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  Subjects -> ENVIRONMENTAL STUDIES (Total: 768 journals)
    - ENVIRONMENTAL STUDIES (694 journals)
    - POLLUTION (22 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (694 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: 39)
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   (Followers: 2)
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: 14)
American Naturalist     Full-text available via subscription   (Followers: 63)
Annals of GIS     Hybrid Journal   (Followers: 21)
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: 55)
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: 15)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 30)
Aquatic Toxicology     Hybrid Journal   (Followers: 19)
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: 10)
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: 28)
Atmospheric Environment     Hybrid Journal   (Followers: 66)
Austral Ecology     Hybrid Journal   (Followers: 12)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 11)
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: 13)
Behavioral Ecology     Hybrid Journal   (Followers: 46)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 30)
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: 33)
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: 40)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 12)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 21)
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  
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: 19)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 14)
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: 18)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 20)
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: 4)
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: 30)
Conservation Science     Open Access   (Followers: 19)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 5)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 13)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 22)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 12)
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: 13)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 7)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 15)
Developments in Earth and Environmental Sciences     Full-text available via subscription   (Followers: 6)
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: 5)
Developments in Integrated Environmental Assessment     Full-text available via subscription   (Followers: 6)
Disaster Prevention and Management     Hybrid Journal   (Followers: 20)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 14)
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: 3)
Earth System Science Data (ESSD)     Open Access   (Followers: 6)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 5)
Earthquake Science     Hybrid Journal   (Followers: 10)
EchoGéo     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 11)
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: 135)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecological Complexity     Hybrid Journal   (Followers: 8)
Ecological Indicators     Hybrid Journal   (Followers: 17)
Ecological Informatics     Hybrid Journal   (Followers: 5)
Ecological Management & Restoration     Hybrid Journal   (Followers: 14)
Ecological Modelling     Hybrid Journal   (Followers: 92)
Ecological Monographs     Full-text available via subscription   (Followers: 30)
Ecological Processes     Open Access   (Followers: 5)
Ecological Questions     Open Access   (Followers: 7)
Ecological Research     Hybrid Journal   (Followers: 9)
Ecological Restoration     Full-text available via subscription   (Followers: 23)
Ecologist, The     Full-text available via subscription   (Followers: 27)
Ecology     Full-text available via subscription   (Followers: 285)
Ecology and Evolution     Open Access   (Followers: 57)
Ecology Letters     Hybrid Journal   (Followers: 188)
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: 27)
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)
Empowering Sustainability International Journal     Open Access   (Followers: 2)
Energy & Environmental Science     Full-text available via subscription   (Followers: 24)
Energy & Environment     Hybrid Journal   (Followers: 18)
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: 19)
Environment and Ecology Research     Open Access   (Followers: 6)
Environment and Natural Resources Research     Open Access   (Followers: 11)
Environment and Planning A     Full-text available via subscription   (Followers: 46)
Environment and Planning B : Planning and Design     Full-text available via subscription   (Followers: 34)
Environment and Planning C : Government and Policy     Full-text available via subscription   (Followers: 33)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 45)
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: 33)
Environment, Space, Place     Full-text available via subscription   (Followers: 5)
Environment: Science and Policy for Sustainable Development     Hybrid Journal   (Followers: 43)
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: 4)
Environmental Bioindicators     Hybrid Journal   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Claims Journal     Hybrid Journal   (Followers: 1)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 18)
Environmental Development     Hybrid Journal   (Followers: 3)
Environmental Disease     Open Access  
Environmental Education Research     Hybrid Journal   (Followers: 14)
Environmental Engineering Science     Hybrid Journal   (Followers: 8)
Environmental Ethics     Hybrid Journal   (Followers: 8)
Environmental Evidence     Open Access   (Followers: 1)
Environmental Fluid Mechanics     Hybrid Journal   (Followers: 5)
Environmental Forensics     Hybrid Journal   (Followers: 1)
Environmental Geosciences     Full-text available via subscription   (Followers: 4)
Environmental Geotechnics     Hybrid Journal   (Followers: 5)
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)

        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  [1583 journals]
  • Safety, Pharmacokinetics and Pharmacodynamics of Hetrombopag Olamine, a
           Novel TPO-R Agonist, in Healthy Subjects
    • Authors: Li Zheng; Mao-zhi Liang, Xiao-ling Zeng, Cai-zheng Li, Yi-fan Zhang, Xiao-yan Chen, Xi Zhu, An-bo Xiang
      Abstract: Hetrombopag olamine (hetrombopag) is a novel small-molecule, orally bioavailable, non-peptide thrombopoietin (TPO) receptor agonist that is being developed as the treatment for thrombocytopenia. Two randomized, placebo-controlled phase I studies were conducted in 72 healthy subjects to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of hetrombopag. Hetrombopag was orally administered with a single dose in 5 dose cohorts (5 mg, 10 mg, 20 mg, 30 mg or 40 mg) in the first study, and given once daily for 10 days in 3 dose cohorts (2.5 mg, 5.0 mg or 7.5 mg) in the second study, respectively. Hetrombopag was well tolerated, and the majority of adverse events associated with medicine were platelet elevations significantly above the normal range in healthy subjects. The single dose escalation study revealed a Tmax of approximate 8 hr, and a t1/2 of 11.9 hr to 40.1 hr in a dose-prolonged manner. A dose-proportional increase in maximum concentration (Cmax) of hetrombopag was observed, with area under the curve (AUC) increasing in a greater-than-dose-proportional manner. The plasma concentration of hetrombopag reached the steady state after 7 days. The steady-state AUC0-24hr and Cmax were dose-proportionally elevated from the 5.0 mg to 7.5 mg dose level. The potent pharmacological effect of the hetrombopag-induced platelet elevation was observed in a time- and dose-dependent manner. Furthermore, the thrombopoietic response was significantly (p
      PubDate: 2017-05-24T18:20:27.95253-05:0
      DOI: 10.1111/bcpt.12815
  • A Critical Note on Treatment of a Severe Diltiazem Intoxication; High-Dose
           Calcium and Glucagon Infusions
    • Authors: N M Van Veggel; G J Van der Veen, T C Jansen, E M Westerman
      Abstract: The morbidity and mortality of a severe calcium channel blocker intoxication is high due to serious toxic cardiac effects. Its treatment is supported by low-quality evidence from heterogeneous literature. We describe a case of a severe diltiazem intoxication and critically appraise the efficacy and role of high-dose calcium and glucagon infusions.A 53-year-old woman was admitted to the emergency department with a cardiogenic shock with complete AV block, not responding to atropine, isoprenaline and an external pacemaker. Later on, it became clear that she had a severe diltiazem intoxication which was successfully treated with isotone fluids, inotropics, vasopressors and continuous infusion of high-dose calcium and glucagon. The patient developed, however, an acute, necrotizing pancreatitis, probably related to iatrogenic high calcium levels.This case demonstrates lack of consensus regarding target levels of serum calcium for treatment of a severe diltiazem intoxication. Goal-directed tapering of calcium should prevent side-effects of iatrogenic hypercalcaemia. The contribution of glucagon infusions is doubtful due to the instability of solubilized glucagon. This might explain why the effect of glucagon is variable in the literature.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-15T02:30:33.304554-05:
      DOI: 10.1111/bcpt.12809
  • Analysis of National Pharmacovigilance Data Associated with Statin Use in
           Korea. Adverse Drug Reactions with Statins
    • Authors: Hyunah Kim; Namhyo Kim, Da Hee Lee, Hun-Sung Kim
      Abstract: The aim of this study was to evaluate clinical manifestations, age distribution and risk factors of adverse drug reactions (ADRs) of statins.Korean Adverse Event Reporting System (KAERS) database records (July 2009 – June 2014) on statin-treated adults were used. ADRs classified as “certain,” “probable” and “possible” based on the WHO-Uppsala Monitoring Centre criteria were analysed. The frequency of ADRs was compared between adults (18-64 years) and older people (age ≥ 65 years) groups.In total, 2161 ADRs from 1690 patients (579, 34.3% older people) were included for analysis. Mean patient age and ADRs per patient were 60.46 ± 12.72 years and 1.28, respectively. ADRs were reported with atorvastatin (48.4%), rosuvastatin (23.0%), pitavastatin (10.4%) and simvastatin (9.1%). The frequent ADRs were gastrointestinal (421 events, 19.5%), musculoskeletal (331, 15.3%), skin (312, 14.4%) and hepatobiliary disorders (286, 13.2%). Skin disorders were significantly more frequent in adults compared to those in older patients (16.3% versus 12.4%, p = 0.021). Common clinical symptoms were myalgia (263 events, 12.2%), dyspepsia (133, 6.2%) and pruritus (103, 4.8%). Myalgia was more frequently reported in adults (12.7% versus 9.5%, p = 0.039) and dizziness was more frequent in older people (3.4% versus 5.8%, p = 0.015).According to KAERS data, leading statin ADRs were gastrointestinal and musculoskeletal disorders. Myalgia and dyspepsia were the common clinical symptoms.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-13T09:45:27.076062-05:
      DOI: 10.1111/bcpt.12808
  • Severe Acute Valproic Acid Intoxication Successfully Treated with Liver
           Support Therapy
    • Authors: Yongchun Ge; Bin Xu, Chuan Li, Qunpeng He, Tingting Zhu, Rong Fan, Dehua Gong
      Abstract: Valproic acid (VPA) is widely used for treatment of epilepsy. However, its overdose can cause intoxication and could be life-threatening. Due to lack of specific antidote and poorness of endogenous clearance, extracorporeal treatment for severe intoxication cases is indicated. Here, we report a case of severe intoxication of VPA which was successfully treated with liver support therapy. A previously healthy woman was admitted due to coma and hypotension after intentional ingestion of 20 g of sodium valproate. Her serum concentration of VPA measured on admission was 420.84 mg/L. In addition to standard therapy, she received two sessions of extracorporeal blood purification using a system based on fractionated plasma separation and adsorption mode integrated with continuous veno-venous hemofiltration (FPSA-CVVH), which is usually used for liver support therapy at our hospital. Her serum concentration of VPA decreased dramatically to 40.18 mg/L and her consciousness recovered completely within 24 hr after admission. Therefore, although hemodialysis has been reported to be effective in treatment of VPA poisoning, FPSA-CVVH may provide an option for patients who require bedside therapy but have an unstable haemodynamic status or other conditions that result in inability to endure hemodialysis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-08T10:35:24.144751-05:
      DOI: 10.1111/bcpt.12807
  • The Pig-a Gene Mutation Assay in Mice and Human Cells: A Review
    • Authors: Ann-Karin Olsen; Stephen D. Dertinger, Christopher T. Krüger, Dag M. Eide, Christine Instanes, Gunnar Brunborg, Andrea Hartwig, Anne Graupner
      Abstract: This MiniReview describes the principle of mutation assays based on the endogenous Pig-a gene and summarizes results for two species of toxicological interest, mice and humans. The work summarized here largely avoids rat-based studies, as are summarized elsewhere. The Pig-a gene mutation assay has emerged as a valuable tool for quantifying in vivo and in vitro mutational events. The Pig-a locus is located at the X-chromosome, giving the advantage that one inactivated allele can give rise to a mutated phenotype, detectable by multi-colour flow cytometry. For in vivo studies, only minute blood volumes are required, making it easily incorporated into on-going studies or experiments with limited biological materials. Low blood volumes also allows subjects to serve as their own controls, providing temporal information of the mutagenic process, and/or outcome of intervention. These characteristics make it a promising exposure marker. To date, the Pig-a gene mutation assay has been most commonly performed in rats, while reports regarding its usefulness in other species are accumulating. Besides its applicability to in vivo studies, it holds promise for genotoxicity testing using cultured cells, as shown in recent studies. In addition to safety assessment roles, it is becoming a valuable tool in basic research to identify mutagenic effects of different interventions or to understand implications of various gene defects by investigating modified mouse models or cell systems. Human blood-based assays are also being developed that may be able to identify genotoxic environmental exposures, treatment- and life-style-related factors, or endogenous host factors that contribute to mutagenesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-08T10:30:29.180343-05:
      DOI: 10.1111/bcpt.12806
  • Evolution of Novel 3D Culture Systems for Studies of Human Liver Function
           and Assessments of the Hepatotoxicity of Drugs and Drug Candidates
    • Authors: Tommy B. Andersson
      Abstract: The pharmaceutical industry urgently needs reliable pre-clinical models to evaluate the efficacy and safety of new chemical entities before they enter the clinical trials. Development of in vitro model systems that emulate the functions of the human liver organ has been an elusive task. Cell lines exhibit a low drug-metabolizing capacity and primary liver cells rapidly de-differentiate in culture, which restrict their usefulness substantially. Recently, the development of hepatocyte spheroid cultures has shown promising results. The proteome and transcriptome in the spheroids were similar to the liver tissue, and hepatotoxicity of selected substances was detected at in vivo-relevant concentrations.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T03:40:28.917744-05:
      DOI: 10.1111/bcpt.12804
  • Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai
           Autistic Children and Adolescents
    • Authors: Nopphadol Nuntamool; Nattawat Ngamsamut, Natchaya Vanwong, Apichaya Puangpetch, Monpat Chamnanphon, Yaowaluck Hongkaew, Penkhae Limsila, Chuthamanee Suthisisang, Bob Wilffert, Chonlaphat Sukasem
      Abstract: The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcomes in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI-I, aggressive, over-activity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), over-activity (71.95%), repetitive (70.89%) behavior and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI-I score. Patients in the non-stable symptom group had DRD2 Taq1A non-wildtype (TT and CT) frequencies higher than the clinically stable group (P = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non-stable clinical outcome (χ2 = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcomes. On the other hand, risperidone dose, 9-OH Risperidone levels and prolactin levels were significantly higher in the non-stable compared to the stable symptom group (P = 0.013, P = 0.044, P = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body weight, whereas it was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long-term treatment. However, Taq1A T – carrier of dopamine2 receptor gene is associated with non-stable response in risperidone-treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T02:55:35.678686-05:
      DOI: 10.1111/bcpt.12803
  • Clinical Effects of a Pharmacist Intervention in Acute Wards- A
           Randomised, Controlled Trial
    • Authors: Trine R. H. Nielsen; Per H. Honoré, Mette Rasmussen, Stig E. Andersen
      Abstract: The purpose of the study was to investigate the clinical effect of a clinical pharmacist (CP) intervention upon admission to hospital on in-patient harm and to assess a potential educational bias.Over16 months, 593 adult patients taking ≥ 4 medications daily were included from three Danish acute medicine wards. Patients were randomised to 'either the CP intervention or the usual care (prospective control). To assess a potential educational bias or educational bias, a retrospective control group was formed by randomisation. The CP intervention comprised medication history, medication reconciliation, medication review and entry of proposed prescriptions into the electronic prescribing system. The primary outcome of in-patient harm was identified by using triggers from the IHI Global Trigger Tool. Harms were validated and rated for severity by two independent and blinded outcome panels. Secondary endpoints were harms per patient, length of hospital stay, readmissions and one-year mortality.Harm affected 11% of the patients in the intervention group compared to 17% in the combined control group, odds ratio (OR) 0.57 (CI 0.32 to 1.02, p=0.06). The incidence of harm was similar in the intervention and prospective control groups, OR 0.80 (CI 0.40 to 1.59, p=0.52) but occurred less frequently in the intervention than in the retrospective control group OR 0.46 (CI 0.25 to 0.85, p=0.01). An educational bias from the intervention to the control group might have contributed to this negative outcome. In conclusion, the CP intervention at admission to hospital had no statistically significant effect on in-patient harm.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-29T09:28:31.310133-05:
      DOI: 10.1111/bcpt.12802
  • Azilsartan Medoxomil, an Angiotensin II Receptor Antagonist for the
           Treatment of Hypertension
    • Authors: Marie Harthøj Hjermitslev; Daniela Grimm, Markus Wehland, Ulf Simonsen, Marcus Krüger
      Abstract: Azilsartan medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both in blood pressure (BP) reduction and in tolerability, but has not yet been taken into practice to the same extent as other angiotensin-II receptor blockers (ARBs) that have been on the market for a longer period.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-26T10:35:43.714962-05:
      DOI: 10.1111/bcpt.12800
  • Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced
           Non-Small-Cell Lung Cancer (NSCLC) Receiving Erlotinib Treatment
    • Authors: Zinnia P. Parra-Guillen; Peter B. Berger, Manuel Haschke, Massimiliano Donzelli, Daria Winogradova, Bogumila Pfister, Martin Früh, Charlotte Kloft, Stephan Krähenbühl, Silke Gillessen, Markus Joerger
      Abstract: Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD. was initiated, and the 2 oral probe drugs midazolam (2mg) and caffeine (100mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R2 = 0.960, P < 0.0001), OSI-420 (R2 = 0.971, P < 0.0001), midazolam (R2 = 0.995, P < 0.0001) and caffeine (R2 = 0.968, P < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R2 = 0.33, P = 0.048), while midazolam clearance was not (R2 = -0.09, P = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, P = 0.086 for Student's T). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in cancer patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-26T10:35:40.21372-05:0
      DOI: 10.1111/bcpt.12801
  • Autonomic Receptor-Mediated Regulation of Production and Release of Nitric
           Oxide in Normal and Malignant Human Urothelial Cells
    • Authors: Michael Winder; Renata Vesela, Patrik Aronsson, Bhavik Patel, Thomas Carlsson
