it is suggested that GER has anti‐nociceptive activity, especially in pain related to inflammation, and in part related to reduced peripheral nerve excitability.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-21T21:11:01.410154-05:
      DOI: 10.1111/bcpt.12630
       
  • A Danish Survey of Antihistamine Use and Poisoning Patterns
    • Authors: Louise Line Jensen; Janne Rømsing, Kim Dalhoff
      Abstract: The first‐generation antihistamine, promethazine, became a prescription‐only drug in Denmark as of December 2014. First‐generation antihistamines are known to have a higher toxic potential than second‐generation antihistamines. The aim of this study was to provide a nationwide description of the antihistamine use and poisoning pattern from 2007 to 2013 in Denmark based on two independent databases.There were 1049 antihistamine exposures in the national, advisory telephone service specialized in poisonings, the Danish Poison and Information Centre (DPIC), and 456 exposures in the three registers used within the State Serum Institute of Denmark (SSI), a department under the Danish Ministry of Health dealing with research‐based health surveillance in Denmark. First‐generation antihistamines constitute 61% and 73% of antihistamine registrations in DPIC and SSI, respectively. Antihistamine exposures increased by 7 exposures/10,000 enquiries per year in DPIC and 6 admissions per year in SSI – this increase is not significant due to a sudden decrease in 2012. Intentional exposures constituted 65% in DPIC of which 82% was due to suicide attempts, and 78% of the involved antihistamines were first‐generation antihistamines. Accidental exposures constituted 33% of which 61% were due to play and 29% involved first‐generation antihistamines. Single antihistamine exposures constituted 65% of DPIC exposures of which 98% involved only one brand of antihistamine. Multi‐drug exposures constituted 35% of DPIC exposures with equally distributed coingestants. Hospitalization was recommended in 78% of DPIC exposures. Admissions required only one day of treatment in 91% of the SSI exposures. One of the 14 identified deaths in the SSI study population was directly related to antihistamine poisoning. Results support the limited disclosure of promethazine in Denmark and illustrate a generation‐specific pattern indicating a suspected replacement of promethazine with other first‐generation antihistamines.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-21T21:10:54.600558-05:
      DOI: 10.1111/bcpt.12632
       
  • Do Diuretics have Antinociceptive Actions: Studies of Spironolactone,
           Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone
           and Morphine
    • Authors: Viljami Jokinen; Tuomas Lilius, Jouko Laitila, Mikko Niemi, Oleg Kambur, Eija Kalso, Pekka Rauhala
      Abstract: Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, e.g. via mineralocorticoid receptor antagonism. In co‐administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms.Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.) and morphine (3 mg/kg, s.c.) induced antinociception using tail‐flick and hot plate tests in male Sprague‐Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry.In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-21T21:10:43.977567-05:
      DOI: 10.1111/bcpt.12634
       
  • Absorption of Bupivacaine after Administration of a Lozenge as Topical
           Treatment for Pain from Oral Mucositis
    • Authors: Stine Mogensen; Eva Sverrisdóttir, Kolbrún Sveinsdóttir, Charlotte Treldal, Kenneth Jensen, Anders Bonde Jensen, Claus Andrup Kristensen, Jette Jacobsen, Mads Kreilgaard, Janne Petersen, Ove Andersen
      Abstract: The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis.A lozenge containing 5 mg, 10 mg, 25 mg and 50mg bupivacaine, respectively, was administered as single dose to 10 healthy invididuals and lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to 5 HNC patients. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the HNC patients, respectively, after administration. The plasma concentration‐time profiles of bupivacaine were fitted to pharmacokinetic models using non‐linear mixed effects modelling, evaluating demographics and health status as covariates.The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two‐compartment distribution model with absorption transit compartments. All observed plasma concentrations were well below bupivacaine concentrations (2000‐2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was 2‐fold higher in HNC patients with oral mucositis grade 1‐2, and 3‐fold higher in HNC patients with oral mucositis grade 3‐4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for 5 days.The 25 mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every 2 hr for 16 hr a day, the lozengscan be administered with minimum risk of exceeding the toxic limit.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-19T01:50:33.256595-05:
      DOI: 10.1111/bcpt.12644
       
