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  Subjects -> ENVIRONMENTAL STUDIES (Total: 765 journals)
    - ENVIRONMENTAL STUDIES (690 journals)
    - POLLUTION (23 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (690 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: 3)
Acta Oecologica     Hybrid Journal   (Followers: 9)
Acta Regionalia et Environmentalica     Open Access  
Advances in Ecological Research     Full-text available via subscription   (Followers: 40)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 20)
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  
Ambiência     Open Access  
Ambiens. Revista Iberoamericana Universitaria en Ambiente, Sociedad y Sustentabilidad     Open Access  
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: 7)
American Journal of Environmental Sciences     Open Access   (Followers: 16)
American Journal of Microbiology     Open Access   (Followers: 13)
American Naturalist     Full-text available via subscription   (Followers: 63)
Annals of GIS     Hybrid Journal   (Followers: 20)
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: 52)
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: 12)
Applied and Environmental Soil Science     Open Access   (Followers: 15)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 16)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 29)
Aquatic Toxicology     Hybrid Journal   (Followers: 18)
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: 9)
Archives of Environmental Protection     Open Access   (Followers: 6)
Archives of Toxicology     Hybrid Journal   (Followers: 16)
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: 27)
Atmospheric Environment     Hybrid Journal   (Followers: 60)
Austral Ecology     Hybrid Journal   (Followers: 12)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 10)
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: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 47)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 33)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 27)
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: 18)
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: 32)
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: 3)
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: 12)
Climate Policy     Hybrid Journal   (Followers: 29)
Coastal Engineering Journal     Hybrid Journal   (Followers: 3)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 10)
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: 29)
Conservation Science     Open Access   (Followers: 19)
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: 11)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 5)
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: 19)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 12)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 6)
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: 10)
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: 17)
Ecological Informatics     Hybrid Journal   (Followers: 5)
Ecological Management & Restoration     Hybrid Journal   (Followers: 15)
Ecological Modelling     Hybrid Journal   (Followers: 88)
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: 24)
Ecologist, The     Full-text available via subscription   (Followers: 27)
Ecology     Full-text available via subscription   (Followers: 265)
Ecology and Evolution     Open Access   (Followers: 53)
Ecology Letters     Hybrid Journal   (Followers: 175)
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     Open Access   (Followers: 4)
Ecosystem Services     Hybrid Journal   (Followers: 6)
Ecosystems     Hybrid Journal   (Followers: 26)
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: 2)
Energy & Environmental Science     Full-text available via subscription   (Followers: 22)
Energy & Environment     Hybrid Journal   (Followers: 16)
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: 45)
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: 32)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 43)
Environment and Pollution     Open Access   (Followers: 11)
Environment and Society     Full-text available via subscription   (Followers: 7)
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: 31)
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: 3)
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: 4)
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: 25)
Environmental Impact Assessment Review     Hybrid Journal   (Followers: 21)

        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  [1605 journals]
  • Use of Moderate-Intensity Statins for Low-Density Lipoprotein Cholesterol
           Level above 190 mg/dL at Baseline in Koreans
    • Authors: Hun-Sung Kim; Hyeseon Lee, Sue Hyun Lee, Yoo Jin Jeong, Tong Min Kim, So Jung Yang, Sun Jung Baik, Hyunah Kim, Seung-Hwan Lee, Jae Hyoung Cho, In-Young Choi, Kun-Ho Yoon, Ju Han Kim