      Abstract: In the urinary bladder, the main source of NO seems to be the urothelium and the underlying suburothelium. In this study, we aimed to characterize how receptors in the human urothelium regulate the production and release of NO. For this, we cultured two human urothelial cell lines - the normal immortalized cell line UROtsa and the malignant cell line T24. These were treated with an array of agonists and antagonists with affinity for adrenergic, muscarinic and purinergic receptors. The production of NO and expression of nitric oxide synthase (NOS) was studied by immunocytochemistry and western blotting. The amount of released NO was measured indirectly by detecting nitrite using amperometry and a Griess reaction kit. The results showed that NO, endothelial NOS and inducible NOS were predominantly produced and expressed in the close vicinity of the nucleus in untreated human urothelial cells. Upon treatment with a beta-adrenoceptor agonist, but not any of the other agonists or antagonists, the pattern of NO production changed, showing a more even production throughout the cytosol. The pattern of expression of endothelial NOS changed in a similar way upon dobutamine treatment. The release of nitrite, as a measurement of NO, increased following treatment with dobutamine from 0.31±0.029 to 1.97±0.18 nmol and 0.80±0.12 to 3.27±0.24 nmol in UROtsa and T24, respectively. In conclusion, our results show that the expression of NOS and production of NO as well as the release of NO from human urothelial cells is regulated by beta-adrenoceptor activation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-24T10:21:16.194567-05:
      DOI: 10.1111/bcpt.12799
  • Effects of Aluminium on long-term Memory in Rats and on SIRT1 Mediating
           the Transcription of CREB-Dependent Gene in Hippocampus
    • Authors: Dongying Yan; Cuihong Jin, Yang Cao, Lulu Wang, Xiaobo Lu, Jinghua Yang, Shengwen Wu, Yuan Cai
      Abstract: Epidemiological investigations have shown that aluminium (Al) is an important neurotoxicant which can be absorbed by organisms via various routes. Previous studies have confirmed that exposure to Al could cause neurodegenerative diseases, decline CREB phosphorylation and then down-regulate the transcription and protein expression of its target genes including BDNF. However, recent studies revealed that CREB activation alone was far from enough to activate the expression of long-term memory (LTM) related genes; there might be other regulatory factors involved in this process. Several studies showed that TORC1 might be involved in regulating the transcription of downstream target genes as well. Also, TORC1 could be mediated by SIRT1 during the formation of LTM. However, the role of CREB regulating system in Al-induced LTM impairment was still not utterly elucidated till now. This study was designed to establish the rat model of subchronic Al exposure to observe the neuroethology, regulatory factor levels and molecular biological alterations in hippocampal cells. The results showed that, with the increasing AlCl3 dose, blood Al content increased gradually; morphology of the hippocampus and neuronal ultrastructure were aberrant; in the Morris water maze test, the escape latency and distance travelled became longer, swimming traces turned more complicated in the place navigation test; intracellular Ca2+, cAMP levels declined significantly in AlCl3-treated rats, followed by abated nuclear translocation of TORC1 and decreased SIRT1, TORC1 and pCREB levels. These results indicate that SIRT1 and TORC1 might play an important mediating role in Al-induced LTM impairment.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-21T04:15:40.848701-05:
      DOI: 10.1111/bcpt.12798
  • A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in
           a Hospital-wide Population of Patients Receiving Conventional Dosing: Is
    • Authors: Federico Pea; Pier Giorgio Cojutti, Massimo Baraldo
      Abstract: A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (Cmin) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of Cmin was set between 2 and 7 mg/L (under-exposure, Cmin < 2 mg/L; over-exposure, Cmin > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid Cmin. One thousand forty-nine patients had 2484 linezolid Cmin assessed during treatment with conventional doses. Median (IQR) linezolid Cmin was 5.08 mg/L (2.78 – 8.52 mg/L). Linezolid Cmin were within the desired range in 50.8% of cases (1262/2484). Over-exposure (n=821; 33%) occurred much more frequently than under-exposure (n=401;16.2%), and was severe (> 20 mg/L) in 3.9% of cases (98/2484). Linezolid over-exposure was significantly associated with CrCLC-G estimates ≤ 40 mL/min (OR 1.463; 95% CI 1.124 – 1.904, P = 0.005). Linezolid under-exposure resulted significantly associated with CrCLC-G estimates > 100 mL/min (OR 3.046; 95% CI 2.234 – 4.152, P < 0.001. Linezolid Cmin was not correlated linearly to CrCLC-G (R2 = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid Cmin variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-17T03:05:52.007671-05:
      DOI: 10.1111/bcpt.12797
  • Therapeutic Drug Monitoring of Venlafaxine in an Everyday Clinical
           Setting: Analysis of Age, Sex and Dose Concentration Relationships
    • Authors: Morten Rix Hansen; Ida Berglund Kuhlmann, Anton Pottegård, Per Damkier
      Abstract: Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we identified all adults for whom the treating physician had requested clinical advice on the TDM result for venlafaxine between 2002 and 2012. We identified 1,077 TDM samples of venlafaxine from 334 males and 743 females (median age 45 years), and the median daily dose was 225 mg. Median plasma concentration of venlafaxine and o-desmethyvenlafaxine (ODV) were 306 nmol/L and 861 nmol/L, respectively. The median dose-corrected serum level for venlafaxine was 1.49 nmol/L/mg., while the dose-corrected serum level of men and women were 1.21 nmol/L/mg and 1.60 nmol/L/mg, respectively. The dose-corrected sum of venlafaxine and ODV was 8.91 nmol/L/mg (IQR 6.56-12.26) versus 5.52 nmol/L/mg (IQR 4.16-7.52) for patients above 64 years and below the age of 65 years, respectively. Dose-corrected plasma concentrations of venlafaxine and ODV are increased to a clinically significant degree in patients above the age of 64, and initiation of venlafaxine therapy in the elderly should be made cautiously and supported by drug measurements.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-11T02:25:28.363702-05:
      DOI: 10.1111/bcpt.12796
  • Matrix Metalloproteinase (MMP)-2 Activity is Associated with Divergent
           Regulation of Calponin-1 in Conductance and Resistance Arteries in
           Hypertension-Induced Early Vascular Dysfunction and Remodelling
    • Authors: Juliana M. Parente; Camila A. Pereira, Gustavo H. Oliveira-Paula, José Eduardo Tanus-Santos, Rita C. Tostes, Michele M. Castro
      Abstract: Matrix metalloproteinase (MMP)-2 participates in hypertension-induced maladaptive vascular remodelling by degrading extra and intracellular proteins. The consequent extracellular matrix rearrangement and phenotype switch of vascular smooth muscle cells (VSMC) lead to increased cellular migration and proliferation. As calponin-1 degradation by MMP-2 may lead to VSMC proliferation during hypertension, the hypothesis of this study is that increased MMP-2 activity contributes to early hypertension-induced maladaptive remodelling in conductance and resistance arteries via regulation of calponin-1. The main objective was to analyse whether MMP-2 exerts similar effects on the structure and function of the resistance and conductance arteries during early hypertension. Two-kidney, one-clip (2K-1C) hypertensive male rats and corresponding controls were treated with doxycycline (30 mg/kg/day) or water until reaching one week of hypertension. Systolic blood pressure (SBP) was increased in 2K-1C rats and doxycycline did not reduce it. Aortas and mesenteric arteries were analysed. MMP-2 activity and expression were increased in both arteries and doxycycline reduced it. Significant hypertrophic remodelling and VSMC proliferation were observed in aortas but not in mesenteric arteries of 2K-1C rats. The contractility of mesenteric arteries to phenylephrine was increased in 2K-1C rats and doxycycline prevented this alteration. The potency of phenylephrine to contract aortas of 2K-1C rats was increased and doxycycline decreased it. Whereas calponin-1 expression was increased in 2K-1C mesenteric arteries, calponin-1 was reduced in aortas. Doxycycline treatment reverted changes in calponin-1 expression. MMP-2 contributes to hypertrophic remodelling in aortas by decreasing calponin-1 levels, which may result in VSMC proliferation. On the other hand, MMP-2-dependent increased calponin-1 in mesenteric arteries may contribute to vascular hypercontractility in 2K-1C rats. Divergent regulation of calponin-1 by MMP-2 may be an important mechanism that leads to maladaptive vascular effects in hypertension.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T07:06:05.206976-05:
      DOI: 10.1111/bcpt.12787
  • Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling
           Pathway in Autoimmune Hepatitis with Failure of Standard Treatment
    • Authors: Peter Lykke Eriksen; Martin Kreutzfeldt, Henning Grønbæk, Kasper Thorsen, Søren Vang, Niels Jessen, Hendrik Vilstrup
      Abstract: The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants.Fifty-six consecutive patients with AIH (41 female and 15 male; median age 42 years (12-76)) were retrospectively stratified according to being responders to standard therapy (n=33) or patients with failure of standard therapy (n=23). Their blood DNA was exome-captured and sequenced. Genomic variants were filtered and compared between the groups using Ingenuity Variant Analysis (3.1.20150407)The exome sequencing and data processing revealed glucocorticoid receptor signalling to be the most prominently affected pathway among the patients with failure of standard therapy (highly significant). Standard treatment failure was not associated with thiopurine S-methyltransferase variants or the HLA-DRB1*03 genotype.In conclusion, enrichment of variants related to glucocorticoid receptor signalling was a particular genomic trait of the AIH patients in whom standard treatment failed and alternative immunosuppression was required. If confirmed, a future application of this finding may be to identify prospective cases of failure of standard treatment already at diagnosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T06:55:46.924306-05:
      DOI: 10.1111/bcpt.12788