  • Human Hepatic HepaRG Cells Maintain an Organotypic Phenotype with High
           Intrinsic CYP450 Activity/Metabolism and Significantly Outperform Standard
           HepG2/C3A Cells for Pharmaceutical and Therapeutic Applications
    • Authors: Leonard J. Nelson; Katie Morgan, Philipp Treskes, Kay Samuel, Catherine J. Henderson, Claire LeBled, Natalie Homer, M. Helen Grant, Peter C. Hayes, John N. Plevris
      Abstract: Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, inter‐donor functional variability and early phenotypic alterations of PHHs restrict their use; whilst standard cell lines such as HepG2 lack a substantial and variable set of liver‐specific functions such as CYP450 activity. Alternatives include the HepG2‐derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype. Human HepaRG cells are an alternative organotypic co‐culture model of hepatocytes and cholangiocytes reported to maintain in vivo‐like liver‐specific functions, including intact Phase 1‐3 drug metabolism. In this study, we compared C3A and human HepaRG cells using phenotypic profiling, CYP450 activity and drug metabolism parameters to assess their value as hepatic models for pre‐clinical drug testing or therapeutics. Compared with C3As, HepaRG co‐cultures, exhibit a more organotypic phenotype, including evidence of hepatic polarity with strong expression of CYP3A4, the major isoform involved in the metabolism of over 60% of marketed drugs. Significantly greater CYP450 activity and expression of CYP1A2, CYP2E1 and CYP3A4 genes in HepaRG cells (comparable with that of human liver tissue) was demonstrated. Moreover, HepaRG cells also preferentially expressed the hepatic integrin α5β1 – an important modulator of cell behaviour including growth and survival, differentiation and polarity. Drug metabolite profiling of phenacetin (CYP1A2) and testosterone (CYP3A4) using LC‐MS/MS and HPLC, respectively, revealed HepaRGs had more intact (Phase 1‐2) metabolism profile. Thus, HepaRG cells significantly outperform C3A cells for potential pharmaceutical and therapeutic applications.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-15T21:00:33.854368-05:
      DOI: 10.1111/bcpt.12631
       
  • Pharmacokinetic Profile of Oral Magnesium Hydroxide
    • Authors: Mette Konow Bøgebjerg Dolberg; Lars Peter Nielsen, Ronald Dahl
      Abstract: Despite the presumption of a beneficial effect of magnesium (Mg) supplementation on various diseases, little is known concerning the pharmacokinetics of Mg hydroxide. This study was designed to provide a pharmacokinetic profile of Mg hydroxide after a single oral dose.Ten healthy male adults participated in this cross‐over study with three 24‐hr study days. Interventions were: 1) none (baseline), 2) oral intake of three (3 x 360 mg) tablets of Mg hydroxide (Mablet®) and 3) IV bolus infusion of 2 g Mg sulphate (index drug). Blood samples were collected before the single dose, after (i.e. post treatment administration) 15, 30, 60, 90 and 120 min. – and after 3, 4, 6, 8, 12 and 24 hr. Urine was collected in four 6‐hr periods per study day.Blood (N=10) and urine (N=6) Mg were analysed by descriptive statistics. Bioavailability was 14.9% (CI: 8.3; 26.8), blood clearance was 5.1 L/hr (CI: 2.1; 17.0), apparent volume of distribution was 60.2 L (CI: 35.6; 102.0), elimination constant was 0.08 hr−1 (CI: 0.05; 0.14), half‐life was 8.3 hr (CI: 4.8; 14.1), Cmax was 0.11 mmol/L (CI: 0.07; 0.14), and AUC(0‐24) was 92.3 mmol/L x minutes (CI: 45.5; 139.1). Urine Mg excretion augmented by 17.7% (CI: 8.9; 35.0) from baseline. No severe side effects.Mg hydroxide demonstrates a 15% bioavailability, and it constitutes a clinically relevant option for oral Mg supplementation. No severe side effects were seen.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-14T04:40:20.819729-05:
      DOI: 10.1111/bcpt.12642
       