      Abstract: The ACC/AHA 2013 guideline recommends high-intensity statin therapy for a decrease in low-density lipoprotein cholesterol (LDL-C) level by >50% among patients with baseline values of ≥190 mg/dL (approximately 4.872 mmol/L); however, this value should be modified before applying it to Korean populations. We investigated the statin-specific LDL-C-lowering effects in Korean patients with baseline LDL-C value ≥ 4.872 mmol/L. Data of patients prescribed a statin for the first time from January 2009 to December 2013 were assessed. In patients with baseline LDL-C value ≥ 4.872 mmol/L, laboratory data for a maximum of 6 months from the date of first statin prescription were collected. Among 33,721 patients who were prescribed a statin for the first time, 655 patients had a baseline LDL-C value ≥ 4.872 mmol/L (1.9%). Of these, 179 patients were analysed. Patients receiving moderate-intensity statins were divided into 2 groups based on LDL-C reduction rate (p=0.0002), defined as moderate-high- (atorvastatin 20 mg, rosuvastatin 10 mg, simvastatin 20 mg) and moderate-low-intensity (atorvastatin 10 mg, pitavastatin 2 mg, pravastatin 40 mg) statin groups. LDL-C reduction rates did not significantly differ between the moderate-high- and high-intensity statin groups (p=0.4895). We found that some moderate-intensity statins demonstrated a LDL-C lowering effect of more than 50% in Korean patients with a baseline LDL-C value ≥ 4.872 mmol/L. Our results reflect the need of a large-scale, randomized, controlled trial on partial reclassification of statins for patients with baseline LDL-C value ≥ 4.872 mmol/L before adopting ACC/AHC guidelines in Korea.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-06T09:46:26.685007-05:
      DOI: 10.1111/bcpt.12765
  • Odense Pharmacoepidemiological Database (OPED): A Review of Use and
    • Authors: Jesper Hallas; Maja Hellfritzsch, Morten Rix, Morten Olesen, Mette Reilev, Anton Pottegård
      Abstract: The Odense University Pharmacoepidemiological Database (OPED) is a prescription database established in 1990 by the University of Southern Denmark, covering reimbursed prescriptions from the county of Funen in Denmark and the region of Southern Denmark (1.2 million inhabitants). It is still active and thereby has more than 25 years’ of continuous coverage.In this MiniReview, we review its history, content, quality, coverage, governance and some of its uses. OPED's data include the Danish Civil Registration Number (CPR), which enables unambiguous linkage with virtually all other health-related registers in Denmark. Among its research uses, we review record-linkage studies of drug effects, advanced drug utilization studies, some examples of method development and use of OPED as sampling frame to recruit patients for field studies or clinical trials.With the advent of other, more comprehensive sources of prescription data in Denmark, OPED may still play a role as in certain data-intensive regional studies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-05T21:25:26.017925-05:
      DOI: 10.1111/bcpt.12764
  • The CYP2C19*2 and CYP2C19*17 Polymorphisms play a Vital Role in
           Clopidogrel Responsiveness after Percutaneous Coronary Intervention: A
           Pharmacogenomics Study
    • Authors: Faruk Saydam; İrfan Değirmenci, Alparslan Birdane, Mahmut Özdemir, Taner Ulus, Cansu Özbayer, Ertuğrul Çolak, Necmi Ata, Hasan Veysi Güneş
      Abstract: Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study. Platelet reactivity (PRU) and % inhibition were measured with VerifyNow P2Y12 assay in blood samples collected from patients who took a standard dose of clopidogrel (75 mg/day) for at least 7 days. The variants in the CYP2C19, CYP3A4, CYP2B6, ABCB1, ITGB3 and PON1 genes were genotyped using the Sequenom MassARRAY system. When grouped, the patients with PRU values >208 as non-responsiveness to clopidogrel therapy; 104 (30%) patients were non-responders and 243 (70%) patients were responders. A significant association was found between the CYP2C19*2 (G636A) polymorphism and non-responsiveness to clopidogrel therapy (P
      PubDate: 2017-01-30T17:55:28.157648-05:
      DOI: 10.1111/bcpt.12763
  • Modification of the Fc Region of a Human Anti-Oncostatin M Monoclonal
           Antibody for Higher Affinity to FcRn and Extension of Half-life in
           Cynomolgus Monkeys
    • Authors: Ivo P. Nnane; Chao Han, Qun Jiao, Susan Tam, Hugh M. Davis, Zhenhua Xu
      Abstract: The purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T1/2), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n=3). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n=5). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two-compartment population PK model with first-order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mLday−1kg−1, volume of distribution of central compartment (V1) = 31.3 mLkg−1, volume of distribution of peripheral compartment (V2) = 23.3 mLkg−1, absolute bioavailability (F) = 0.84 and T1/2 = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mLday−1kg−1, V1 = 39.8 mLkg−1, V2 = 32.6 mLkg−1, F = 0.75 and T1/2 = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V1 + V2) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T1/2 of CNTO 8212 was significantly (p < 0.05) longer (by about 2.7-fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti-OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half-life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK following a single IV dose (1 to 20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half-life in humans and may likely allow less frequent dosing in the clinical setting.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-28T20:35:36.171353-05:
      DOI: 10.1111/bcpt.12761
  • Switching, Adverse Effects and Use of Over-the-Counter Analgesics among
           Users of Oral Anticoagulants: A Pharmacy-based Survey
    • Authors: Maja Hellfritzsch; Lea Maria Rønneberg Hyllested, Line Meegaard, Alexander Wiberg-Hansen, Erik Lerkevang Grove, Anton Pottegård