  • Apoptosis, Dysbiosis and Expression of Inflammatory Cytokines are
           Sequential Events in the Development of 5-Fluorouracil-induced Intestinal
           Mucositis in Mice
    • Authors: Nahla Hamouda; Tatsushi Sano, Yosuke Oikawa, Toru Ozaki, Masaki Shimakawa, Kenjiro Matsumoto, Kikuko Amagase, Kazuhide Higuchi, Shinichi Kato
      Abstract: The chemotherapeutic agent 5-fluorouracil (5-FU) causes intestinal mucositis with severe diarrhoea but the pathogenesis is not fully understood. In the present study, we investigated the pathogenic effects of 5-FU in mice, focusing on apoptosis, enterobacteria and inflammatory cytokines. Repeated administration of 5-FU caused severe intestinal mucositis on day 6, accompanied by diarrhoea and body weight loss. TNF-α expression increased one day after exposure to the drug, and spiked a second time on day 4, at which point myeloperoxidase activity and IL-1β expression also increased. Apoptotic cells were observed in intestinal crypts only on day 1. 5-FU also induced dysbiosis, notably decreasing the abundance of intestinal Firmicutes while increasing the abundance of Bacteroidetes and Verrucomicrobia. Twice-daily co-administration of oral antibiotics significantly reduced the severity of intestinal mucositis and dysbiosis, and blocked the increase in myeloperoxidase activity and cytokine expression on day 6, without affecting apoptosis and TNF-α upregulation on day 1. In cultured colonic epithelial cells, exposure to 5-FU also upregulated TNF-α expression. Collectively, the data suggest that crypt apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of intestinal mucositis after exposure to 5-FU. In particular, 5-FU appears to directly induce apoptosis via TNF-α and to suppress intestinal cell proliferation, thereby resulting in degradation of the epithelial barrier, as well as in secondary inflammation mediated by inflammatory cytokines.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:31:05.911109-05:
      DOI: 10.1111/bcpt.12793
  • PPARα Activation Suppresses Cytochrome P450 Induction Potential in Mice
           Treated with Gemfibrozil
    • Authors: Cunzhong Shi; Luo Min, Julin Yang, Manyun Dai, Danjun Song, Huiying Hua, Gangming Xu, Frank J. Gonzalez, Aiming Liu
      Abstract: Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in Cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than that in wild-type mice. So, gemfibrozil induced CYP and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:31:00.285252-05:
      DOI: 10.1111/bcpt.12794
  • Mathematical Modelling of Glucose-Dependent Insulinotropic Polypeptide and
           Glucagon-like Peptide-1 following Ingestion of Glucose
    • Authors: Rikke M. Røge; Jonatan I. Bagger, Oskar Alskär, Niels R. Kristensen, Søren Klim, Jens J. Holst, Steen H. Ingwersen, Mats O. Karlsson, Filip K. Knop, Tina Vilsbøll, Maria C. Kjellsson
      Abstract: The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semi-mechanistic model describing the release of GIP and GLP-1 following ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:15:38.245696-05:
      DOI: 10.1111/bcpt.12792
  • Angiotensin II Receptor Blockers Inhibit the Generation of
           Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9,
           CYP2J2 and Human Liver Microsomes
    • Authors: Asuna Senda; Yuji Mukai, Toru Hayakawa, Yuka Kato, Erik Eliasson, Anders Rane, Takaki Toda, Nobuo Inotsume
      Abstract: Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), have cardioprotective effects including anti-inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2, and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50) of AA metabolism was losartan < telmisartan < irbesartan < candesartan < olmesartan < valsartan via CYP2C9, and telmisartan < irbesartan < olmesartan < losartan < candesartan and valsartan via CYP2J2. The order for the HLMs was losartan < telmisartan < irbesartan < olmesartan < candesartan < valsartan. Some ARBs having lower concentration of IC50 indicate that these ARBs might inhibit the AA metabolism in the liver.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:11:02.808987-05:
      DOI: 10.1111/bcpt.12789
  • Comparative Analysis of the Suspected Heparin-Induced Thrombocytopenia
           Level in Korea
    • Authors: Hun-Sung Kim; Hyunah Kim, Yoo Jin Jeong, Hyunyong Lee, Hyeon Woo Yim, Ji il Kim, In Sung Moon, Jang-Yong Kim
      Abstract: The primary objective of our study was to evaluate the frequency of suspected heparin-induced thrombocytopenia (HIT) among patients treated with different formulations of heparin and investigate the factors that affect the incidence of HIT. This study is an electronic medical record (EMR)-based large-scale retrospective cohort study conducted from 2009 to 2014 in Korea. After hospitalization, patient platelet count was determined before heparin was prescribed, and all platelet count values obtained during hospitalization were extracted. Suspected HIT was estimated by three 4Ts scores (acute thrombocytopenia, timing onset and other possible causes), which when combined yielded a high probability of HIT. Among 6046 patients enrolled in this study, HIT was suspected in 641 cases (10.6%) and a statistically significant increase in HIT incidence rate was observed for three heparins used (p < 0.001). Dalteparin (HR=0.55, p=0.036) and enoxaparin (HR=0.40, p
      PubDate: 2017-04-04T05:10:38.563688-05:
      DOI: 10.1111/bcpt.12791
  • Human BJ Fibroblasts is an Alternative to Mouse BALB/c 3T3 Cells in In
           Vitro Neutral Red Uptake Assay
    • Authors: Marika Mannerström; Tarja Toimela, Jertta-Riina Sarkanen, Tuula Heinonen
      Abstract: The OECD GD 129 BALB/c 3T3 Neutral Red Uptake (NRU) assay is a standardized test method for estimating starting dose for an acute oral systemic toxicity test in rodents. Mouse BALB/c 3T3 fibroblasts are the most commonly used cells in the NRU assay. We have previously transferred and validated BALB/c 3T3 NRU assay in our GLP laboratory. Subsequently, in order to obtain more human relevant cytotoxicity data, we performed an intra-laboratory validation using human BJ fibroblasts in the NRU assay instead of mouse BALB/c 3T3 fibroblasts. Here, we present comparative cytotoxicity data of 26 different test chemicals (pharmaceuticals, industrial chemicals, pesticides and food additives) produced with both BALB/c 3T3 NRU and BJ NRU assays.There were marked differences between these two fibroblasts in their sensitivity to predict cytotoxicity. 46% of the chemicals studied (acetone, acetyl salicylic acid, boric acid, carbamazepine, cupric sulfate pentahydrate, dichlorvos, mercury II chloride, octyl gallate, 2-propranol, sorbic acid and valporic acid) were more toxic to mouse BALB/c 3T3 than to human BJ fibroblasts, 19% (acryl amide, amitriptyline HCl, digoxin, oxytetracycline and propranol) were more toxic to human than to mouse fibroblasts and 23% (sodium selenite, sodium fluoride, sodium dichromate dehydrate, sodium arsenite, nicotine, lithium carbonate and bishenol A) showed equal toxicity to both cells types. Lindane and acetaminophen were only toxic to mouse fibroblasts whereas potassium cyanide exhibited toxicity only to human fibroblasts. The IC50 values of test chemicals in the BJ NRU assay correlated much better with the literature human data (r=0.882 and r=0.788, for TDLo and LDLo, respectively) than did the IC50 values of the same test chemicals in the BALB/c 3T3 assay (r=0.428) proposing that human BJ fibroblast assay could be a potential test to be used to predict acute cytotoxicity of chemicals in humans.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:10:36.997945-05:
      DOI: 10.1111/bcpt.12790
  • Inhibitory Effects of Urothelium-related Factors
    • Authors: Na N. Guan; Lars E. Gustafsson, Karl Svennersten
      Abstract: The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium-derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor, cyclo-oxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD2 from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD2 was found to have an inhibitory influence on nerve-induced contractions in guinea pig urinary bladder and on spontaneous contractions in the outflow region.An altered release of excitatory and inhibitory factors is likely to play an important part of bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-02T20:20:26.144637-05:
      DOI: 10.1111/bcpt.12785
  • Ivabradine: Current and Future Treatment of Heart Failure
    • Authors: Lene Thorup; Ulf Simonsen, Daniela Grimm, Elise Røge Hedegaard
      Abstract: In heart failure (HF), the heart cannot pump blood efficiently and is therefore unable to meet the body's demands of oxygen, and/or there is increased end diastolic pressure. Current treatments for heart failure with reduced ejection fraction (HFrEF) include angiotensin-converting enzyme (ACE)-inhibitors, angiotension receptor type 1 (AT1) antagonists, β-adrenoceptor-antagonists, aldosterone receptor antagonists, diuretics, digoxin and a combination drug with AT1 receptor antagonist and neprilysin inhibitor. In HF, the risk of readmission for hospital and mortality is markedly higher with a heart rate above than below 70 beats per minute. Here, we review the evidence regarding the use of ivabradine for lowering heart rate in HF. Ivabradine is a blocker of an I funny current (I(f)) channel and causes rate-dependent inhibition of the pacemaker activity in the sinoatrial node. In clinical trials of HFrEF, treatment with ivabradine seems to improve clinical outcomes, e.g. improved ejection fraction and less readmission for hospital, but the effect appears most pronounced in patients with heart rates above 70 beats per minute, while the effect on cardiovascular death appears less consistent. The adverse effects of ivabradine include bradycardia, atrial fibrillation, and visual disturbances, but ivabradine avoids the negative inotrope effects observed with β-adrenoceptor antagonists. In conclusion, in patients with stable HFrEF with EF
      PubDate: 2017-04-02T06:35:26.117997-05:
      DOI: 10.1111/bcpt.12784
  • Targeting Tankyrase to Fight WNT-dependent Tumours
    • Authors: Tor Espen Thorvaldsen
