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  Subjects -> ENVIRONMENTAL STUDIES (Total: 763 journals)
    - ENVIRONMENTAL STUDIES (689 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (41 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (689 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 378 Journals sorted alphabetically
Acta Ecologica Sinica     Open Access   (Followers: 8)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Oecologica     Hybrid Journal   (Followers: 9)
Acta Regionalia et Environmentalica     Open Access  
Advances in Ecological Research     Full-text available via subscription   (Followers: 40)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 20)
Advances in Life Science and Technology     Open Access   (Followers: 14)
Aeolian Research     Hybrid Journal   (Followers: 5)
African Journal of Environmental Science and Technology     Open Access   (Followers: 2)
Agricultura Tecnica     Open Access   (Followers: 6)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10)
Amazon's Research and Environmental Law     Open Access  
Ambiência     Open Access  
Ambiens. Revista Iberoamericana Universitaria en Ambiente, Sociedad y Sustentabilidad     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Environmental Engineering     Open Access   (Followers: 16)
American Journal of Environmental Protection     Open Access   (Followers: 7)
American Journal of Environmental Sciences     Open Access   (Followers: 16)
American Journal of Microbiology     Open Access   (Followers: 14)
American Naturalist     Full-text available via subscription   (Followers: 63)
Annals of GIS     Hybrid Journal   (Followers: 20)
Annals of Warsaw University of Life Sciences - SGGW. Land Reclamation     Open Access  
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (Followers: 56)
Annual Review of Environment and Resources     Full-text available via subscription   (Followers: 15)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 26)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 12)
Applied and Environmental Soil Science     Open Access   (Followers: 15)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 16)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 31)
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: 63)
Austral Ecology     Hybrid Journal   (Followers: 12)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 10)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Avicenna Journal of Environmental Health Engineering     Open Access   (Followers: 2)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 9)
Basic and Applied Ecology     Hybrid Journal   (Followers: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 47)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 33)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 27)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 5)
Bioremediation Journal     Hybrid Journal   (Followers: 5)
BioRisk     Open Access   (Followers: 3)
BMC Ecology     Open Access   (Followers: 18)
Boletín Semillas Ambientales     Open Access  
Boston College Environmental Affairs Law Review     Open Access   (Followers: 7)
Bothalia : African Biodiversity & Conservation     Open Access   (Followers: 1)
Built Environment     Full-text available via subscription   (Followers: 4)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 10)
Bulletin of the American Meteorological Society     Open Access   (Followers: 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: 13)
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   (Followers: 1)
Challenges in Sustainability     Open Access   (Followers: 3)
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 18)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 13)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 60)
Civil and Environmental Engineering     Open Access   (Followers: 7)
Civil And Environmental Engineering Reports     Open Access   (Followers: 4)
Civil and Environmental Research     Open Access   (Followers: 17)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 19)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 6)
Cleanroom Technology     Full-text available via subscription   (Followers: 1)
Climate Change Economics     Hybrid Journal   (Followers: 12)
Climate Policy     Hybrid Journal   (Followers: 29)
Coastal Engineering Journal     Hybrid Journal   (Followers: 3)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 10)
Computational Ecology and Software     Open Access   (Followers: 9)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 4)
Conservation and Society     Open Access   (Followers: 10)
Conservation Letters     Open Access   (Followers: 29)
Conservation Science     Open Access   (Followers: 19)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 6)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 13)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 21)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 6)
Current Environmental Health Reports     Hybrid Journal  
Current Forestry Reports     Hybrid Journal  
Current Opinion in Environmental Sustainability     Hybrid Journal   (Followers: 12)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 7)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 16)
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: 6)
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: 12)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 6)
E3S Web of Conferences     Open Access  
Earth Interactions     Full-text available via subscription   (Followers: 11)
Earth Science Informatics     Hybrid Journal   (Followers: 4)
Earth System Science Data (ESSD)     Open Access   (Followers: 7)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 6)
Earthquake Science     Hybrid Journal   (Followers: 10)
EchoGéo     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 10)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 3)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 132)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecological Complexity     Hybrid Journal   (Followers: 8)
Ecological Indicators     Hybrid Journal   (Followers: 17)
Ecological Informatics     Hybrid Journal   (Followers: 5)
Ecological Management & Restoration     Hybrid Journal   (Followers: 15)
Ecological Modelling     Hybrid Journal   (Followers: 90)
Ecological Monographs     Full-text available via subscription   (Followers: 30)
Ecological Processes     Open Access   (Followers: 6)
Ecological Questions     Open Access   (Followers: 7)
Ecological Research     Hybrid Journal   (Followers: 9)
Ecological Restoration     Full-text available via subscription   (Followers: 24)
Ecologist, The     Full-text available via subscription   (Followers: 27)
Ecology     Full-text available via subscription   (Followers: 271)
Ecology and Evolution     Open Access   (Followers: 55)
Ecology Letters     Hybrid Journal   (Followers: 177)
Economics and Policy of Energy and the Environment     Full-text available via subscription   (Followers: 8)
Économie rurale     Open Access   (Followers: 1)
Ecoprint : An International Journal of Ecology     Open Access   (Followers: 2)
Ecopsychology     Hybrid Journal   (Followers: 6)
Ecosphere     Open Access   (Followers: 4)
Ecosystem Services     Hybrid Journal   (Followers: 6)
Ecosystems     Hybrid Journal   (Followers: 26)
Ecotoxicology     Hybrid Journal   (Followers: 11)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 7)
Ecozon@ : European Journal of Literature, Culture and Environment     Open Access   (Followers: 4)
Ekologija     Open Access  
Electronic Green Journal     Open Access   (Followers: 6)
Empowering Sustainability International Journal     Open Access   (Followers: 2)
Energy & Environmental Science     Full-text available via subscription   (Followers: 23)
Energy & Environment     Hybrid Journal   (Followers: 16)
Energy and Environment Focus     Free   (Followers: 6)
Energy and Environment Research     Open Access   (Followers: 11)
Energy and Environmental Engineering     Open Access   (Followers: 6)
Engenharia Sanitaria e Ambiental     Open Access  
Envigogika     Open Access  
Environment and Behavior     Hybrid Journal   (Followers: 18)
Environment and Ecology Research     Open Access   (Followers: 6)
Environment and Natural Resources Research     Open Access   (Followers: 11)
Environment and Planning A     Full-text available via subscription   (Followers: 45)
Environment and Planning B : Planning and Design     Full-text available via subscription   (Followers: 33)
Environment and Planning C : Government and Policy     Full-text available via subscription   (Followers: 32)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 43)
Environment and Pollution     Open Access   (Followers: 11)
Environment and Society     Full-text available via subscription   (Followers: 7)
Environment International     Hybrid Journal   (Followers: 11)
Environment of Care News     Full-text available via subscription   (Followers: 1)
Environment Systems & Decisions     Hybrid Journal   (Followers: 4)
Environment, Development and Sustainability     Hybrid Journal   (Followers: 32)
Environment, Space, Place     Full-text available via subscription   (Followers: 5)
Environment: Science and Policy for Sustainable Development     Hybrid Journal   (Followers: 44)
Environmental & Engineering Geoscience     Full-text available via subscription   (Followers: 3)
Environmental & Socio-economic Studies     Open Access  
Environmental and Climate Technologies     Open Access   (Followers: 3)
Environmental and Molecular Mutagenesis     Hybrid Journal   (Followers: 4)
Environmental Bioindicators     Hybrid Journal   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 6)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 3)
Environmental Claims Journal     Hybrid Journal   (Followers: 1)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 19)
Environmental Development     Hybrid Journal   (Followers: 3)
Environmental Education Research     Hybrid Journal   (Followers: 14)
Environmental Engineering Science     Hybrid Journal   (Followers: 9)
Environmental Ethics     Hybrid Journal   (Followers: 7)
Environmental Evidence     Open Access   (Followers: 1)
Environmental Fluid Mechanics     Hybrid Journal   (Followers: 4)
Environmental Forensics     Hybrid Journal   (Followers: 1)
Environmental Geosciences     Full-text available via subscription   (Followers: 3)
Environmental Geotechnics     Hybrid Journal   (Followers: 4)
Environmental Hazards     Hybrid Journal   (Followers: 2)
Environmental Health     Open Access   (Followers: 10)
Environmental Health Insights     Open Access   (Followers: 4)
Environmental Health Perspectives (EHP)     Open Access   (Followers: 15)
Environmental History     Hybrid Journal   (Followers: 25)
Environmental Impact Assessment Review     Hybrid Journal   (Followers: 21)
Environmental Innovation and Societal Transitions     Hybrid Journal   (Followers: 4)