      Abstract: Oral anticoagulants are widely used but information on important aspects in that respect is not available from medical registers or clinical databases. Therefore, we conducted a survey including patients filling a prescription for oral anticoagulants at two large Danish community pharmacies. We collected information concerning the patients’ knowledge of their anticoagulant treatment including prior drug switching. Further, patients were asked about use of over-the-counter analgesics, adverse effects, and how the treatment affected their everyday life.Among 335 eligible patients, 301 (90%) agreed to participate. Atrial fibrillation was the most common indication (65%), and most patients filled a prescription for a non-vitamin K antagonist oral anticoagulant (NOAC) (58%). Among the 12% (n=35) of participants who had switched oral anticoagulant treatment, 69% had switched from a vitamin K antagonist (VKA) to a NOAC. Switching was most frequently caused by inconvenience (34%) and adverse effects (23%). Although half of all patients had recently bought over-the-counter analgesics, purchase of ibuprofen and aspirin was rare (6%). More VKA users than NOAC users felt limited in their everyday life because of anticoagulant treatment (18% vs. 9%). Among non-incident NOAC users, 21% had experienced adverse effects during their current treatment.Based on first-hand information from a large sample of anticoagulant users, we conclude that the main drug-related issues leading to anticoagulant switching and perceived limitations in everyday life were inconvenience and adverse effects. This varied between drug groups. Further, use of NSAIDs obtained over the counter was rare.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-28T20:35:33.713744-05:
      DOI: 10.1111/bcpt.12762
  • Genetic Influences of OPRM1, OPRD1 and COMT on Morphine Analgesia in a
           Multi-Modal, Multi-Tissue Human Experimental Pain Model
    • Authors: Lecia Møller Nielsen; Lona Louring Christrup, Hiroe Sato, Asbjørn Mohr Drewes, Anne Estrup Olesen
      Abstract: Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate if genetic variants of mu, kappa and delta opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia.The study was a randomised, double-blind, two-way, cross-over, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (P=0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (P=0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (P=0.01) and rs533123 (P=0.046).The study was explorative and hypothesis-generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males, may contribute to the variability in morphine analgesia in experimental pain models.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-13T01:25:22.86354-05:0
      DOI: 10.1111/bcpt.12757
  • Clinical Pharmacology Research Internships at the Interface of Academia
           and Industry: Students’ Perceptions and Scientific Output
    • Authors: Sebastiaan C Goulooze; Kari L Franson, Adam F Cohen, Robert Rissmann
      Abstract: The Centre for Human Drug Research (CHDR) is a non-profit clinical research institute at the interface between academia and the pharmaceutical industry. CHDR hosts a research internship program for undergraduate (bio)medical students. The aim of this study was i) to investigate the student perceptions of the undergraduate research internship ii) quantify the scientific output related to these internships. We surveyed former interns at the CHDR from the years 2007 – 2014 and quantified their scientific output with a PubMed search. There was a response rate to the survey of 61%, with a good overall rating of the internships. Many students considered their internship at CHDR to be (much) more broad (55%) and with a (much) stricter planning (48%), compared to previous internships at academic research groups. In turn, there were many aspects reported to be similar to academic research internships such as focus on research methodology and ‘outcome-drivenness’ Twenty-four percent of the internships resulted in a co-authorship on papers published in peer-reviewed journals with an average impact factor of 3.3. In conclusion, with appropriate management and supervision, effective research electives are possible in the more commercial environment of a clinical research organization.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-08T05:20:27.020991-05:
      DOI: 10.1111/bcpt.12756
  • Global Research Trends in Lithium Toxicity from 1913 to 2015: A
           Bibliometric Analysis
    • Authors: Sa'ed H. Zyoud; W. Stephen Waring, Waleed M. Sweileh, Samah W. Al-Jabi