      Abstract: Aberrant WNT signalling activity is linked to various diseases due to the WNT dependency of fundamental processes during development and in adult tissue homeostasis. Mutations in components of the multiprotein β-catenin destruction complex promote excessive amounts of the main transcriptional activator β-catenin and are particularly common in colorectal cancer (CRC). The tankyrase enzymes were recently implicated as negative regulators of destruction complex activity by mediating degradation of the scaffolding protein AXIN. Indeed, tankyrase inhibitors (TNKSi) have emerged as promising therapeutics by restoring functional signal-limiting destruction complexes in CRCs. Furthermore, as TNKSi-induced destruction complexes (so-called degradasomes) can be visualized by microscopy, they have served as a valuable experimental model system to address unresolved aspects regarding the structure, function and composition of the β-catenin destruction complex. This MiniReview provides an overview of the current knowledge on the regulatory mechanisms and interactions that govern the β-catenin destruction complex activity. It further highlights the potential of TNKSi as anti-cancer drugs and as a novel research tool to dissect the WNT signalling pathway.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-02T06:35:23.841733-05:
      DOI: 10.1111/bcpt.12786
  • Essential Medicines List Implementation Dynamics: A Case Study using
           Brazilian Federal Medicines Expenditures
    • Authors: Rachel Magarinos-Torres; Larry David Lynd, Tatiana Chama Borges Luz, Paulo Eduardo Potyguara Coutinho Marques, Claudia Garcia Serpa Osorio-de-Castro
      Abstract: The aim was to analyse the implementation dynamics of the Essential Medicines List (EML). We used the government expenditures on medicines and Brazil as a case study. Drug purchases were considered as a proxy for utilization. The essential medicines (EMs) expenditures were followed over time by Brazilian National EMLs lifetime and defined by broad therapeutic categories and by specific medicines. Brazil increased the number of the EMs during the last four editions of your Brazilian National EMLs and the federal government expenditures on them. The EML implementation dynamics changed the distribution of expenditures on EMs. We identified a common set of 404 EMs present in all four editions of the Brazilian National EMLs. There was a proportional decrease in expenditures on anti-infectives for systemic use, blood and blood-forming organs and alimentary tract and metabolism, and increase in expenditures on antineoplastic and immunomodulating agents. The expenditures distribution per specific medicines revealed that a small set of essential medicines was responsible for 50% or more of expenditures considering Brazilian National EML lifetime for all four periods. The increase in expenditures on EMs in Brazil was a consequence of the newer medicines incorporated over time in the Brazilian National EMLs. The use of the medicines expenditures as a source of data and the definition of an EML lifetime permitted follow-up of the implementation dynamics of different versions of the Brazilian National EMLs. Our results have implications for policy-makers and stakeholders to gain a better understanding of the role EMLs play in health system sustainability and in the provision of the most beneficial heath care.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T12:14:30.284597-05:
      DOI: 10.1111/bcpt.12783
  • Effects of Nano-Graphene Oxide on Testis, Epididymis and Fertility of
           Wistar Rats
    • Authors: Naresh Kumar Nirmal; Kumud Kant Awasthi, Placheril Joseph John
      Abstract: Nanoscale graphene oxide (NGO) has great potential in biomedicine by the virtue of its facile functionalization and tunable characteristics. Toxicity assessments have, therefore, become essential prior to its biomedical applications. The present study examined the effects of NGO exposure on male reproductive function of adult Wistar rats. Rats were exposed intraperitoneally to three increasing doses, namely low (0.4 mg/kg BW), mid (2.0 mg/kg BW) and high (10.0 mg/kg BW) dose of NGO. Repeated exposure of NGO for 15 and 30 days resulted in decreased epididymal sperm counts and elevated sperm abnormalities. Percentage of motile sperms was also significantly reduced due to the exposure. Activities of SOD, GPx and malondialdehyde concentration in testes increased in a dose-specific manner. Results of the study demonstrated that high-dose NGO (10.0 mg/kg BW) resulted in considerable histological damage to testicular tissue which included atrophy of seminiferous tubules with reduction in germinal epithelium, germ cell loss and vacuolization. Low and mid doses of NGO were not associated with sperm dysfunction or testis damage. Withdrawal of treatment for 30 days demonstrated significant recovery potential. Histology of epididymis and male fertility potential were not affected due to the NGO exposure. These findings are important for assessment of the risk involved in manufacturing, use and processing of the graphene oxide-based materials towards male reproductive function.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T12:14:27.931488-05:
      DOI: 10.1111/bcpt.12782
  • Population Exposure to Phthalate-Containing Drugs
    • Authors: Anne Broe; Zandra Nymand Ennis, Anton Pottegård, Jesper Hallas, Thomas Ahern, Per Damkier
      Abstract: Phthalates are known endocrine disruptors. Not commonly recognised, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate-containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the ‘defined daily dose’ (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1,000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethylphthalate (DEP) and dibutylphthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate-containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low-molecular-weight phthalates and three high-molecular-weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1,000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multienzymes (24.6-32.8 mg per DDD) and mesalazine (12.5-26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate-containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T07:36:06.239346-05:
      DOI: 10.1111/bcpt.12781
  • The Effect of Desmopressin on the Amount of Bleeding and Transfusion
           Requirements in Patients undergoing Heart Transplant Surgery
    • Authors: Alireza Jahangirifard; Mohammad Reza Razavi, Zargham Hosein Ahmadi, Mohammad Forozeshfard
      Abstract: One of the most common risks after a heart transplant is bleeding. In this study, the effect of desmopressin administration on the amount of bleeding and transfusion requirements following heart transplant surgery was investigated.In a double-blind clinical trial, 48 patients who were candidates for heart transplant surgery were randomly assigned to two groups. In the intervention group, patients received desmopressin 0.3 μg/kg, 30 min. before surgery. Patients in the control group received normal saline at the same amount and time. Homeostasis was evaluated using activated clotting time (ACT), PT, PTT and PLT before, 12 and 24 hr after surgery, and also, chest tube drainage, blood products transfusion requirements during the first day in both groups.No significant differences were found between the groups in terms of ACT, PT, PTT and PLT at all times. Transfusion of packed red blood cells and the mean drainages of chest tube during the first 24 hr after surgery were significantly lower in the desmopressin group compared to the saline group.Desmopressin may reduce postoperative bleeding in patients undergoing heart transplant surgery. Further studies are required to confirm the potential effect of desmopressin on establishing hemostasis following heart transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-22T02:55:44.616845-05:
      DOI: 10.1111/bcpt.12780
  • Baclofen and Alcohol-dependent Patients: A Real Risk of Severe
    • Authors: David Boels; Caroline Victorri-Vigneau, Marie Grall-Bronnec, Ali Touré, Anais Garnier, Alain Turcant, Gaël Le Roux
      Abstract: Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, since baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders and psychiatric illnesses determine predictors of severity.This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014.111 cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39±12). Poisoning severities were: “null” (9 cases), “minor” (37 cases), “moderate” (19 cases) and “high” (46 cases, including 4 deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR=2.9; p=0.03).Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-19T20:16:07.669889-05:
      DOI: 10.1111/bcpt.12779
  • Development of a Robust Mammalian Cell-based Assay for Studying
           Recombinant α4β1/3δ GABAA Receptor Subtypes
    • Authors: Christina B. Falk-Petersen; Rikke Søgaard, Kenneth L. Madsen, Anders B. Klein, Bente Frølund, Petrine Wellendorph
      Abstract: δ-Containing GABAA receptors are located extrasynaptically and mediate tonic inhibition. Their involvement in brain physiology positions them as interesting drug targets. There is thus a continued interest in establishing reliable recombinant expression systems for δ-containing GABAA receptors. Inconveniently, the recombinant expression of especially α4β1/3δ receptors has been found to be notoriously difficult, due to mixed receptor populations and/or stoichiometries and differential pharmacology depending on the expression system used. With the aim of developing a facile and robust 96-well format cell-based assay for extrasynaptic α4β1/3δ receptors, we have engineered and validated a HEK293 Flp-In™ cell line stably expressing the human δ-subunit. Upon co-transfection of α4 and β1/3 subunits, at optimized ratios, we have established a well-defined system for expressing α4β1/3δ receptors and used the fluorescence-based FLIPR Membrane Potential (FMP) assay to evaluate their pharmacology. Using the known reference compounds GABA and THIP, ternary α4β1/3δ and binary α4β1/3 receptors could be distinguished based on potency and kinetic profiles but not efficacy. As expected, DS2 was able to potentiate only δ-containing receptors, whereas Zn2+ had an inhibitory effect only at binary receptors. By contrast, the hitherto reported δ-selective compounds, AA29504 and 3-OH-2'MeO6MF were non-selective. The expression system was further validated using patch clamp electrophysiology, in which the superagonism of THIP was confirmed. The established FMP assay setup, based on transient expression of human α4 and β1/3 subunits into a δ-subunit stable HEK293 Flp-In™ cell line, portrays a simple 96-well format assay as a useful supplement to electrophysiological recordings on δ-containing GABAA receptors.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-16T02:25:58.962503-05:
      DOI: 10.1111/bcpt.12778
  • 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) were found to have greater AUC0–2 hr 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 haemoglobin 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.