        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  [1616 journals]
  • 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
           Self-Poisoning
    • 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
       
  • Activated Charcoal Haemoperfusion in the Treatment of Experimental
           Amitriptyline Poisoning in Pigs – The Effect on Amitriptyline Plasma
           Concentration and Haemodynamic Parameters
    • Authors: Tejs Jansen; Henrik Petersen, Cecilie M. Malskær, Charlotte Gabel-Jensen, Kim Dalhoff, Thomas Eriksen, Bo Belhage, Lotte C. G. Hoegberg
      Abstract: Coated activated charcoal haemoperfusion (CAC-HP) is a well-known treatment modality. Case reports have revealed conflicting results about the efficacy of CAC-HP in the treatment of amitriptyline (AT) poisoning, and no randomized clinical trials have been identified in the literature. This study aimed at quantifying the efficacy of modern CAC-HP as an adjunctive treatment of AT intoxication compared with standard care alone. Fourteen female Danish landrace pigs were randomized to either standard care or standard care plus 4 hr of CAC-HP. The pigs were anaesthetized, and vital parameters were continuously recorded. Amitriptyline infusion (7.5 mg/kg) was completed in 20 min. Thirty minutes after AT infusion, activated charcoal was instilled orally in both groups. In the intervention group, CAC-HP was initiated 60 min. after AT infusion. Blood and urine samples were collected as were vital parameters at specific time intervals. The protocol was approved by the Danish Experimental Animal Expectorate and complied with the NIH guide for care and use of laboratory animals. Data were managed according to the ARRIVE guidelines. No statistical significant differences between intervention and control groups were found when analysing for differences in AT levels in plasma at any time-point. Furthermore, significant differences between the control and intervention groups in regard to vital parameters could not be found either. In our animal model, the addition of CAC-HP did not improve the clearance of AT compared with standard treatment alone. We suggest that the effect of modern CAC-HP as a treatment modality in AT-poisoned human patients may be inadequate.
      PubDate: 2017-03-15T04:00:26.154283-05:
      DOI: 10.1111/bcpt.12704
       
  • 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
           Patients
    • 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
       
  • Do not Forget Gastrointestinal Decontamination in the Early Management of
           Lithium Poisoning
    • Authors: Dominique Vodovar; Bruno Mégarbane
      PubDate: 2017-03-10T10:33:10.530445-05:
      DOI: 10.1111/bcpt.12758
       
  • 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
       
  • Response to: Do not Forget Gastrointestinal Decontamination in the Early
           Management of Lithium Poisoning
    • Authors: Nasim Zamani; Maryam Paeezi, Hossein Hassanian-Moghaddam
      PubDate: 2017-03-08T02:35:26.340119-05:
      DOI: 10.1111/bcpt.12759
       
  • Odense Pharmacoepidemiological Database: A Review of Use and Content
    • Authors: Jesper Hallas; Maja Hellfritzsch, Morten Rix, Morten Olesen, Mette Reilev, Anton Pottegård
      Abstract: The Odense University Pharmacoepidemiological Database (OPED) is a prescription database established in 1990 by the University of Southern Denmark, covering reimbursed prescriptions from the county of Funen in Denmark and the region of Southern Denmark (1.2 million inhabitants). It is still active and thereby has more than 25 years of continuous coverage. In this MiniReview, we review its history, content, quality, coverage, governance and some of its uses. OPED's data include the Danish Civil Registration Number (CPR), which enables unambiguous linkage with virtually all other health-related registers in Denmark. Among its research uses, we review record linkage studies of drug effects, advanced drug utilization studies, some examples of method development and use of OPED as sampling frame to recruit patients for field studies or clinical trials. With the advent of other, more comprehensive sources of prescription data in Denmark, OPED may still play a role as in certain data-intensive regional studies.
      PubDate: 2017-03-08T02:30:27.501232-05:
      DOI: 10.1111/bcpt.12764
       