  • Drug‐Mediated Gene Regulation of Vitamin D3 Metabolism in Primary
           Human Dermal Fibroblasts
    • Authors: Maria Norlin; Johan Lundqvist, Maria Ellfolk, Maritta Hellström Pigg, Jan Gustafsson, Kjell Wikvall
      Abstract: Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug‐mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25‐hydroxyvitamin D3 and 1α,25‐dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3 metabolising system. High incidence of low bone mineral density is a concern for HIV‐infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug‐mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy and the 1α,25‐dihydroxyvitamin D3 levels and relative mRNA‐levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly down‐regulated the bioactivating CYP2R1 and up‐regulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1α,25‐dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-12T07:50:27.400683-05:
      DOI: 10.1111/bcpt.12641
       
  • In Vitro Effects of the Neolignan 2,3‐Dihydrobenzofuran against
           Leishmania Amazonensis
    • Authors: Luciano Gomes Castro Oliveira; Lucas Moreira Brito, Michel Muálem Moraes Alves, Layane Valéria Amorim, Enoque Pereira Costa Sobrinho‐Júnior, Camila Ernanda Sousa Carvalho, Klinger Antonio da Franca Rodrigues, Daniel Dias Rufino Arcanjo, Antônia Maria das Graças Lopes Citó, Fernando Aécio Amorim Carvalho
      Abstract: Leishmaniasis is an infectious disease complex caused by a protozoa from the Leishmania genus, which presents a broad spectrum of clinical manifestations: cutaneous, mucocutaneous and visceral forms. The current treatments are unsatisfactory considering few drugs are available and present some level of toxicity. Many lignans and neolignans have been used for the development of new anti‐Leishmania drugs. The capability in vitro of the neolignan 2,3‐dihydrobenzofuran (2,3‐DBF), a commonly found constituent of propolis and other plants, to inhibit the growth of promastigote and macrophages‐internalized amastigote forms of Leishmania amazonensis was investigated. The cytotoxicity of this compound was assessed by MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide) test in Balb/c murine macrophages and human erythrocyte lysis assay. The 2,3‐DBF was active against promastigotes (IC50=1.042 μM) and amastigotes (IC50=1.43 μM) forms, indicating a potent anti‐leishmanial effect. There was no evidence of cytotoxicity to macrophages or erythrocytes at concentrations ranging from 13 to 0.5 μM, after 48 hr of exposure. The anti‐leishmanial activity is probably mediated by the activation of macrophages, since treatment with 2,3‐DBF increases both phagocytic and lysosomal activities, as well as the nitrite (NO2‐) levels. These results suggest that 2,3‐DBF may be a potential candidate for the development of a new promising anti‐leishmanial drug. Further studies are needed to determine its potential in vivo effect as well as additional mechanisms underlying the anti‐leishmanial and immunomodulatory activities.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-11T08:45:25.285704-05:
      DOI: 10.1111/bcpt.12639
       
  • Concentration‐Response Relationship of Hearing Impairment Caused by
           Quinine and Salicylate: Pharmacological Similarities but different
           molecular mechanisms
    • Authors: Gunnar Alvan; Erik Berninger, Lars L. Gustafsson, Kjell K. Karlsson, Gilles Paintaud, Monique Wakelkamp
      Abstract: This review has the purpose to summarise concentration‐effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine‐induced increase in hearing threshold and its recovery can be analysed according to “the psychophysical power function”. The power function is a special case of the Hill equation when the stimulus (e.g., a drug concentration) is exceedingly small compared with the concentration that would elicit a half maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence presence, magnitude and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self‐attained most comfortable speech level and the acoustic stapedius reflex are not affected, i.e. the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but using different molecular mechanisms.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-11T08:36:02.847666-05:
      DOI: 10.1111/bcpt.12640
       