      PubDate: 2017-03-15T04:00:39.218286-05:
      DOI: 10.1111/bcpt.12727
  • Triggering Mechanisms and Inflammatory Effects of Combustion Exhaust
           Particles with Implication for Carcinogenesis
    • Authors: Johan Øvrevik; Magne Refsnes, Marit Låg, Bendik C. Brinchmann, Per E. Schwarze, Jørn 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 and non-genotoxic implications and is considered to play a central role in development of various health outcome 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.
      PubDate: 2017-03-15T03:50:31.751807-05:
      DOI: 10.1111/bcpt.12746
  • Neonatal Exposure to Endocrine Disrupting Chemicals Impairs Learning
           Behaviour by Disrupting Hippocampal Organization in Male Swiss Albino Mice
    • Authors: Rakesh Bhaskar; Ashish K. Mishra, Banalata Mohanty
      Abstract: Hippocampus is highly susceptible to endocrine disrupting chemicals exposure particularly during the critical phase of brain development. In this study, mice offspring were exposed to endocrine disruptors mancozeb (MCZ) and imidacloprid (IMI) individually (40 mg MCZ and 0.65 mg IMI/kg/day) as well as to their equimixture (40 mg MCZ + 0.65 mg IMI/kg/day) through the diet of lactating mothers from post-natal day (PND) 1 to PND 28. Half of the randomly selected male offspring were killed at PND 29, and the rest half were left unexposed and killed at PND 63. Brain weight, histology, plasma hormone profile and working memory performance were the various end-points studied. Brain weight was significantly decreased in the mixture-exposed group at PND 29, which persisted to PND 63. Total thickness of pyramidal cell layers decreased significantly along with misalignment, shrinkage and degeneration of pyramidal neurons in CA1 and CA3 regions of the IMI and mixture-exposed groups. The length and branch points of dendrites of pyramidal neurons were decreased significantly in mixture-exposed group at both PND 29 and PND 63. Dendritic spine density was also reduced in mixture-exposed group offspring. Testosterone level was significantly decreased only at PND 29, but corticosterone level was increased at both PND 29 and PND 63 in mixture-exposed offspring. T-maze task performance revealed significantly increased time duration and reduced path efficiency in mixture-exposed group offspring. The results thus indicate that pesticide mixture exposure could lead to changes in learning behaviour even at doses that individually did not induce any adverse effect on hippocampal organization.
      PubDate: 2017-03-15T03:21:28.668792-05:
      DOI: 10.1111/bcpt.12767
  • Shortage of Digitoxin and Switching to Digoxin in Norway: A Retrospective
           Study of Blood Samples Submitted to a Clinical Pharmacology Laboratory
    • Authors: Jan Schjøtt; Hilde Marie Torgauten, Tormod Karlsen Bjånes
      PubDate: 2017-03-15T03:21:19.14758-05:0
      DOI: 10.1111/bcpt.12770
  • 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 physicochemical 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 extracellular 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.
      PubDate: 2017-03-15T03:21:17.834737-05:
      DOI: 10.1111/bcpt.12698
  • Naloxone Antagonizes 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 antagonized 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 antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors.
      PubDate: 2017-03-15T03:21:11.632166-05:
      DOI: 10.1111/bcpt.12745
  • Ticagrelor Compared with Clopidogrel Increased Adenosine and Cyclic
           Adenosine Monophosphate Plasma Concentration in Acute Coronary Syndrome
    • Authors: Xiaoye Li; Qibing Wang, Ying Xue, Jiahui Chen, Qianzhou 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 patients with acute coronary syndrome (ACS) 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 patients with ACS.
      PubDate: 2017-03-14T01:10:59.490427-05:
      DOI: 10.1111/bcpt.12752
  • 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.
      PubDate: 2017-03-14T01:10:57.670623-05:
      DOI: 10.1111/bcpt.12743
  • Mass Spectrometry-Based Tools to Characterize DNA–Protein
           Cross-Linking by Bis-Electrophiles
    • 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 to 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 after 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 also 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.
      PubDate: 2017-03-14T01:10:51.375551-05:
      DOI: 10.1111/bcpt.12751
  • 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. A total of 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 < 0.001). An allele frequency of this single nucleotide polymorphism was high in non-responders; its odds ratio was 2.92 compared with G allele (p < 0.001). PRU values of CT genotypes were lower (p = 0.029) and % inhibition values of CT genotypes were higher (p = 0.008) compared with CC genotypes for the CYP2C19*17 (C806T) polymorphism. None of the other genetic variants were found to be statistically associated with non-responsiveness to clopidogrel and antiplatelet activity. Our findings suggest that the CYP2C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2C19*17 polymorphism enhances antiplatelet activity of clopidogrel. Depending on haplotypes of these two polymorphisms, clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events.
      PubDate: 2017-03-14T01:10:34.378698-05:
      DOI: 10.1111/bcpt.12763
  • Genetic Influences of OPRM1, OPRD1 and COMT on Morphine Analgesia in a
           Multi-Modal, Multi-Tissue Human Experimental Pain Model
    • Authors: Lecia M. Nielsen; Lona L. Christrup, Hiroe Sato, Asbjørn M. Drewes, Anne E. 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 whether 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 randomized, double-blind, two-way, crossover, 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.
      PubDate: 2017-03-14T01:10:31.922313-05:
      DOI: 10.1111/bcpt.12757
  • The European Environmental Mutagenesis and Genomics Society Annual
           Meeting, 14–18 August 2016, Copenhagen, Denmark
    • Authors: Jørn A. Holme; Roland Froetschl, Lisbeth E. Knudsen
      PubDate: 2017-03-14T01:10:27.78869-05:0
      DOI: 10.1111/bcpt.12750
  • Synergistic Combination for Chemoprevention of Hepatocellular Carcinoma:
           An In Silico and In Vitro Approach
    • Authors: Savita Mishra; Deepshikha Pande Katare
      Abstract: Combination therapy is one of the best methods to manage the fatality rate in hepatocellular carcinoma (HCC). This 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 5 μM 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.
      PubDate: 2017-03-10T10:35:07.496489-05:
      DOI: 10.1111/bcpt.12730
  • Evaluation of DNA Damage in HepG2 Cells and Mutagenicity of
           Garcinielliptone FC, A Bioactive Benzophenone
    • Authors: Lismare Silva Prado; Juliana 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 colorimetric 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 2–30 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.
      PubDate: 2017-03-10T10:33:12.54689-05:0
      DOI: 10.1111/bcpt.12753
  • Statin Use Correlates with Reduced Risk of Pyogenic Liver Abscess: A
           Population-based Case-Control Study
    • Authors: Kuan-Fu Liao; Kao-Chi Cheng, Cheng-Li Lin, Shih-Wei Lai
      Abstract: Little research is available on the relationship between statin use and pyogenic liver abscess. The objective of the study was to determine whether prior use of statins is associated with pyogenic liver abscess. This case-control study was conducted to analyse the claim data of the Taiwan National Health Insurance Program. There were 1828 participants aged 20 to 84 years with first-episode of pyogenic liver abscess from 2000 to 2013 as the cases and 1828 randomly selected participants without pyogenic liver abscess matched with sex, age and index year as the controls. Statin use was defined as ‘current’, ‘recent’ or ‘past’ if the statin prescription was filled ≤3 months, 3-6 months or>6 months before the date of pyogenic liver abscess diagnosis, respectively. Relative risk of pyogenic liver abscess associated with statin use was estimated by the odds ratio (OR) with 95% confidence interval (CI) using the multivariable logistic regression model. After controlling for potential confounders, the adjusted ORs of pyogenic liver abscess were 0.65 for participants with current use of statins (95% CI 0.50, 0.84), 0.74 for participants with recent use of statins (95% CI 0.49, 1.11), and 1.10 for participants with past use of statins (95% CI 0.90, 1.34), compared with participants with never use of statins. In the further analysis, the adjusted ORs of pyogenic liver abscess were 0.65 for participants with cumulative duration of statin use ≥12 months (95% CI 0.48, 0.88) and 0.68 for participants with cumulative duration of statin use
      PubDate: 2017-03-08T13:25:32.015997-05:
      DOI: 10.1111/bcpt.12777
  • Associations of CYP2C9 and CYP2A6 Polymorphisms with the Concentrations of
           Valproate and its Hepatotoxin Metabolites and VPA-Induced Hepatotoxicity
    • Authors: Mingming Zhao; Ti Zhang, Guofei Li, Feng Qiu, Yaxin Sun, Limei Zhao
      Abstract: The aim of this study was to compare genetic polymorphisms and concentrations of hepatotoxic metabolites in patients with epilepsy and liver injury and those with normal liver function receiving valproate monotherapy to identify risk factors for VPA-induced hepatotoxicity. A total of 279 Chinese patients with epilepsy were divided into an abnormal liver function (ANLFT) group (n=79) and a normal liver function (NLFT) group (n=200). PCR-RFLP, nested-PCR and direct sequencing were applied to identify the frequency of 8 SNPs in candidate genes. Serum concentrations of VPA and its major metabolites were determined by UPLC-MS/MS. Significant differences were found in genotype distributions of CYP2A6 and CYP2C9 between the two groups. The values of 4-ene-VPA and 2, 4-diene-VPA in the ANLFT group were significantly higher than in the NLFT group. Only CYP2A6 polymorphisms had associations with the concentrations of 4-ene-VPA and 2, 4-diene-VPA. CYP2A6*1/*4 and CYP2A6*4/*4 variant carriers had higher CDR4-ene-VPA and CDR2, 4-diene-VPA values than CYP2A6*1/*1 carriers. The logistic regression analysis showed that CYP2C9 and CYP2A6 were significant risk factors for hepatotoxicity by increasing the risk by 7.50- and 5.13-fold, respectively. These findings provide preliminary evidence that CYP2A6 and CYP2C9 are associated with hepatotoxicity. However, only the CYP2A6 polymorphism was found to be associated with concentrations of 4-ene-VPA and 2, 4-diene-VPA. Potential important risk factors include mutated genotypes of CYP2C9 and CYP2A6, and higher concentrations of VPA, 4-ene-VPA and 2, 4-diene-VPA.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-08T13:25:28.71759-05:0
      DOI: 10.1111/bcpt.12776
  • 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% versus 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.