      Abstract: Lithium salts have been used to treat psychiatric disorders since the 1940s and are currently used in prophylaxis and treatment of depression and bipolar disorder. Therefore, we conducted this study to assess lithium toxicity-related publications using bibliometric approaches from a health point of view to assess global research trends in the lithium toxicity field to offer guidance to future research in this field. The data were retrieved from the online version of Scopus database on 6 August 2016. All records with the term “lithium” in the title were retrieved, and those related to lithium toxicity were evaluated. There were a total of 1,241 publications related to lithium toxicity published from 1913 to 2016. Articles (971 or 78.2%) were the most common type, followed by letters (179 or 14.4%) and reviews (61 or 4.9%). The annual publication of articles increased slightly after 1950 and the total number of publications related to lithium toxicity fluctuated with three peaks occurred in 1978, 1985 and 2014. The USA was the predominant country (25.38%), followed by the UK (7.82%), France (6.85%) and Canada (3.55%). Denmark had the highest productivity of publication after standardization by gross domestic product and population size. The average number of citations per article was 9.24, and the h-index for all publications in the field of lithium toxicity was 46. The highest h-index value was achieved by the USA (31) followed by the UK (21) and Canada (13). The Lancet was the highest ranked journal with 27 articles, followed by American Journal of Psychiatry with 23 articles. This study provides a bibliometric analysis on the global research trends in lithium toxicity studies during 1913–2015. There has been a progressive increase in the number of publications related to lithium toxicity published in the last decade, and most of the studies related to lithium toxicity arose from the USA and the UK.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-08T05:20:25.271584-05:
      DOI: 10.1111/bcpt.12755
  • Opposite Modulatory Effects of Selective and Non-Selective Cyclooxygenase
           Inhibition on Cardiovascular and Autonomic Consequences of Cyclosporine in
           Female Rats
    • Authors: Karim S. Ibrahim; Ahmed F. El-Yazbi, Hanan M. El-Gowelli, Mahmoud M. El-Mas
      Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) and the immunosuppressant drug cyclosporine (CSA) are concurrently administered in arthritis. Here, we investigated whether diclofenac (non-selective inhibitor of cyclooxygenase-1 and 2, COX-1/COX-2), celecoxib (selective COX-2 inhibitor) or SC560 (selective COX-1 inhibitor) interact variably with hemodynamic effects of CSA in conscious female rats. Changes caused by CSA (10 mg/kg i.v.) in blood pressure (BP), heart rate (HR), HR variability (HRV) and myocardial contractility were assessed in absence and presence of individual NSAIDs (10 mg/kg each). Compared with vehicle values, CSA caused immediate and sustained (i) increases in BP and decreases in pulse pressure index (PPI) and HR, (ii) elevations in left ventricular (LV) contractility (dP/dtmax) and isovolumic relaxation constant (Τau), and (iii) increases in the time and frequency domain indices of HRV and shifted the cardiac sympathovagal balance towards parasympathetic dominance. CSA hypertension was abolished in rats pre-treated with celecoxib and intensified in presence of diclofenac or SC560. Alternatively, the CSA-evoked decreases in PPI, increases in HRV indices and cardiac parasympathetic dominance were blunted by celecoxib in contrast to no effect for diclofenac or SC560. Similarly, celecoxib, but not other NSAIDs, eliminated the elevated LV contractility (dP/dtmax) and isovolumic relaxation constant (Τau, τ), which reflect cardiac systolic and diastolic function, respectively, that accompanied the CSA-induced pressure load. The data underscores the preferential capacity of selective COX-2 inhibition by celecoxib to mitigate CSA hypertension and consequent alterations in cardiac performance and autonomic balance. By contrast, CSA effects are preserved or even exacerbated after COX-1 inhibition.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-05T07:50:28.107401-05:
      DOI: 10.1111/bcpt.12754
  • Evaluation of DNA damage in HepG2 cells and mutagenicity of
           garcinielliptone FC, a bioactive benzophenone
    • Authors: Lismare da Silva Prado; Juliana da Silva, Ana Letícia Hilario Garcia, Fernanda Brião Menezes Boaretto, Ivana Grivicich, Lucas Umpierre Conter, Aguisson Oliveira Salvi, Flávio Henrique Reginatto, Suele Bierhals Vencato, Alexandre Barros Falcão Ferraz, Jaqueline Nascimento Picada
      Abstract: Garcinielliptone FC (GFC) is a polyprenylated benzophenone isolated from the hexanic extract of Platonia insignis seeds with potential pharmacological effects on the central nervous system. In a pre-clinical study, this compound showed anticonvulsant action, becoming a candidate to treat epilepsy disorders. However, genotoxicological aspects of GFC should be known to ensure its safe use. This study investigated the cytotoxic, genotoxic and mutagenic effects of GFC. Cytotoxicity was evaluated using the colourimetric assay of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in human hepatoma cells (HepG2) (2 – 100 μg/mL) for 3, 6 and 24 hr. The genotoxic and mutagenic potentials were analysed using the alkaline version of the comet assay, the cytokinesis-block micronucleus cytome assay in HepG2 cells, and the Salmonella/microsome assay with the strains TA98, TA97a, TA100, TA102 and TA1535, with and without metabolic activation. GFC concentrations above 50 μg/mL were cytotoxic at all experimental times. Viability of HepG2 cells was higher than 70% after exposure to GFC 2 μg/mL to 30 μg/mL for 3 hr in the MTT test. No GFC concentration was mutagenic or genotoxic in the Salmonella/microsome and comet assays. Nuclear division index decreased, indicating the cytotoxic effect of the compound, while micronucleus and nuclear bud frequencies rose after treatment with the highest GFC concentration tested (30 μg/mL). Nucleoplasmatic bridges were not observed. The results indicate that GFC is cytotoxic and mutagenic to mammalian cells, pointing to the need for further studies to clarify the toxicological potentials of this benzophenone before proceeding to clinical studies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-05T07:40:20.965882-05:
      DOI: 10.1111/bcpt.12753
  • Ticagrelor Increased Adenosine and Cyclic Adenosine Monophosphate Plasma
           Concentration Compared with Clopidogrel in Acute Coronary Syndromes
    • Authors: Xiao-ye Li; Qi-bing Wang, Ying Xue, Jia-hui Chen, Qian-zhou Lv
      Abstract: Ticagrelor produces a more potent antiplatelet effect than clopidogrel, and inhibits cellular uptake of adenosine, which is associated with several cardiovascular consequences. We aimed to explore the correlation between adenosine and cyclic adenosine monophosphate (cAMP) plasma concentration and antiplatelet effect by clopidogrel or ticagrelor in acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy (DAPT).We conducted a prospective, observational and single-centre cohort study enrolling 68 patients with non-ST-segment elevation ACS from January 2016 to May 2016. We monitored the inhibition of platelet aggregation (IPA) and assessed adenosine, adenosine deaminase (ADA) and cAMP plasma concentrations by immunoassay on admission and 48 hr after coronary angiography. The demographic and clinical data were collected by reviewing their medical records.The two groups exhibited similar baseline characteristics including adenosine, ADA and cAMP. The mean IPA in patients receiving ticagrelor was significantly higher than that in patients receiving clopidogrel (93.5% versus 67.2%; p=0.000). Also, we observed that patients treated with ticagrelor had a significantly higher increase in levels of adenosine and cAMP compared with those treated with clopidogrel (1.04 (0.86;1.41) versus 0.04 (-0.25;0.26); p=0.029 and 0.78 (-1.67;1.81) versus 0.60 (-1.91;4.60); p=0.037, respectively). And there was a weak correlation between IPA and adenosine as well as cAMP plasma concentration (r=0.390, p=0.001 and r=0.335, p=0.005, respectively).Ticagrelor increased adenosine and cAMP plasma concentration compared with clopidogrel in ACS patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-01-04T08:55:51.562841-05:
      DOI: 10.1111/bcpt.12752
  • Mass Spectrometry Based Tools to Characterize DNA-Protein Cross-Linking by
    • Authors: Arnold Groehler; Amanda Degner, Natalia Y. Tretyakova
      Abstract: DNA-protein cross-links (DPCs) are unusually bulky DNA adducts that form in cells as a result of exposure to endogenous and exogenous agents including reactive oxygen species, ultraviolet light, ionizing radiation, environmental agents (e.g. transition metals, formaldehyde, 1,2-dibromoethane, 1,3-butadiene) and common chemotherapeutic agents. Covalent DPCs are cytotoxic and mutagenic due to their ability to interfere with faithful DNA replication and prevent accurate gene expression. Key to our understanding of the biological significance of DPC formation is identifying the proteins most susceptible to forming these unusually bulky and complex lesions and quantifying the extent of DNA-protein cross-linking in cells and tissues. Recent advances in bottom-up mass spectrometry-based proteomics have allowed for an unbiased assessment of the whole protein DPC adductome following in vitro and in vivo exposures to cross-linking agents. This MiniReview summarizes current and emerging methods for DPC isolation and analysis by mass spectrometry-based proteomics. We highlight several examples of successful applications of these novel methodologies to studies of DPC lesions induced by bis-electrophiles such as formaldehyde, 1,2,3,4-diepoxybutane, nitrogen mustards, and cisplatin.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-29T09:31:30.648801-05:
      DOI: 10.1111/bcpt.12751
  • Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4+
           T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate
           Cell Activation: Blockade of Smad3/Smad4 Signalling
    • Authors: Hongjun Zhang; Baoling Ju, Xiaoli Zhang, Yanfei Zhu, Ying Nie, Yuanhong Xu, Qiuxia Lei
      Abstract: Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis, which displays anti-inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune-related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo. In response to ConA stimulation, the CD4+ T cells preferred to polarizing towards CD4+ T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA-treated liver in addition to suppressing interleukin (IL)-17A generation. Hepatic stellate cells were activated in fibrotic liver as evidenced by increased alpha smooth muscle actin (α-SMA) and desmin. More transforming growth factor (TGF)-β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro, the recombinant IL-17A plus TGF-β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up-regulated phospho-Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel anti-fibrotic effect of magnolol on Th17 cell-mediated fibrosis.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-29T02:50:37.99172-05:0
      DOI: 10.1111/bcpt.12749
  • Pharmacological Properties of Melanin and its Function in Health
    • Authors: Adila Salih ElObeid; Afaf Kamal-Eldin, Mohamed Anwar K Abdelhalim, Adil M Haseeb