  • An Effective Machine Learning Approach for Prognosis of Paraquat Poisoning
           Patients Using Blood Routine Indexes
    • Authors: Huiling Chen; Lufeng Hu, Huaizhong Li, Guangliang Hong, Tao Zhang, Jianshe Ma, Zhongqiu Lu
      Abstract: The early identification of toxic paraquat (PQ) poisoning in patients critical to ensure timely and accurate prognosis. Though plasma PQ concentration has been reported as a clinical indicator of PQ poisoning, it is not commonly applied in practice due to the inconvenient necessary instruments and operation. In this study, we explored the use of blood routine indexes to identify the degree of PQ toxicity and/or diagnose PQ poisoning in patients via machine learning approach. Specifically, we developed a method based on support vector machine combined with the feature selection technique to accurately predict PQ poisoning risk status, then tested the method on 79 (42 male and 37 female; 41 living and 38 deceased) patients. The detection method was rigorously evaluated against a real‐world dataset to determine its accuracy, sensitivity and specificity. Feature selection was also applied to identify factors correlated with risk status, and results showed that there are significant differences in blood routine indexes between dead and living PQ‐poisoned individuals (p‐value < 0.01). Feature selection also showed that the most important correlated indexes are white blood cell and neutrophils. In conclusion, the toxicity or prognosis of PQ poisoning can be preliminarily ascertained by blood routine testing without PQ concentration data, representing an additional tool and innovative approach to assess prognosis of PQ poisoning.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-08T02:55:32.799654-05:
      DOI: 10.1111/bcpt.12638
       
  • Issue Information
    • Pages: 521 - 522
      PubDate: 2016-11-10T22:06:40.474742-05:
      DOI: 10.1111/bcpt.12470
       
  • Mechanisms of Action and Toxicity of the Mycotoxin Alternariol: A Review
    • Authors: Anita Solhaug; Gunnar S. Eriksen, Jørn A. Holme
      First page: 533
      Abstract: The mycotoxin alternariol (AOH) is produced by Alternaria fungi. It occurs naturally in foodstuffs and is frequently found as contaminant in fruit and grain products. Most information regarding AOH toxicity and the potential mechanisms involved comes from in vitro studies, as only very limited in vivo studies have been performed. AOH forms reactive oxygen species (ROS) and interacts with DNA topoisomerase, thereby generating both single (SSB) and double strand DNA beaks (DSB). This triggers various DNA damage response pathways. AOH causes a marked reduction in proliferation in mammalian cells due to cell cycle arrest often in the G2/M‐phase. Following an additional inhibition of cytokinesis, cells with abnormal nuclei as well as polyploidy are reported. In macrophages, AOH may increase autophagic activity and induce senescence. Furthermore, AOH is found to change the morphology and phenotype of various human macrophage cell models. Studies so far indicate that the AOH‐induced effects are primarily a result of DSB via its effects on topoisomerase activity. Thus, most probably there will be a threshold for the AOH‐induced effects, typically seen in the 5‐10 μM range. These in vitro mechanistic studies further support the in vivo studies suggesting low acute toxicity. However, a decreased immune response to infections and/or a disturbed balance of the adaptive immune system when exposed together with other mycotoxins cannot be excluded. This hypothesis needs to be further explored with proper in vivo studies.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-10T03:26:58.986664-05:
      DOI: 10.1111/bcpt.12635
       