      PubDate: 2017-03-08T02:35:36.87056-05:0
      DOI: 10.1111/bcpt.12762
  • Modification of the Fc Region of a Human Anti-oncostatin M Monoclonal
           Antibody for Higher Affinity to FcRn Receptor and Extension of Half-life
           in Cynomolgus Monkeys
    • Authors: Ivo P. Nnane; Chao Han, Qun Jiao, Susan H. 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 per group). 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 per group). 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 mL/day/kg, volume of distribution of central compartment (V1) = 31.3 mL/kg, volume of distribution of peripheral compartment (V2) = 23.3 mL/kg, 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 mL/day/kg, V1 = 39.8 mL/kg, V2 = 32.6 mL/kg, 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 after a single IV dose (1–20 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 human beings and may likely allow less frequent dosing in the clinical setting.
      PubDate: 2017-03-08T02:35:35.236986-05:
      DOI: 10.1111/bcpt.12761
  • 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 haemodynamic 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 the 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 the 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 underscore 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.
      PubDate: 2017-03-08T02:10:35.544292-05:
      DOI: 10.1111/bcpt.12754
  • Clinical Pharmacology Research Internships at the Interface between
           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 programme for undergraduate (bio)medical students. The aim of this study was (i) to investigate the student perceptions of the undergraduate research internship and (ii) to quantify the scientific output related to these internships. We surveyed former interns at the CHDR from the year 2007 to 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 per cent 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.
      PubDate: 2017-03-08T02:10:30.638629-05:
      DOI: 10.1111/bcpt.12756
  • 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 demonstrated 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 antifibrotic effect of magnolol on Th17 cell-mediated fibrosis.
      PubDate: 2017-03-07T05:55:39.605324-05:
      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 photoprotective and immunological action, are well recognized. Its antioxidant, anti-inflammatory, immunomodulatory, radioprotective, hepatic, gastrointestinal and hypoglycaemic benefits have only recently been recognized 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.
      PubDate: 2017-03-07T05:55:29.028086-05:
      DOI: 10.1111/bcpt.12748
  • Haemodynamic Influences of Bisoprolol in Hypertensive Middle-Aged Men:
           A Double-Blind, Randomized, Placebo-Controlled Cross-Over Study
    • Authors: Lauri Suojanen; Antti Haring, Antti Tikkakoski, Jenni K. Koskela, Anna M. Tahvanainen, Heini Huhtala, Mika  Kähönen, Kalle Sipilä, Arttu Eräranta, Jukka T. Mustonen, Kari Kivistö, Ilkka H. Pörsti
      Abstract: Treatment with beta-blockers appears to show inferior reduction of central versus peripheral blood pressure. We aimed to examine simultaneous changes in central and peripheral blood pressure, vascular resistance, cardiac function and arterial stiffness during beta-blockade.Haemodynamics were investigated after 3 weeks of bisoprolol treatment (5 mg/d) in a double-blind, randomized, placebo-controlled cross-over trial in never-treated 16 Caucasian males with grade I-II primary hypertension using continuous tonometric pulse wave analysis and whole-body impedance cardiography.Bisoprolol decreased radial (134/80 versus 144/89 mmHg) and aortic blood pressure (122/80 versus 130/90 mmHg) and heart rate (57 versus 68 beats/min) when compared with placebo (p
      PubDate: 2017-03-02T20:30:27.614968-05:
      DOI: 10.1111/bcpt.12771
  • Cis-Nerolidol Induces Endoplasmic Reticulum Stress and Cell Death in Human
           Hepatocellular Carcinoma Cells through Extensive CYP2C19 and CYP1A2
    • Authors: Bruna Isabela Biazi; Thalita Alves Zanetti, Adrivanio Baranoski, Amanda Cristina Corveloni, Mário Sérgio Mantovani
      Abstract: Of late, many studies are attempting to find new molecules with anti-cancer properties, especially those with the capability to inhibit cell growth. The aim of this work was to evaluate nerolidol, a plant-based compound, as its cytotoxicity, genotoxicity, antiproliferative and apoptotic induction, cell cycle, mitochondrial membrane potential, and RT-qPCR of transcripts related to those pathways in the human hepatocellular carcinoma cell line (HepG2/C3A). Only cis-nerolidol (C-NER) demonstrated cytotoxicity (100 to 250 μM) activity and was selected to conduct the following experiments. C-NER did not show genotoxic activity, but altered the mitochondrial membrane potential, reduced cell proliferation by arresting cell cycle in G1 phase and induced cell death. RT-qPCR showed that C-NER down-regulated genes related to apoptosis (BAK1, BAX, CAPN1, CASP8, CASP9, PARP1 and TP53), cell cycle (CCND1, CCNE1, CDK1 and CDK2), xenobiotic metabolism (CYP2D6 and CYP3A4) and paraptosis (IGF1R receptor). Up-regulation was seen in case of genes related to cell survival (BBC3 and MYC) and reticulum stress protein response (EIF2AK3 and ERN1) and xenobiotic metabolism (CYP1A2 and CYP2C19). We deduced that the antiproliferative activity of C-NER is attributable to its modulation of the cyclins and cyclin-dependent kinases as these proteins are necessary for G1/S phase transition. EIF2AK3, ERN1, CYP2C19 and CYP1A2 up-regulation suggests that endoplasmic reticulum stress was induced owing to the increased activity of cytochrome P450 enzymes. Caspase-independent cell death was also observed, indicating that another type of cell death, paraptosis, was triggered. Our results indicate that C-NER has considerable potential in anti-cancer therapy because it modulates important molecular targets of cell survival and proliferation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T20:30:25.399702-05:
      DOI: 10.1111/bcpt.12772
  • Cobalt(II) chloride modifies the phenotype of macrophage activation
    • Authors: Mona Kumanto; Erja-Leena Paukkeri, Riina Nieminen, Eeva Moilanen
      Abstract: Cobalt (Co) is vital for cells in trace amounts, but excessive exposure to Co is possible due to surgical devices such as artificial metal-on-metal joints. Cobalt(II) chloride (CoCl2) has also been shown to imitate hypoxic conditions in cells by stabilizing the transcription factor hypoxia-inducible factor-1α (HIF-1α). The purpose of the present study was to investigate the possible immunomodulatory action of CoCl2 by investigating its effects on the expression of inflammatory genes in macrophages. The following factors were assessed: inducible nitric oxidase synthase (iNOS), NADPH oxidase 2 (NOX2), interleukin 6 (IL-6), arginase-1 and HIF-1α. In the absence of exogenous cytokines, Co enhanced alternative (M2) macrophage activation as evidenced by increased arginase-1 expression, but had no direct effect on inflammatory factors associated with classical (M1) activation. Interestingly, in LPS-stimulated macrophages, Co modified the M1 type activation profile by increasing iNOS expression and nitric oxide production and decreasing NOX2 and IL-6. Also, Co increased HIF-1α levels in unstimulated and LPS-stimulated cells as expected. In conclusion, we showed that Co enhanced alternative (M2) activation in resting macrophages. In addition, Co was found to remodel the classical M1 phenotype of macrophage activation by changing the balance of iNOS, NOX2 and IL-6.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-28T01:30:24.648575-05:
      DOI: 10.1111/bcpt.12773
  • Decrease in Long-Chain Acylcarnitine Tissue Content Determines the
    • Authors: Janis Kuka; Marina Makrecka-Kuka, Helena Cirule, Solveiga Grinberga, Eduards Sevostjanovs, Maija Dambrova, Edgars Liepinsh
      Abstract: Ischaemia in the heart is accompanied by the accumulation of long-chain acylcarnitines (LCACs) which is one of the multiple factors that contribute to the ischaemia-reperfusion damage development. Long-term pre-treatment that decreases carnitine and LCAC contents also reduces ischaemia-reperfusion (IR) damage; however, the duration of the post-treatment effects is not known. The aim of the study was to assess the post-treatment effects of the carnitine transport (OCTN2) inhibitor, methyl-GBB, on LCAC content and the duration of its cardioprotective effect. Male Wistar rats received methyl-GBB (5 mg/kg for 28 days), and the anti-infarction effects on Langendorff-perfused hearts and the acylcarnitine profile in cardiac tissues were measured up to 28 days following the end of the treatment. Methyl-GBB pretreatment for 28 days decreased LCAC heart tissue content by 87%, and the infarct size was decreased by 57%. Fourteen days post-treatment, the LCAC content was still decreased by 69%, and the infarct size was decreased by 32% compared to Control. A significant Pearson correlation (r=0.48, p=0.026) was found between infarct size and LCAC tissue content in the methyl-GBB-treated rat hearts. The addition of 2 mM carnitine to isolated heart perfusate significantly diminished the methyl-GBB-induced decrease in LCACs and infarct size. In conclusion, the anti-infarction effect of methyl-GBB continues for at least 2 weeks post-treatment. No less than a 70% decrease in LCAC content is required to protect ischaemic heart tissues, and the decrease in LCAC levels defines the duration of the post-treatment cardioprotective effect of the OCTN2 inhibitor, methyl-GBB.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-28T01:00:31.51628-05:0
      DOI: 10.1111/bcpt.12775
  • The Choice of Euthanasia Method Affects Metabolic Serum Biomarkers
    • Authors: Pierozan Paula; Jernerén Fredrik, Ransome Yusuf, Karlsson Oskar