      Abstract: The biological pigment melanin is present in most of the biological systems. It manifests a host of biological and pharmacological properties. Its role as a molecule with special properties and functions affecting general health, including photo-protective and immunological action are well recognised. Its antioxidant, anti-inflammatory, immuno-modulatory, radio-protective, hepatic, gastrointestinal and hypoglycaemic benefits have only recently been recognised and studied. It is also associated with certain disorders of the nervous system. In this MiniReview, we consider the steadily increasing literature on the bioavailability and functional activity of melanin. Published literature shows that melanin may play a number of possible pharmacological effects such as protective, stimulatory, diagnostic and curative roles in human health. In this MiniReview, possible health roles and pharmacological effects are considered.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-27T15:45:24.279552-05:
      DOI: 10.1111/bcpt.12748
  • Triggering Mechanisms and Inflammatory Effects of Combustion Exhaust
           Particles with Implication for Carcinogenesis
    • Authors: J. Øvrevik; M. Refsnes, M. Låg, B. Brinchmann, P.E. Schwarze, J.A. Holme
      Abstract: A number of biological responses may contribute to the carcinogenic effects of combustion-derived particulate matter (CPM). Here, we focus on mechanisms that trigger CPM-induced pro-inflammatory responses. Inflammation has both genotoxic as well as non-genotoxic implications and is considered to play a central role in development of various health outcomes associated with CPM exposure, including cancer. Chronic, low-grade inflammation may cause DNA damage through a persistent increased level of reactive oxygen species (ROS) produced and released by activated immune cells. Moreover, a number of pro-inflammatory cytokines and chemokines display mitogenic, motogenic, morphogenic and/or angiogenic properties and may therefore contribute to tumour growth and metastasis. The key triggering events involved in activation of pro-inflammatory responses by CPM and soluble CPM components can be categorized into i) formation of ROS and oxidative stress, ii) interaction with the lipid layer of cellular membranes, iii) activation of receptors, ion channels and transporters on the cell surface, and iv) interactions with intracellular molecular targets including receptors such as the aryl hydrocarbon receptor (AhR). In particular, we will elucidate the effects of diesel exhaust particles (DEP) using human lung epithelial cells as a model system.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-21T10:00:20.959342-05:
      DOI: 10.1111/bcpt.12746
  • Anticholinergic Exposure in a cohort of adults aged 80 years and over
           Associations of the MARANTE scale with mortality and hospitalisation
    • Authors: Maarten Wauters; Therese Klamer, Monique Elseviers, Bert Vaes, Olivia Dalleur, Jan Degryse, Carlos Durán, Thierry Christiaens, Majda Azermai, Robert Vander Stichele
      Abstract: Anticholinergics are frequently prescribed for older adults and can lead to adverse drug events. The novel MARANTE (Muscarinic Acetylcholinergic Receptor ANTagonist Exposure) scale measures the anticholinergic exposure by incorporating potency and dosages of each medication into its calculations.The aims were to assess prevalence and intensity of the anticholinergic exposure in a longitudinal cohort study of community-dwelling patients aged 80 years and over (n=503) and to study the impact on mortality and hospitalisation.Chronic medication use at baseline (November 2008 - September 2009) was entered and codified with the Anatomical Therapeutic Chemical classification. Time-to-event analysis until first hospitalisation or death was performed at 18 months after inclusion, using Kaplan-Meier curves. Cox regression was performed to control for covariates.Mean age was 84 years (range 80 – 102), and mean number of medications was 5 (range 0 – 16). Prevalence of anticholinergic use was 31.8%, with 9% taking ≥2 anticholinergics (range 0 – 4). Main indications for anticholinergics were depression, pain and gastric dysfunction. Female gender, the level of multimorbidity and the number of medications were associated with anticholinergic use.Mortality and hospitalisation rate were 8.9%, and 31.0% respectively. After adjustment for the level of multimorbidity and medication intake, multivariable analysis showed increased risks of mortality (HR 2.3, 95%CI 1.07 – 4.78) and hospitalisation (HR 1.7; 95%CI 1.13 – 2.59) in those with high anticholinergic exposure.The longitudinal study among Belgian community-dwelling oldest old demonstrated great anticholinergic exposure, which was associated with increased risk of mortality and hospitalization after 18 months.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-20T02:40:55.45471-05:0
      DOI: 10.1111/bcpt.12744
  • Naloxone Antagonises Soman-induced Central Respiratory Depression in Rats
    • Authors: Ranko Škrbić; Miloš P. Stojiljković, Slavko S. Ćetković, Silva Dobrić, Dejan Jeremić, Maja Vulović
      Abstract: The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonised the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonising respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonises soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-19T16:50:23.763369-05:
      DOI: 10.1111/bcpt.12745
  • Lithium Toxicity in a Pregnant Woman
    • Authors: Nasim Zamani; Maryam Paeezi, Hossein Hassanian-Moghaddam