  • Curcumin Inhibits 5‐Fluorouracil‐induced Up‐regulation of CXCL1 and
           CXCL2 of the Colon Associated with Attenuation of Diarrhoea Development
    • Authors: Hiroyasu Sakai; Yuki Kai, Aya Oguchi, Minami Kimura, Shoko Tabata, Miyabi Yaegashi, Taiki Saito, Ken Sato, Fumiaki Sato, Tetsuro Yumoto, Minoru Narita
      First page: 540
      Abstract: The compound 5‐fluorouracil (5‐FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C‐X‐C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5‐FU in mice. Curcumin has anti‐inflammatory, anti‐tumourand antioxidant properties. Therefore, we examined the effect of curcumin on 5‐FU‐induced diarrhoea development and CXCL1 and CXCL2 up‐regulation in the colon. Mice were given 5‐FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5‐FU and administered 30 min. before the administration of 5‐FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real‐time RT‐PCR. Curcumin reduced the 5‐FU‐induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up‐regulated by 5‐FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5‐FU application in vitro. The 5‐FU‐induced up‐regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay‐117082 and bortezomib, nuclear factor kappa B (NF‐κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element‐binding protein–histone acetyltransferase (HAT) inhibitor. In conclusion, these finding suggested that curcumin prevented the development of diarrhoea by inhibiting NF‐κB and HAT activation.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-26T03:15:45.205943-05:
      DOI: 10.1111/bcpt.12619
       
  • Visfatin Triggers the Cell Motility of Non‐Small Cell Lung Cancer
           (NSCLC) via Up‐Regulation of Matrix Metalloproteinases (MMPs)
    • Authors: Guanghai Wang; Wenjun Tian, Yiqing Liu, Ying Ju, Yajuan Shen, Shengmei Zhao, Bingchang Zhang, Yu Li
      First page: 548
      Abstract: High levels of visfatin are correlated with worse clinical prognosis of various cancers. Still, the effects and mechanisms of visfatin on progression of non‐small cell lung cancer (NSCLC) remain unclear. Our present study revealed that plasma levels of visfatin in NSCLC patients (585 ± 287 pg/ml) were significantly (p
      PubDate: 2016-07-21T21:05:52.679677-05:
      DOI: 10.1111/bcpt.12623
       
  • Association of Oseltamivir Activation with Gender and Carboxylesterase 1
           Genetic Polymorphisms
    • Authors: Jian Shi; Xinwen Wang, Rachel F. Eyler, Yan Liang, Li Liu, Bruce A. Mueller, Hao‐Jie Zhu
      First page: 555
      Abstract: Oseltamivir, an inactive anti‐influenza virus prodrug, is activated (hydrolyzed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non‐genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1‐mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the ‐816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (P = 0.039) while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (P = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, ‐816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, P = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-21T21:10:52.016112-05:
      DOI: 10.1111/bcpt.12625
       