  • 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
       
  • Lithium Toxicity in a Pregnant Woman
    • Authors: Nasim Zamani; Maryam Paeezi, Hossein Hassanian-Moghaddam
      Abstract: Lithium is recommended in bipolar disorder and can be accompanied by significant toxicity in pregnant women. A 25-year-old single-gestation pregnant woman (28 weeks) was referred with suspicion of lithium toxicity. Serum lithium was 2.1 meq/L. Despite conservative therapy with intravenous fluids, lithium concentration increased to 5.0 meq/L 6 hr after admission mandating an emergent haemodialysis during which foetal heart rate decreased to 90 bpm. The gynaecologist ordered termination of pregnancy while the mother was still on haemodialysis. Caesarean section was carried out, but the born baby had an apgar of 2 and died. Autopsy findings of the foetus revealed a cord blood lithium concentration of 4.8 mEq/L with no physical abnormalities. Although the foetus had the signs/symptoms of distress, continuation of haemodialysis could probably have saved it as it saved its mother's life. In lithium toxicity in a pregnant woman, it is reasonable to continue haemodialysis even with the signs and symptoms of foetal distress. In similar situations, emergency haemodialysis instead of immediate caesarean section should be considered.
      PubDate: 2017-03-07T05:55:32.57776-05:0
      DOI: 10.1111/bcpt.12747
       
  • 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
           Oxidation
    • 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
       
  • Oil-Fortified Maize Porridge Increases Absorption of Lumefantrine in
           Children with Uncomplicated Falciparum Malaria
    • Authors: Norah Mwebaza; Markus Jerling, Lars L. Gustafsson, Antero V. Silva, Anton Pohanka, Celestino Obua, Paul Waako, Olof Beck, Manijeh Vafa Homann, Anna Färnert, Urban Hellgren
      Abstract: Artemether-lumefantrine (AL) is a first-line treatment for uncomplicated malaria. Absorption of lumefantrine (LUM) is fat dependent, and in children, intake is recommended with milk. We investigated whether oil-fortified maize porridge can be an alternative when milk is not available. In an open-label pharmacokinetic study, Ugandan children
      PubDate: 2017-02-22T23:00:30.961593-05:
      DOI: 10.1111/bcpt.12714
       
  • 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
           Identification
    • Authors: Sabine A. S. Langie; Matthieu Moisse, Ken Declerck, Gudrun Koppen, Lode Godderis, Wim Vanden Berghe, Stacy Drury, Patrick De Boever
      Abstract: Is it not more comfortable to spit saliva in a tube than to be pricked with a needle to draw blood to analyse your health and disease risk' 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
       
  • Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress
           and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced
           Diabetic Nephropathy in Rat
    • Authors: Manash P. Borgohain; Mangala Lahkar, Sahabuddin Ahmed, Liakat Chowdhury, Saurabh Kumar, Rajat Pant, Abhinav Choubey
      Abstract: Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation – and might be helpful in early stage of diabetic nephropathy.
      PubDate: 2017-01-23T00:15:37.462439-05:
      DOI: 10.1111/bcpt.12718
       
  • 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
       
  • Vascular Toxicity Risk Assessment of MC18 and MC70, Novel Potential
           Diagnostic Tools for In Vivo PET Studies
    • Authors: Fabio Fusi; Miriam Durante, Claudia Sticozzi, Maria Frosini, Maria G. Perrone, Nicola A. Colabufo, Simona Saponara
      Abstract: The P-glicoprotein (P-gp) inhibitor MC18 has been recently proposed as a valuable PET tracer to measure P-gp expression in vivo. The aim of this study was to evaluate the toxic hazard towards the vasculature of MC18 along with the structurally related and more potent P-gp inhibitor MC70. Their effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of fresh and cultured rat aorta rings as well as on Cav1.2 channel current (ICa1.2) of A7r5 cells were studied. At concentrations>10 μM, MC18 and MC70 decreased cell viability causing evident morphological changes. In fresh rat aorta rings, both compounds (0.1–100 μM) antagonized phenylephrine-induced contraction in a concentration-dependent manner, with IC50 values in the range of 1.67–14.49 μM, whereas only MC18 caused a concentration-dependent decrease of the 60 mM K+ (K60)-induced responses. In rings cultured for 7 days with both compounds (1–10 μM), 10 μM MC70 significantly reduced, while 10 μM MC18 completely prevented the contractile response to both phenylephrine and K60. MC18 and MC70 (0.1–100 μM) inhibited ICa1.2 in a concentration-dependent manner with IC50 values of 16.81 and 32.13 μM, respectively. These findings demonstrate that MC18-induced vascular effects took place at concentrations that are at least three orders of magnitude higher than those (≤10 nM) allowing in vivo measurement of P-gp expression. Thus, MC18, and possibly MC70, can be considered promising PET tools for in vivo P-gp quantification.
      PubDate: 2017-01-16T02:55:24.305205-05:
      DOI: 10.1111/bcpt.12719
       