      Abstract: Lithium is recommended in bipolar disorder and can be accompanied by significant toxicity in pregnant women.A 25-year-old single-gestation pregnant woman (28 weeks) was referred with suspicion of lithium toxicity. Serum lithium was 2.1 meq/L. Despite conservative therapy with intravenous fluids, lithium concentration increased to 5.0 meq/L 6 hr post admission mandating an emergent hemodialysis during which foetal heart rate decreased to 90 bpm. The gynaecologist ordered termination of pregnancy while the mother was still on hemodialysis. Cesarean section was done but the born baby had an apgar of 2 and died. Autopsy findings of the foetus revealed a cord blood lithium concentration of 4.8 mEq/L with no physical abnormalities.Although the foetus had the signs/symptoms of distress, continuation of hemodialysis could probably have saved it as it saved its mother's life. In lithium toxicity in a pregnant woman, it is reasonable to continue hemodialysis even with the signs and symptoms of foetal distress. In similar situations, emergency hemodialysis instead of immediate cesarean section should be considered.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-19T16:50:21.572501-05:
      DOI: 10.1111/bcpt.12747
  • Dissection of the Effects of Quercetin on Mouse Myocardium
    • Authors: Michel Santana Santos; Evaleide Diniz Oliveira, Artur Santos-Miranda, Jader Santos Cruz, Antônio Nei Santana Gondim, José Evaldo Rodrigues Menezes-Filho, Diego Santos Souza, Leidiane Pinho-da-Silva, Itamar Couto Guedes Jesus, Danilo Roman-Campos, Silvia Guatimosim, Aline Lara, Eduardo Antônio Conde-Garcia, Carla Maria Lins Vasconcelos
      Abstract: Quercetin is a plant flavonoid with several biological activities. This study aimed to describe quercetin effects on contractile and electrophysiological properties of the cardiac muscle as well as on calcium handling. Quercetin elicited positive inotropism that was significantly reduced by propranolol indicating an involvement of the sympathetic nervous system. In cardiomyocytes, 30 μM quercetin increased ICa,L at 0 mV from −0.95 ± 0.01 A/F to −1.21 ± 0.08 A/F. The membrane potential at which 50% of the channels are activated (V0.5) shifted towards more negative potentials from -13.06 ± 1.52 mV to -19.26 ± 1.72 mV and did not alter the slope factor. Furthermore, quercetin increased [Ca2+]i transient by 28% when compared to control. Quercetin accelerated [Ca2+]i transient decay time which could be attributed to SERCA activation. In resting cardiomyocytes, quercetin did not change amplitude or frequency of Ca2+ sparks. In isolated heart, quercetin increased heart rate and decreased PRi, QTc and duration of the QRS complex. Thus, we showed that quercetin activates β-adrenoceptors, leading to increased L-type Ca2+ current and cell-wide intracellular Ca2+ transient without visible changes in Ca2+ sparks.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-19T16:45:21.938556-05:
      DOI: 10.1111/bcpt.12743
  • Synergistic combination for chemoprevention of hepatocellular carcinoma:
           an in-silico and in-vitro approach
    • Authors: Savita Mishra; DeepshikhaPande Katare
      Abstract: Combination therapy is one of the best methods to manage the fatality rate in hepatocellular carcinoma (HCC). The current study aimed to formulate a synergistic combination of synthetic and herbal compounds for the treatment of HCC as well as to elucidate a possible signalling mechanism. MTT and enzymatic assay were performed to determine the synergistic effect of drug combination (sorafenib, vitamin K1 and trans-chalcone) on HepG2 cell lines after intoxication with H2O2. Protein-protein interaction and docking studies were performed using Pathwaylinker2.0 and Schrödinger's software application to find out the mechanism of action and major targets for drug combination. The overall in vitro result showed that combination of trans-chalcone, vitamin K1 and sorafenib (10, 5 and 5μM concentration, respectively) enhanced the resistance against oxidative stress generated by H2O2. The interaction studies helped in identification of few targets for docking of ligands (trans-chalcone, vitamin K1 and sorafenib). The study reports the synergistic effects of the formulation that can protect the cells from oxidative stress and restore normal levels of cellular enzymes in HepG2 cell line. We were able to determine the mechanism of action of herbal and synthetic formulation through in silico studies. Finally, docking studies confirmed potential targets for inhibition of hepatocarcinogenesis.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-17T16:51:09.212909-05:
      DOI: 10.1111/bcpt.12730
  • Sulforaphane Improves Neuronal Mitochondrial Function in Brain Tissue in
           Acute Carbon Monoxide Poisoning Rats
    • Authors: Mingjun Bi; Qin Li, Dadong Guo, Xiaoyu Ding, Weikang Bi, Yueheng Zhang, Yong Zou