  • Antinociceptive and Anti‐Inflammatory Effects of Ketamine and the
           Relationship to its Antidepressant Action and GSK3 Inhibition
    • Authors: Eduardo Mulato Vale; Cecília Coelho Xavier, Brenda Gomes Nogueira, Bruna Caldas Campos, Pedro Everson Alexandre Aquino, Roberta Oliveira Costa, Luzia Kalyne Almeida Moreira Leal, Silvânia Maria Mendes Vasconcelos, Kelly Rose Tavares Neves, Glauce Socorro Barros Viana
      First page: 562
      Abstract: Ketamine (KET), a NMDA antagonist, exerts an antidepressant effect at subanesthetic doses and possesses analgesic and anti‐inflammatory activities. We evaluated the involvement of KET antinociceptive and anti‐inflammatory effects with its antidepressant action. Male Swiss mice were subjected to formalin, carrageenan‐induced paw oedema and forced swimming tests, for assessing antinociceptive, anti‐inflammatory and antidepressant effects. The treatment groups were: control, KET (2, 5 and 10 mg/kg), lithium (LI: 5 mg/kg) and KET2+LI5 combination. Immunohistochemistry analyses (TNF‐alpha, iNOS, COX‐2 and GSK3) in oedematous paws were performed. KET5 and KET10 reduced licking times in neurogenic (22 and 38%) and inflammatory (67 and 78%) phases of the formalin test, respectively, as related to controls. While LI5 inhibited the 2nd phase by 24%, the licking time was inhibited by 26 and 59% in the KET2+LI5 group (1st and 2nd phases). Furthermore, oedema volumes were reduced by 37 and 45% in the KET5 and KET10 groups, respectively. Oedema reductions were 29% in the LI5 group and 48% in the KET2+LI5 group. In the forced swimming test, there were 23, 38 and 53% decreases of the immobility time in KET2, KET5 and KET10 groups, respectively. While LI5 caused no significant effect, decreases of 52% were observed with KET2+LI5. KET also decreased TNF‐alpha, iNOS, COX‐2 and GSK3 immunostainings in oedematous paws, effects intensified with KET2+LI5. We showed that KET presents antinociceptive and anti‐inflammatory effects associated to its antidepressant response. Furthermore, our results indicate the close involvement of GSK3 inhibition and blockade of inflammatory responses, in the antidepressant drug effect.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-23T21:05:46.942553-05:
      DOI: 10.1111/bcpt.12637
       
  • Safety, Pharmacokinetics and Pharmacodynamics of the Selective
           Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy
           Volunteers
    • Authors: Viktoria Werkström; Susanne Prothon, Ella Ekholm, Carin Jorup, Staffan Edsbäcker
      First page: 574
      Abstract: AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This paper reports the initial, first‐in‐man, single and repeat dose‐escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once‐daily treatment. Plasma exposure suggested dose proportional pharmacokinetics and dose‐related effects on 24‐hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (Osteocalcin, TRAP5b, DHEA‐S and 4βOH‐cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus‐pituitary‐adrenal (HPA) effects appeared to be marginally greater in the Japanese versus the Caucasian dominant study population. AZD5423, inhaled via nebulisation, can be used in healthy individuals at doses of at least 300 μg for two weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit risk ratio may be improved relative to conventional inhaled steroids.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-08T03:25:26.404287-05:
      DOI: 10.1111/bcpt.12621
       
  • Neuromuscular Effects of Rocuronium Bromide in Patients in Statin Therapy
           for at least Three Months
    • Authors: Hongwei Ren; Huangwei Lv
      First page: 582
      Abstract: Statins cause skeletal muscle myopathy. However, the neuromuscular effects of non‐depolarizing neuromuscular blocking agent in patients in long‐term statin therapy remain unclear. Hence, we investigated the neuromuscular effects of rocuronium and muscle injury in patients in long‐term statin therapy. Eighteen statin users using statins for at least 3 months were included in the statin group and 18 non‐statin users were included in the non‐statin group. General anaesthesia was induced with intravenous midazolam, etomidate, sufentanil and rocuronium 0.9mg·kg‐1 (3ED95) for intubation. Anaesthesia was maintained with 1% propofol and remifentanil. The onset time and duration 10% T1 and 25% T1 of rocuronium was recorded. Blood samples were obtained before induction, and 5 min., 1 hr, 2 hr, 4 hr, 12 hr and 24 hr after rocuronium administration to measure creatine kinase (CK), myoglobin and potassium. Myalgia was determined at 2 hr and 24 hr after surgery. There were no significant differences in the basic clinical characteristics between the two groups. The onset time of the statin group was significantly shorter than that of the non‐statin group (p=0.02), while the duration 10% T1 and 25% T1 of the statin group was significantly longer than that of the non‐statin group (p=0.006; p=0.045). The myoglobin and CK concentrations increased after rocuronium administration as compared to baseline in both groups. CK concentration in the statin group was significantly higher than in the non‐statin group just at 24 hr (p=0.000003). However, myoglobin showed no significant difference between the two groups. The onset time of rocuronium decreases and its duration time increases in patients in long‐term statin therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2016-06-24T01:45:24.955624-05:
      DOI: 10.1111/bcpt.12628
       