  • ABCC3 Polymorphisms and mRNA Expression Influence the Concentration of a
           
    • Authors: André Ducati Luchessi; Marta Concheiro, Juliana de Freitas Germano, Vivian Nogueira Silbiger, Raul Hernandes Bortolin, Angelines Cruz, Oscar Quintela, Maria Brion, Angel Carracedo, Andres Iñiguez, Marisol Bravo, Manuel López-Rivadulla, Rosario Dominguez Crespo Hirata, Amanda Guerra Moraes Rego Sousa, Mario Hiroyuki Hirata
      Abstract: Acetylsalicylic acid (ASA) and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome (ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 (ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid (SA) and a carboxylic acid metabolite (CAM). Clopidogrel, CAM and SA plasma concentrations were measured simultaneously by liquid chromatography–tandem mass spectrometry (LCMS/MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392 and rs739923) and CYP2C19*2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression (r = 0.494, p < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers (p = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression (p = 0.017), rs757421 AA genotype (p = 0.001), blood collection time (p = 0.018) and clopidogrel dose (p = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19*2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel.
      PubDate: 2017-01-16T00:25:57.724966-05:
      DOI: 10.1111/bcpt.12703
       
  • 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
       
  • Pharmacovigilance Skills, Knowledge and Attitudes in our Future Doctors
           – A Nationwide Study in the Netherlands
    • Authors: Tim Schutte; Jelle Tichelaar, Michael O. Reumerman, Rike Eekeren, Robert Rissmann, Cornelis Kramers, Milan C. Richir, Eugène P. Puijenbroek, Michiel A. Agtmael,
      Abstract: Pharmacovigilance centres monitor the safety of drugs, based on adverse drug reactions (ADRs) reported by doctors, pharmacists and pharmaceutical companies. However, the under-reporting of ADRs remains a major problem. Our aim was to investigate preparedness of future doctors for their role in pharmacovigilance, by assessing their pharmacovigilance awareness, skills and knowledge. The study was a nationwide e-survey among medical students (third to sixth year) of all eight medical schools in the Netherlands. The survey consisted of questions regarding pharmacovigilance awareness, skills and knowledge. Overall, 874 students provided informed consent and participated (response 12%). Almost all students (96%) intended to report serious ADRs in their future practice. Almost half (44%) of the students did not know where to report an ADR, and 78% did not know which items were necessary for a good-quality ADR report. While more than 78% of the students agreed that pharmacovigilance is an important topic in their medical education, only 26% found that their current curriculum covered pharmacovigilance adequately. Although ADR reporting is considered relevant and important among future doctors, many do not know where and what to report. This is highly undesirable and should have consequences for pharmacotherapy teaching.
      PubDate: 2017-01-11T23:00:27.58147-05:0
      DOI: 10.1111/bcpt.12712
       
  • 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
       
  • Carnitine and γ-Butyrobetaine Stimulate Elimination of Meldonium due to
           Competition for OCTN2-mediated Transport
    • Authors: Edgars Liepinsh; Elina Makarova, Eduards Sevostjanovs, Dace Hartmane, Helena Cirule, Olga Zharkova-Malkova, Solveiga Grinberga, Maija Dambrova
      Abstract: Meldonium (3-(2,2,2-trimethylhydrazinium)propionate) is the most potent clinically used inhibitor of organic cation transporter 2 (OCTN2). Inhibition of OCTN2 leads to a decrease in carnitine and acylcarnitine contents in tissues and energy metabolism optimization-related cardioprotective effects. The recent inclusion of meldonium in the World Anti-Doping Agency List of Prohibited Substances and Methods has raised questions about the pharmacokinetics of meldonium and its unusually long elimination time. Therefore, in this study, the rate of meldonium washout after the end of the treatment was tested with and without administration of carnitine, γ-butyrobetaine (GBB) and furosemide to evaluate the importance of competition for OCTN2 transport in mice. Here, we show that carnitine and GBB administration during the washout period effectively stimulated the elimination of meldonium. GBB induced a more pronounced effect on meldonium elimination than carnitine due to the higher affinity of GBB for OCTN2. The diuretic effect of furosemide did not significantly affect the elimination of meldonium, carnitine and GBB. In conclusion, the competition of meldonium, carnitine and GBB for OCTN2-mediated transport determines the pharmacokinetic properties of meldonium. Thus, due to their affinity for OCTN2, GBB and carnitine but not furosemide stimulated meldonium elimination. During long-term treatment, OCTN2-mediated transport ensures a high muscle content of meldonium, while tissue clearance depends on relatively slow diffusion, thus resulting in the unusually long complete elimination period of meldonium.
      PubDate: 2017-01-10T03:40:24.512157-05:
      DOI: 10.1111/bcpt.12729
       
  • 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
       
  • Usefulness of Transthoracic Echocardiography Parameters and Brain
           Natriuretic Peptide as Mortality Predictors in Hospitalized Acutely
           Poisoned Patients: A Prospective Observational Study
    • Authors: Catalina Lionte; Victorita Sorodoc, Cristina Bologa, Cristina Tuchilus, Elisabeta Jaba
      Abstract: Acute poisonings represent a common cause of morbidity and mortality worldwide. The prognostic utility of the transthoracic echocardiography (TTE) parameters combined with brain natriuretic peptide (BNP) in acute poisoning with different xenobiotics, upon admission in the hospital, was not evaluated. This prospective observational cohort study included 229 acutely poisoned non-diabetic adults, with a median age of 44 years (range 18–90 years), 50.7% women, with an in-hospital mortality rate of 8.7%. Univariate logistic regression analysis showed that age, the left ventricle kinetic abnormalities, the E-wave deceleration time (EDT) and BNP correlated significantly with mortality in acutely poisoned patients. Multivariate logistic regression showed that only EDT [odds ratio (OR) 3.44, 95% confidence interval (CI) 1.54–7.69, p 0.003], BNP (OR 1.61, 95% CI: 1.02–2.55, p 0.04) and age (OR 2.66, 95% CI: 1.23–5.76, p 0.013) are predictive for mortality. The receiver-operating characteristic (ROC) analysis proved EDT [area under the ROC curve (AUC), 0.85; CI: 0.76–0.94; p 0.001], BNP (AUC, 0.83; CI: 0.75–0.91; p 0.001) and age (AUC, 0.82; CI: 0.74–0.90; p 0.001) as indicators for fatalities. In hospitalized patients acutely intoxicated with undifferentiated poisons, EDT as a parameter of left ventricle diastolic function and BNP are useful to early predict mortality.
      PubDate: 2017-01-06T03:35:24.333708-05:
      DOI: 10.1111/bcpt.12711
       