      Abstract: Carbonmonoxide (CO) poisoning is one of the leading causes of toxicity-related mortality and morbidity worldwide, primarily manifested by acute and delayed central nervous system (CNS) injuries and other organ damages. However, its definite pathogenesis is poorly understood. The aim of the present study was to explore the pathogenesis of the ultrastructural and functional impairment of mitochondria and the protection of sulforaphane (SFP) at different dosages on hippocampus neurons in rats after exposure to CO. We found that CO poisoning could induce advanced cognitive dysfunction, while the mitochondrial ultrastructure of neurons in rats of the CO poisoning group was seriously damaged and mitochondrial membrane potential (ΔΨm) was accordingly reduced by transmission electron microscopy (TEM) and JC-1 fluorescent probe assay. CO poisoning could also increase the expressions of both nuclear factor erythroid 2-related factor 2 (Nrf-2) and Thioredoxin-1 (Trx-1) proteins and their mRNA in brain tissue with immunohistochemistry and quantitative PCR (qPCR) techniques. Early administration of either middle-dose or high-dose SFP could efficiently improve mitochondrial structure and function, enhance the anti-oxidative stress ability, and thus exerting a positive effect against brain damage induced by acute CO poisoning.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-16T10:50:49.216048-05:
      DOI: 10.1111/bcpt.12728
  • Carnitine and γ-butyrobetaine Stimulate Elimination of Meldonium due to
           Competition for OCTN2-mediated Transport
    • Authors: Edgars Liepinsh; Elina Makarova, Eduards Sevostjanovs, Dace Hartmane, Helena Cirule, Olga Zharkova-Malkova, Solveiga Grinberga, Maija Dambrova
      Abstract: Meldonium (3-(2,2,2-trimethylhydrazinium)propionate) is the most potent clinically used inhibitor of organic cation transporter 2 (OCTN2). Inhibition of OCTN2 leads to a decrease in carnitine and acylcarnitine contents in tissues and energy metabolism optimization-related cardioprotective effects. The recent inclusion of meldonium in the World Anti-Doping Agency List of Prohibited Substances and Methods has raised questions about the pharmacokinetics of meldonium and its unusually long elimination time. Therefore, in this study, the rate of meldonium washout after the end of treatment was tested with and without administration of carnitine, γ-butyrobetaine (GBB) and furosemide to evaluate the importance of competition for OCTN2 transport in mice. Here, we show that carnitine and GBB administration during the washout period effectively stimulated the elimination of meldonium. GBB induced a more pronounced effect on meldonium elimination than carnitine due to the higher affinity of GBB for OCTN2. The diuretic effect of furosemide did not significantly affect the elimination of meldonium, carnitine and GBB.In conclusion, the competition of meldonium, carnitine and GBB for OCTN2-mediated transport determines the pharmacokinetic properties of meldonium. Thus, due to their affinity for OCTN2, GBB and carnitine but not furosemide stimulated meldonium elimination. During long-term treatment, OCTN2-mediated transport ensures a high muscle content of meldonium, while tissue clearance depends on relatively slow diffusion, thus resulting in the unusually long complete elimination period of meldonium.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-16T09:10:19.746895-05:
      DOI: 10.1111/bcpt.12729
  • Metabolic Response to Olanzapine in Healthy Chinese Subjects with
           rs7093146 Polymorphism in Transcription Factor 7-like 2 Gene (TCF7L2): A
           Prospective Study
    • Authors: Qing Li; Dong Guo, Hong Yang, Zhi Ye, Jin Huang, Yan Shu
      Abstract: Olanzapine is a widely used atypical antipsychotic with significant weight gain and other metabolic side effects. The locus of the transcription factor 7-like 2 (TCF7L2) gene is strongly associated with type 2 diabetes (T2D). The goal of this study was to determine whether polymorphic TCF7L2 is involved in the susceptibility to the metabolic changes associated with the atypical antipsychotic agents (AAPs). In this study, a parallel clinical study with 3-day consecutive administration of olanzapine (10 mg/day) was conducted in 17 healthy subjects with a genotype of TCF7L2 rs7903146 CC (N=10) or CT (N=7). Olanzapine caused rapid metabolic changes including body weight gain, increased triglycerides level and reduced HDL-cholesterol level in the healthy subjects. rs7093146 T carriers (CT) was found to have greater AUC0-2hr of insulin during OGTT compared to those (CC) bearing only reference alleles before and after olanzapine treatment. However, the triglyceride level in the subjects with the CT genotype was found to be significantly lower than that in the subjects with CC genotype. Moreover, a significant interaction between the effect by genotype and that by olanzapine treatment on triglyceride level was identified. Acute olanzapine treatment also significantly caused total protein, albumin and hemoglobin decrease and uric acid increase in the healthy subjects. In conclusion, even acute olanzapine treatment induces significant and rapid metabolic changes, and TCF7L2 polymorphism is a genetic risk factor of olanzapine-associated metabolic side effects.This article is protected by copyright. All rights reserved.
      PubDate: 2016-12-16T08:45:27.27838-05:0
      DOI: 10.1111/bcpt.12727
  • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
  • 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
  • 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
    • 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
  • 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
  • Prophylactic Melatonin Attenuates Isoflurane‐induced Cognitive
           Impairment in Aged Rats through Hippocampal Melatonin Receptor 2 ‐ CREB
    • 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
  • 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
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Heriot-Watt University
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