  • Low‐Chlorinated Non‐Dioxin‐like PCBs Present in Blood and Breast
           Milk Induce Higher Levels of Reactive Oxygen Species in Neutrophil
           Granulocytes than Highly Chlorinated Congeners
    • Authors: Hanne Friis Berntsen; Frode Fonnum, Sven Ivar Walaas, Inger Lise Bogen
      First page: 588
      Abstract: Despite their ban several decades ago, polychlorinated biphenyls (PCBs) still pose a health threat to human beings due to their persistent and accumulative nature and continued presence in the environment. Non‐dioxin‐like (NDL)‐PCBs have earlier been found to have effects on the immune system, including human neutrophil granulocytes. The aim of this study was to investigate differences between ortho‐chlorinated NDL‐PCBs with a low or high degree of chlorination in their capability to induce the production of reactive oxygen species (ROS) in human neutrophil granulocytes in vitro. We used some of the congeners occurring at the highest levels in blood, breast milk and food; PCB 52 representing the low chlorinated and PCB 180 the high chlorinated congeners. In addition, the extensively studied PCB 153 was included as a reference compound. ROS production was assessed with the luminol‐amplified chemiluminescence and DCF fluorescence assays. The involvement of intracellular signalling mechanisms was investigated using different pharmacological substances. At high concentrations (10‐20 μM), PCB 52 induced more ROS than PCB 153 and PCB 180. The role of extracellular signal regulated kinase (ERK) 1/2 and/or ERK 5 signalling in PCB‐induced ROS production was implicated through the reduction in ROS in the presence of the specific inhibitor U0126, whereas reduced ROS production after use of SB203580 and SP600125 indicated involvement of the p38 mitogen activated protein kinase (MAPK) and c‐Jun amino‐terminal kinase (JNK) pathways, respectively. In addition, the calcineurin inhibitor FK‐506, the intracellular calcium chelator BAPTA‐AM and the anti‐oxidant vitamin E reduced the levels of ROS. The intracellular signalling mechanisms involved in ROS production in human neutrophil granulocytes appeared to be similar for PCB 52, PCB 153 and PCB 180. Based on the results from the present and previous studies, we conclude that for abundant ortho‐chlorinated PCBs found in blood, low chlorinated congeners induce higher production of ROS in neutrophil granulocytes than highly chlorinated congeners. This could be relevant during acute exposure scenarios when high concentrations of PCBs are present.This article is protected by copyright. All rights reserved.
      PubDate: 2016-06-12T23:20:31.771742-05:
      DOI: 10.1111/bcpt.12620
       
  • Cyclophsopahmide‐induced Down‐Regulation of Uroplakin II in the Mouse
           Urinary Bladder Epithelium is Prevented by S‐Allyl Cysteine
    • Authors: Sayed Alilul Hasan Abdi; Abul Kalam Najmi, Sheikh Raisuddin
      First page: 598
      Abstract: The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP‐induced HC. In this study, we studied the modulatory effect of the thiol‐rich compound S‐allyl cysteine (SAC) on the mRNA level of uroplakin II by real‐time PCR and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)‐induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP‐induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulfonic acid (mesna) (40 mg/kg), a known thiol‐rich drug, SAC, which has been in clinical application, was found to be more efficacious in affording protection in urinary bladder tissues. Role or uroplakins in CP‐induced urinary bladder toxicity has not been well investigated. The present study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-21T21:10:58.715411-05:
      DOI: 10.1111/bcpt.12627
       