  • Electrocardiogram Alterations Associated With Psychotropic Drug Use and
           CACNA1C Gene Variants in Three Independent Samples
    • Authors: Chiara Fabbri; Giuseppe Boriani, Igor Diemberger, Maria Giulia Filippi, Gloria Ravegnini, Patrizia Hrelia, Alessandro Minarini, Diego Albani, Gianluigi Forloni, Sabrina Angelini, Alessandro Serretti
      Abstract: Several antipsychotics and antidepressants have been associated with QTc prolongation or other electrocardiogram (ECG) alterations, but their impact is still debated and other risk factors are known to affect QTc. We investigated the effect of antidepressants and antipsychotics on QTc and other ECG intervals/waves in three samples. Two discovery samples (cross-sectional sample n = 145 and prospective sample n = 68, naturalistic treatment) and a replication prospective sample (Clinical Antipsychotic Trials of Intervention Effectiveness, n = 515, randomized treatment) were analysed. In both prospective samples, baseline/follow-up changes in ECG parameters were analysed in relation to the number of psychotropic drugs stratified according to their known cardiovascular risk. In the cross-sectional sample, ECG parameters were compared among drugs with different risk profile. The possible effect of single nucleotide polymorphisms (SNPs) in the CACNA1C gene on QTc was also investigated. There was no evidence of mean QTc prolongation or increased risk of clinically relevant QTc prolongation (≥20 msec.) in association with psychotropic drugs stratified according to their known cardiovascular risk. The prescription of drugs with cardiovascular risk was less common in older individuals or individuals with cardiovascular comorbidities. Other factors (gender, baseline QTc, renal function) affected QTc. rs1006737 and SNPs in linkage disequilibrium with it modulated QTc duration/changes in all samples. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not observed. A number of factors other than psychotropic drugs may influence QTc. CACNA1C rs1006737 may modulate QTc in patients treated with psychotropic drugs.
      PubDate: 2017-01-05T04:55:52.088493-05:
      DOI: 10.1111/bcpt.12720
       
  • Colchicine Increases Ventricular Vulnerability in an Experimental
           Whole-Heart Model
    • Authors: Gerrit Frommeyer; Julius Krawczyk, Dirk G. Dechering, Simon Kochhäuser, Patrick Leitz, Michael Fehr, Lars Eckardt
      Abstract: The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole-heart model. Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, colchicine was administered in two concentrations (1 and 3 μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose-dependent significant decrease of effective refractory period (ERP; 1 μM: −19 ms, 3 μM: −22 ms; p < 0.05). In the present study, acute infusion of colchicine in isolated rabbit hearts resulted in a reduction of ERP in the presence of a stable myocardial repolarization. This led to a significantly elevated inducibility of ventricular fibrillation. In 4 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a pro-arrhythmic or toxic effect of colchicine and underline that further clinical studies on potential adverse effects should be conducted before the drug can be recommended for routine use after atrial fibrillation ablation.
      PubDate: 2017-01-05T04:45:31.63787-05:0
      DOI: 10.1111/bcpt.12702
       
  • Issue Information
    • Pages: 325 - 326
      PubDate: 2017-03-12T21:41:48.42754-05:0
      DOI: 10.1111/bcpt.12734
       
  • Lipid-soluble Cigarette Smoke Particles Induced Vascular Endothelin Type A
           Receptor Up-Regulation through Activation of ERK1/2 Signal Pathways
    • Authors: Yaping Zhang; Wei Zhang, Lars Edvinsson, Cang-Bao Xu
      Pages: 327 - 334
      Abstract: Abnormal contraction of vessels termed ‘vasospasm’ is associated with various cardiovascular diseases. Smoking is a well-known risk factor that increases vasospasm. However, the molecular mechanisms by which smoking leads to vasospasm and cardiovascular disease are not fully understood. This study was designed to examine whether DMSO-extracted cigarette smoke particles (DSP) could induce up-regulation of vascular endothelin type A (ETA) receptors, and whether ETA receptor is up-regulated through activation of extracellular regulated protein kinases 1 and 2 (ERK1/2) signal pathways. Mesenteric arterial segments from rats were cultured in the presence of DSP, water-extracted cigarette smoke particles (WSP) or equivalent concentration of nicotine for up to 24 hr. The results showed that DSP, but not WSP or nicotine, induced ETA receptor up-regulation with increased ETA receptor-mediated contraction (myograph, p < 0.001). Simultaneously, the expression of ETA receptor mRNA (real-time PCR, p < 0.001) and protein (immunohistochemistry) were enhanced in the smooth muscle cells, suggesting that the lipid-soluble substances contained in cigarette smoke were responsible for the effects of DSP. Actinomycin D (a general transcriptional inhibitor) decreased ETA receptor mRNA expression and attenuated receptor-mediated contraction (p < 0.001), while DSP accelerated ETA receptor mRNA degradation (p < 0.01) and promoted the translation of ETA receptor mRNA into protein. Furthermore, the up-regulation of ETA receptors was significantly attenuated by inhibition of ERK1/2 signal pathways (p < 0.001). In conclusion, DSP most likely activate ERK1/2 signal pathway-mediated transcriptional and post-transcriptional (translational) mechanisms that lead to vascular ETA receptor up-regulation, which might contribute to vasospasm and the development of smoking-associated cardiovascular diseases.
      PubDate: 2017-02-02T22:25:29.085841-05:
      DOI: 10.1111/bcpt.12688
       