      Abstract: The impact of euthanasia methods on endocrine and metabolic parameters in rodent tissues and biological fluids is highly relevant for the accuracy and reliability of the data collected. However, few studies concerning this issue are found in the literature. We compared the effects of three euthanasia methods currently used in animal experimentation (i.e. decapitation, CO2 inhalation, and pentobarbital injection) on the serum levels of corticosterone, insulin, glucose, triglycerides, cholesterol and a range of free fatty acids in rats. The corticosterone and insulin levels were not significantly affected by the euthanasia protocol used. However, euthanasia by an overdose of pentobarbital (120 mg/kg intraperitoneal injection) increased the serum levels of glucose, and decreased cholesterol, stearic and arachidonic acids levels compared with euthanasia by CO2 inhalation and decapitation. CO2 inhalation appears to increase the serum levels of triglycerides, while euthanasia by decapitation induced no individual discrepant biomarker level. We conclude that choice of the euthanasia methods are critical for the reliability of serum biomarkers and indicate the importance of selecting adequate euthanasia methods for metabolic analysis in rodents. Decapitation without anaesthesia may be the most adequate method of euthanasia when taking both animal welfare and data quality in consideration.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-28T01:00:27.123224-05:
      DOI: 10.1111/bcpt.12774
  • Letter to the Editor
    • Authors: Adriana Oller
      PubDate: 2017-02-22T23:00:21.279889-05:
      DOI: 10.1111/bcpt.12760
  • 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 interesting 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 remain in the lung for months or even years after 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 translocate from the alveolar space to the near pulmonary region including lymph nodes, subpleura and pleura (
      PubDate: 2017-02-22T02:22:07.267547-05:
      DOI: 10.1111/bcpt.12705
  • Toxicological Effects during and following Persistent Insulin-Induced
           Hypoglycaemia in Healthy Euglycaemic Rats
    • Authors: Vivi F. H. Jensen; Anne-Marie Mølck, Line O. Berthelsen, Lene Alifrangis, Lene Andersen, Melissa Chapman, Jens Lykkesfeldt, Ingrid B. Bøgh
      Abstract: New insulin analogues with a longer duration of action and a “peakless” pharmacokinetic profile have been developed to improve efficacy, safety and convenience for diabetic patients. During non-clinical development, according to regulatory guidelines, these analogues are tested in healthy euglycaemic rats rendering them persistently hypoglycaemic. Little is known about the effect of persistent (24 hr/day) insulin-induced hypoglycaemia (IIH) in rats, complicating interpretation of results in pre-clinical studies with new longer-acting insulin analogues. In the present study, we investigated the effects of persistent IIH and their reversibility in euglycaemic rats. Histopathological changes in insulin-infused animals included partly reversible axonal and reversible myofibre degeneration in peripheral nerve and skeletal muscle tissue, respectively, as well as reversible pancreatic islet atrophy and partly reversible increase in unilocular adipocytes in brown adipose tissue. Additionally, results suggested increased gluconeogenesis. The observed hyperphagia, the pancreatic, peripheral nerve and skeletal muscle changes were considered related to the hypoglycaemia. Cessation of insulin infusion resulted in transient hyperglycaemia, decreased food consumption and body weight loss before returning to control levels. The implications for the interpretation of non-clinical studies with long-acting insulin analogues are discussed.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-20T15:05:22.797625-05:
      DOI: 10.1111/bcpt.12769
  • Efficacy and Tolerability of an Inhaled Selective Glucocorticoid Receptor
           modulator - AZD5423 - in COPD Patients: Phase II Study Results
    • Authors: Piotr Kuna; Magnus Aurivillius, Carin Jorup, Susanne Prothon, Ziad Taib, Staffan Edsbäcker
      Abstract: AZD5423 is a novel, inhaled, selective glucocorticoid receptor modulator (SGRM), which in an allergen challenge model in asthmatics improved lung function and airway hyper-reactivity. In the current trial, AZD5423 was for the first time tested in patients with chronic obstructive pulmonary disease (COPD).In this double-blind, randomised and parallel group study, we examined airway and systemic effects of two doses of AZD5423, inhaled via Turbuhaler for 12 weeks, in 353 symptomatic COPD patients (average pre-bronchodilator forced expiratory volume in one second (FEV1) at screening was 50-52% of predicted normal). Pre-bronchodilator FEV1 was primary variable, with other lung function parameters plus symptoms and 24-hr plasma cortisol being secondary variables. Plasma concentrations of AZD5423 were also measured. Effects were compared against placebo and a reference glucocorticoid receptor agonist control.Neither AZD5423, at doses which have shown to be efficacious in allergen-induced asthma, nor the reference control, at double the approved dose, had any clinically meaningful effect in the patient population studied in regard to lung function or markers of inflammation. Both GR modulators were well tolerated and did suppress 24-hr cortisol.The present study suggests that the selected population of COPD patients does not respond to treatment with AZD5423 as regards lung function, whilst showing the expected systemic effects. It cannot be ruled out that a favourable lung function response of AZD5423 can be evoked using another experimental setting and/or within a different population of COPD patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-17T13:01:11.925661-05:
      DOI: 10.1111/bcpt.12768
  • 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' Many 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 genomewide 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.
      PubDate: 2017-02-10T04:11:46.263571-05:
      DOI: 10.1111/bcpt.12721
  • 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
  • Modelling Mutation Spectra of Human Carcinogens Using Experimental Systems
    • Authors: Maria Zhivagui; Michael Korenjak, Jiri Zavadil
      Abstract: Mutation spectra in cancer genomes provide information on the disease aetiology and the causality underlying the evolution and progression of cancer. Genome-wide mutation patterns reflect the effects of mutagenic insults and can thus reveal past carcinogen-specific exposures and inform hypotheses on the causative factors for specific cancer types. To identify mutation profiles in human cancers, single-gene 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 become revealed on a large scale, in human primary tumours and in experimental models, enabling deeper investigations of the functional and structural impact of 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.
      PubDate: 2017-02-03T03:30:27.970513-05:
      DOI: 10.1111/bcpt.12690
  • 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 1241 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.
      PubDate: 2017-01-30T04:00:51.517801-05:
      DOI: 10.1111/bcpt.12755
  • 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 outcome, 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 2 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 times. Dimercaptopropane sulphonate 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.
      PubDate: 2017-01-17T23:35:32.477178-05:
      DOI: 10.1111/bcpt.12725
  • A Novel Scale Linking Potency and Dosage to Estimate Anticholinergic
           Exposure in Older Adults: the Muscarinic Acetylcholinergic Receptor
           ANTagonist Exposure 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 authoritative 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 three 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 and 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 system on the list of anticholinergic and proposed anticholinergic potency and dosage values is advised.
      PubDate: 2017-01-16T00:25:55.06562-05:0
      DOI: 10.1111/bcpt.12699
  • An Adductomic Approach to Identify Electrophiles In Vivo
    • Authors: Henrik Carlsson; Margareta Törnqvist
      Abstract: Human beings 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 Mini-Review focuses on the development and application of an adductomic approach for the screening of unknown adducts to N-terminal valine (Val) in haemoglobin (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 six 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.
      PubDate: 2017-01-11T00:55:30.184559-05:
      DOI: 10.1111/bcpt.12715
  • 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, there is sufficient evidence of the carcinogenicity of diesel exhaust in human beings. 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 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 was comparable. Both nitro-PAH 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.
      PubDate: 2017-01-06T03:35:40.115409-05:
      DOI: 10.1111/bcpt.12693
  • Issue Information
    • Pages: 513 - 514
      PubDate: 2017-05-11T00:02:06.341836-05:
      DOI: 10.1111/bcpt.12736
  • Is Nickel Chloride really a Non-Genotoxic Carcinogen'
    • Authors: Leanne Stannard; Shareen H. Doak, Ann Doherty, Gareth J. Jenkins
      Abstract: Human beings 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 such as 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 end-points, 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 supports 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. The focus of this MiniReview is on research into the molecular mechanisms of nickel-induced carcinogenicity and potential genotoxicity, with a focus on one of the salts of greatest commercial importance, nickel chloride.
      PubDate: 2016-12-22T05:00:34.349568-05:
      DOI: 10.1111/bcpt.12689
  • 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
  • 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
  • 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
  • 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
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