  • Prognostic Factors in Emergency Department Patients with
           Glyphosate‐Surfactant Intoxication: Point‐of‐Care Lactate Testing
    • Authors: Yong Hwan Kim; Jun Ho Lee, Kwang Won Cho, Dong Woo Lee, Mun Ju Kang, Kyoung Yul Lee, Young Hwan Lee, Seong Youn Hwang, Na Kyoung Lee
      First page: 604
      Abstract: An increasing number of suicide attempts involve the ingestion of glyphosate surfactant; hence, clinical toxicologists may encounter severe cases of glyphosate‐surfactant intoxication. In several other clinical conditions, serum lactate is used to predict outcome. We investigated the relationship between lactate levels and 30‐day mortality from glyphosate‐surfactant poisoning.This retrospective analysis involved 232 patients who were admitted to the emergency department after acute glyphosate‐surfactant poisoning between January 2004 and June 2014. We used a receiver operating characteristic (ROC) curve to define the optimal cut‐off point for lactate levels. A Kaplan‐Meier 30‐day survival curve was then analysed in terms of the defined cut‐off level. We used multivariate Cox proportional hazards regression analysis to determine the risk factors for 30‐day mortality.Of the 232 patients, 29 died, yielding a case fatality rate of 12.5%. Lactate was significantly higher in non‐survivors (6.5±3.1 mmol/L) than in survivors (3.3±2.2 mmol/L; p 59 years, corrected QT interval > 495 ms and potassium > 5.5 mmol/L were independent risk factors for 30‐day mortality.Lactate is an independent predictor of 30‐day mortality in patients with glyphosate‐surfactant poisoning. Early measurement of lactate levels may be a simple and practical way to assess the severity of intoxication.This article is protected by copyright. All rights reserved.
      PubDate: 2016-08-23T21:05:37.394025-05:
      DOI: 10.1111/bcpt.12624
       
  • Silencing Op18/stathmin by RNA interference promotes the sensitivity of
           nasopharyngeal carcinoma cells to taxol and high grade differentiation of
           xenografted tumours in nude mice
    • Authors: Xuechi Lin; Ting Yu, Lingxi Zhang, Sangyan Chen, Xian Chen, Ying Liao, Dan Long, Fang Shen
      First page: 611
      Abstract: Nasopharyngeal carcinoma (NPC) is a refractory tumour, and chemotherapy is one of the primary treatment modalities. Oncoprotein 18 (Op18)/stathmin is a conserved small cytosolic phosphoprotein and highly expressed in tumours, which plays a vital role in maintaining the malignant phenotype of tumours. Taxol (fig. 1) is a clinically widely used chemotherapeutics agent for a broad range of taxol‐resistant tumours. This study showed that Op18/stathmin silencing by RNA interference (RNAi) combined taxol cooperatively improved cellular apoptosis in CNE1 cells mainly via initiating endogenous death receptor pathway, impaired the capabilities of cellular proliferation and cellular migration, down‐regulated the half maximal inhibitory concentration (IC50) of taxol, meanwhile, decreased the expression of the upstream extracellular regulated kinase 1 (ERK1) in vitro. Evidences also showed that taxol cytotoxicity was markedly augmented for Op18/stathmin RNAi in other NPC cells. In vivo animal experiments have demonstrated that early combination of Op18/stathmin silencing and taxol evidently inhibited tumourigenicity of CNE1 cells and growth of xenografted tumours in nude mice. Remarkably, silencing Op18/stathmin by RNAi still promoted transformation of late‐stage CNE1 cells in NPC‐xenografted tumours from moderately to highly differentiated, inhibited the pleiotropic cytokine interleukin 10 (IL‐10) autocrine by transplanted tumours. These findings suggest that silencing Op18/stathmin by RNAi promotes chemosensitization of NPC to taxol and reverses malignant phenotypes of NPC, which provides a new clue for treating drug‐resistant tumours.This article is protected by copyright. All rights reserved.
      PubDate: 2016-07-12T02:26:01.112288-05:
      DOI: 10.1111/bcpt.12633
       
 
 
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