  • Lipopolysaccharides, but not Angiotensin ll, lnduces Direct
           Pro-lnflammatory Effects in Cultured Mouse Arteries and Human Endothelial
           and Vascular Smooth Muscle Cells
    • Authors: Emilie M. Outzen; Marina Zaki, Rahila Mehryar, Bahareh Abdolalizadeh, Waseem Sajid, Harrie C. M. Boonen, Anette Sams, Majid Sheykhzade
      Pages: 335 - 347
      Abstract: Angiotensin II (Ang II) might induce pro-inflammatory effects directly in the vascular wall independently of its haemodynamic effects. The aim of our study was to investigate the putative direct pro-inflammatory and vasomotor effects of Ang II and compare to those of lipopolysaccharides (LPS) in mouse isolated mesenteric resistance-sized arteries (MRA) supported by experiments in cultured human primary endothelial and vascular smooth muscle cells. Results showed that 24-hr organ culture of mouse MRA with 10 nM Ang II had, unlike 100 ng/mL LPS, no effects on IL-6 or MCP-1 secretion, VCAM1 mRNA expression or endothelial function, while Ang II significantly decreased maximal vasomotor responses to phenylephrine. In support, 24-hr organ culture of mouse MRA significantly suppressed Agtr1a mRNA and augmented Tlr4 mRNA along with attenuated vasomotor responses to Ang II. Moreover, contrary to LPS and TNF-α, Ang II and [Sar1]-Ang II had no concentration- or time-dependent effects on IL-6 and MCP-1 secretion in human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HASMC). AGTR1 or AGTR2 mRNA expression was undetectable in HUVEC, whereas HASMC expressed only AGTR1 mRNA. In summary, contrary to previous studies and the observed effects of LPS, we could not demonstrate direct vascular pro-inflammatory effects of Ang II ex vivo or in vitro. As indicated by our results, down-regulation or desensitization of AT1R during culture may explain our findings.
      PubDate: 2017-01-06T03:35:43.709947-05:
      DOI: 10.1111/bcpt.12697
       
  • Acute Treatment with Lauric Acid Reduces Blood Pressure and Oxidative
           Stress in Spontaneously Hypertensive Rats
    • Authors: Naiane Ferraz Bandeira Alves; Thyago Moreira Queiroz, Rafael Almeida Travassos, Marciane Magnani, Valdir Andrade Braga
      Pages: 348 - 353
      Abstract: The effects of acute administration of lauric acid (LA), the most abundant medium-chain fatty acid of coconut oil, on blood pressure, heart rate and oxidative stress were investigated in spontaneously hypertensive rats (SHR). Intravenous doses of LA reduced blood pressure in a dose-dependent fashion (1, 3, 4, 8 and 10 mg/kg) in both SHR and Wistar Kyoto rats. LA (10−8 to 3 × 10−3 M) induced vasorelaxation in isolated superior mesenteric artery rings of SHR in the presence (n = 7) or absence (n = 8) of functional endothelium [maximum effect (ME) = 104 ± 3 versus 103 ± 4%]. After exposure to KCl (60 mM), LA also induced concentration-dependent vasorelaxation (n = 7) compared to that under Phe-induced contraction (ME = 113.5 + 5.1 versus 104.5 + 4.0%). Furthermore, LA-induced vasorelaxation in vessels contracted with S(−)-BayK8644 (200 nM), a L-type Ca2+ channel agonist (ME = 91.4 + 4.3 versus 104.5 + 4.0%, n = 7). Lastly, LA (10−3 M) reduced NADPH-dependent superoxide accumulation in the heart (18 ± 1 versus 25 ± 1 MLU/min/μg protein, n = 4, p < 0.05) and kidney (82 ± 3 versus 99 ± 4 MLU/min/μg protein, n = 4, p < 0.05). Our data show that LA reduces blood pressure in normotensive and hypertensive rats. In SHR, this effect might involve Ca+2 channels in the resistance vessels and by its capability of reducing oxidative stress in heart and kidneys.
      PubDate: 2017-01-05T04:51:03.943825-05:
      DOI: 10.1111/bcpt.12700
       
  • Clinical Pharmacist-Provided Services In Iron-Overloaded Beta-Thalassaemia
           Major Children: A New Insight Into Patient Care
    • Authors: Salma M. Bahnasawy; Lamia M. El Wakeel, Nagham El Beblawy, Manal El-Hamamsy
      Pages: 354 - 359
      Abstract: Iron-overloaded β-thalassaemia major (BTM) children have high risk of delayed sexual/physical maturation, liver/heart diseases and reduced life expectancy. The lifelong need to use iron chelators, their unpleasant administration, side effects and lack of awareness regarding iron overload risks all hamper BTM patient compliance to iron chelators. This study evaluated the impact of clinical pharmacist-provided services on the outcome of iron-overloaded BTM children. Forty-eight BTM children were randomly assigned to either control group, who received standard medical care, or intervention group, who received standard medical care plus clinical pharmacist-provided services. Services included detection of drug-related problems (DRPs) and their management, patient education regarding disease nature and iron chelators, as well as providing patient-tailored medication charts. After six months of study implementation, there was a highly significant difference between the control and intervention groups in serum ferritin (SF) (mean: 3871 versus 2362, μg/l, p = 0.0042), patient healthcare satisfaction (median: 24.47 versus 90.29, p < 0.0001) and quality of life (QoL) (median: 49.84 versus 63.51, p = 0.0049). The intervention group showed a decline from baseline to the end of study in DRPs (64–4), the number of non-compliant patients (24–3) and mean SF levels (3949–2362 μg/l, p < 0.0001). Clinical pharmacist-provided services can positively impact the outcome of BTM children.
      PubDate: 2017-02-16T05:25:29.368663-05:
      DOI: 10.1111/bcpt.12695
       
  • Trends in Off-Label Prescribing of Sedatives, Hypnotics and
           Antidepressants among Children and Adolescents – A Danish, Nationwide
           Register-Based Study
    • Authors: Eva Skovslund Nielsen; Lotte Rasmussen, Maja Hellfritzsch, Per Hove Thomsen, Mette Nørgaard, Torben Laursen
      Pages: 360 - 367
      Abstract: In recent years, psychotropic drug use among children and adolescents in Europe and USA has increased. However, the majority of psychotropic drugs are not formally approved for use in children and adolescents, and consequently, use is often off-label. The objectives were to describe time trends in off-label prescribing rates and the most commonly used types of psychotropic drugs by age and gender in Danish children and adolescents. Using the Register of Medicinal Product Statistics, we identified all prescriptions for sedatives, hypnotics and antidepressants filled for children and adolescents in 2006–2012. Information on diagnoses was obtained from the Danish National Registry of Patients and allowed classification of prescriptions as either on- or off-label. We identified 186,831 prescriptions filled for 29,851 children and adolescents: 88.0% of these were classified as off-label. During 2006–2012, off-label rates for sedatives and hypnotics increased significantly, except for prescriptions for girls aged 15–17 years [range 24.1–98.2% (girls), 31.9% to 99.0% (boys)]. In the same period, the number of registered melatonin prescriptions (all off-label) increased expansively. For antidepressants, we found decreasing trends in off-label rates over time [range 94.5–65.6% (girls), 93.8–71.2% (boys)]. Off-label prescribing of psychotropic drugs to Danish children and adolescents is common. Off-label rates for sedatives and hypnotics increased in the period of 2006–2012, whereas off-label rates for antidepressants declined. Off-label rates might be underestimated and should be considered a conservative estimate.
      PubDate: 2017-01-05T04:51:09.50621-05:0
      DOI: 10.1111/bcpt.12706
       
  • Topical Antimycotics for Oral Candidiasis in Warfarin Users
    • Authors: Maja Hellfritzsch; Anton Pottegård, Andreas James Thestrup Pedersen, Alaa Burghle, Fatima Mouaanaki, Jesper Hallas, Erik Lerkevang Grove, Per Damkier
      Pages: 368 - 372
      Abstract: Treatment for oral candidiasis in warfarin users may be complicated by drug–drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998–2012 (n ≈ 7400). We collected data on cohort members’ measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1–2.8) to 3.8 (95% CI: 2.8–4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3–2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3–3.1) before and 2.5 (95% CI: 2.2–2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug–drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis.
      PubDate: 2017-01-11T05:15:21.537347-05:
      DOI: 10.1111/bcpt.12722
       
  • Utilization of Stimulants and Atomoxetine for
           Attention-Deficit/Hyperactivity Disorder among 5.4 Million Children Using
           Population-Based Longitudinal Data
    • Authors: Kari Furu; Øystein Karlstad, Helga Zoega, Jaana E. Martikainen, Shahram Bahmanyar, Helle Kieler, Anton Pottegård
      Pages: 373 - 379
      Abstract: Use of stimulants to treat attention-deficit/hyperactivity disorder (ADHD) has increased over the past two decades and varies substantially between countries. The objective of this multinational population-based study was to examine utilization of ADHD drugs (stimulants and atomoxetine) including comedication with other psychotropic drugs in the entire child population in the five Nordic countries. We included longitudinal data on dispensed ADHD drugs from five Nordic prescription registers during 2008–2012, which in 2012 comprised 48,296 individuals among 5.42 million inhabitants aged 0–17 years. Prevalence of filling ≥1 prescriptions of ADHD drugs among children aged 6–17 years increased during 2008–2012 from 5.9 to 11.2 and 19.4 to 31.0 per 1000 girls and boys, respectively. Prevalence by country showed that Iceland, Finland and Sweden had a steady increase during the study period, while in Norway the prevalence was quite stable and in Denmark it levelled off from 2010. Use in preschoolers (aged 0–5 years) was rare. Iceland had much higher prevalence and incidence than the other Nordic countries. The incidence of ADHD drug use increased during the study period, from 4.0 to 4.9 and from 1.5 to 2.3 per 1000 boys and girls, respectively. The increasing number of new users levelled off somewhat after 2010. Comedication with other psychotropic drugs was more common among girls (33.9%) than boys (27.0%) and was mainly melatonin, followed by antidepressants and antipsychotics. Overall prevalence of ADHD drug use increased among Nordic girls and boys aged 6–17 years, whereas the incidence increased slightly during 2008–2010 but levelled off through 2012. The substantial differences in ADHD drug use across the Nordic countries and high degree of comedication with other psychotropic drugs underscore the importance of close monitoring of treatment for ADHD among children.
      PubDate: 2017-01-30T21:55:47.23556-05:0
      DOI: 10.1111/bcpt.12724
       
  • Integrin Targeting and Toxicological Assessment of Peptide-Conjugated
           Liposome Delivery Systems to Activated Endothelial Cells
    • Authors: Ali Kermanizadeh; Klaus Villadsen, Ragnhild G. Østrem, Knud J. Jensen, Peter Møller, Steffen Loft
      Pages: 380 - 389
      Abstract: Utilization of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines after exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells.
      PubDate: 2017-01-06T03:35:32.983614-05:
      DOI: 10.1111/bcpt.12692
       
  • Extended Low-Dose Exposure to Saxitoxin Inhibits Neurite Outgrowth in
           Model Neuronal Cells
    • Authors: Katie O'Neill; Ian F. Musgrave, Andrew Humpage
      Pages: 390 - 397
      Abstract: The potent neurotoxin saxitoxin (STX) belongs to a group of structurally related analogues produced by both marine and freshwater phytoplankton. The toxins act by blocking voltage-gated sodium channels stopping the inflow of sodium ions and the generation of action potentials. Exposure from marine sources occurs as a result of consuming shellfish which have concentrated the toxins, and freshwater exposure can occur from drinking water although there have been no acute poisonings from the latter source to date. Previously, the majority of research into this group of toxins, collectively known as the paralytic shellfish toxins, has focused on acute exposure resulting in paralytic shellfish poisoning. While acute exposure guidelines exist for both sources, there are no chronic exposure guidelines and there has been minimal research into this pattern of exposure despite the known role of electrical activity in neurogenesis. We aimed to investigate this pattern of exposure and its potential effects on neurodevelopment using model neuronal cells. PC12 and SH-SY5Y cells were exposed to STX (0.25–3 μg/l) for 7 days, after which time they were stained with TRITC-Phalloidin, to observe adverse morphological effects. Cells exposed to STX had a significant decrease (18–85%) in long axonlike projections, instead exhibiting a significant increase in shorter projections classified as filopodia (p < 0.05). The results suggest that extended low-dose exposure to STX can inhibit proper neurite outgrowth at concentrations well below guideline levels for both sources of exposure making it a potential public health concern.
      PubDate: 2017-02-22T03:10:38.039038-05:
      DOI: 10.1111/bcpt.12701
       
  • Adverse Effect Profile of Topical Ocular Administration of Fingolimod for
           Treatment of Dry Eye Disease
    • Authors: Weibao Xiao; Li Sun, Nan Zhang, Wen Ye
      Pages: 398 - 406
      Abstract: Fingolimod is a promising prodrug in attenuating multiple sclerosis and prolonging survival of organ allograft, with many other protective effects. Its mechanism of action is related to the internalization of sphingosine 1-phosphate receptors (S1PRs). Our previous study indicated that fingolimod eyedrops was efficacious in inhibiting ocular inflammation in a dry eye disease (DED) model of non-obese diabetic (NOD) mice. In the current study, we evaluated potential adverse effects of fingolimod eyedrops. Inbred 10-week-old BALB/c mice were randomly divided into four groups, fingolimod-treated groups at three different concentrations (0.01%, 0.1% and 0.5%) and a negative control group without intervention. Our results showed that in the 0.5% fingolimod group, adverse effects such as photophobia, catacleisis and corneal oedema were observed after 1 week of treatment. 1 month later, corneal opacity, oedema and neovascularization persisted till the mice were killed 2 months later. In contrast, there was no significant abnormality in the negative control group, and 0.01% and 0.1% fingolimod-treated groups. During a 2-month treatment period, we did not detect fingolimod, nor significant change in blood cells in peripheral blood, nor pathological changes in retina and systemic organs. Combined with our previous study and the current results, we recommend that an optimal range of safe and effective concentration of fingolimod as eyedrops is between 0.005% and 0.1%.
      PubDate: 2017-01-22T23:40:38.956028-05:
      DOI: 10.1111/bcpt.12717
       
  • Corrigendum
    • Pages: 411 - 411
      PubDate: 2017-03-12T21:41:49.561144-05:
      DOI: 10.1111/bcpt.12766
       
  • 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
       
  • Crocin Attenuates Kindling Development and Associated Cognitive
           Impairments in Mice via Inhibiting Reactive Oxygen Species-Mediated NF-κB
           Activation
    • Authors: Arindam Ghosh Mazumder; Pallavi Sharma, Vikram Patial, Damanpreet Singh
      Abstract: Crocin is a pharmacologically active carotenoid pigment mainly present in the stigmas of Crocus sativus L. (Iridaceae). It has been well explored in experimental animal models of cognitive impairments, depression, anxiety and epilepsy. This study was designed to understand the effect of crocin on pentylenetetrazol (PTZ)-induced kindling development and its associated cognitive deficit in mouse. Crocin treatment at 5, 10 and 20 mg/kg p.o. doses showed a marked reduction in severity of PTZ-induced seizures. There was an increase in novel object preference index and discrimination ratio in the crocin-treated groups in the novel object recognition test. Its treatment also increased percentage spontaneous alternations in T-maze test at all the tested doses. Histopathological examination by Nissl staining showed a reduction in dark neurons in the hippocampal pyramidal layer of crocin-treated animals in contrast to vehicle control, indicating a decrease in neuronal damage. Biochemical estimations showed a significant increase in superoxide dismutase activity and reduced reactive oxygen species (ROS) in the hippocampus of crocin-treated animals. Immunohistochemistry results revealed attenuation in the levels of nuclear factor-κB (NF-κB) and phosphorylated NF-κB in the hippocampal sections of crocin-treated animals. The results of this study concluded that crocin treatment increased seizure threshold, thus inhibiting PTZ-induced kindling development and improving cognitive functions. The effect was found to be due to suppression of seizure-induced ROS generation and its linked NF-κB pathway-associated neuronal damage.
      PubDate: 2016-12-12T00:55:28.096433-05:
      DOI: 10.1111/bcpt.12694
       
  • 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
           Disease
    • Authors: Mustafa Tugrul Goktas; R. Ozgur Karaca, Said Kalkisim, Lokman Cevik, Levent Kilic, Ali Akdogan, Melih O. Babaoglu, Atilla Bozkurt, Leif Bertilsson, Umit Yasar
      Abstract: Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down-regulated due to inflammation. In the same Turkish BD patients, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5-hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms were made by using PCR-RFLP. The median lansoprazole/5-hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6-fold higher as compared to the healthy control group (p=0.001, 22.6 (1.3-26) and 8.8 (0.5-140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p=0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in 6 patients (p=0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.This article is protected by copyright. All rights reserved.
      PubDate: 2016-11-22T10:15:25.379909-05:
      DOI: 10.1111/bcpt.12710
       
  • Idarucizumab for Reversal of Dabigatran Prior to Acute Surgery: A
           Schematic Approach Based on a Case Report
    • Authors: Lene Rosenberg; Gustav Gerstrøm, Mads Nybo
      Pages: 407 - 410
      Abstract: Dabigatran, an oral direct thrombin inhibitor, is frequently used in treatment of venous thromboembolism and prevention of stroke in non-valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment that reverses the dabigatran effect, was introduced to the market to be used in case of life-threatening bleeding or acute surgery/invasive procedures. Whether usage should be guided by measurement of plasma dabigatran and/or other coagulation parameters is, however, still uncertain. We here describe the use of idarucizumab prior to acute surgery in a patient on dabigatran and acetylsalicylic acid. In this case, the decision to use idarucizumab was based on the clinical manifestations and other routine coagulation parameters, as the plasma dabigatran concentration was not available prior to administration. Due to challenges with the plasma dabigatran analysis and taking the safety of idarucizumab into consideration, it could be questioned whether a dabigatran measurement in general is necessary in this setting. Based on this case, we suggest a scheduled approach when considering requesting a plasma dabigatran measurement prior to administration of idarucizumab.
      PubDate: 2016-12-16T05:10:51.746-05:00
      DOI: 10.1111/bcpt.12696
       
 
 
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