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  Subjects -> ENVIRONMENTAL STUDIES (Total: 770 journals)
    - ENVIRONMENTAL STUDIES (696 journals)
    - POLLUTION (23 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (696 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   (Followers: 2)
Ambiência     Open Access  
Ambiens. Revista Iberoamericana Universitaria en Ambiente, Sociedad y Sustentabilidad     Open Access  
Ambiente & sociedade     Open Access   (Followers: 2)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Environmental Engineering     Open Access   (Followers: 16)
American Journal of Environmental Protection     Open Access   (Followers: 7)
American Journal of Environmental Sciences     Open Access   (Followers: 16)
American Journal of Microbiology     Open Access   (Followers: 15)
American Naturalist     Full-text available via subscription   (Followers: 64)
Annals of GIS     Hybrid Journal   (Followers: 21)
Annals of Warsaw University of Life Sciences - SGGW. Land Reclamation     Open Access  
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (Followers: 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: 27)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 12)
Applied and Environmental Soil Science     Open Access   (Followers: 15)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 15)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 13)
Aquatic Ecology     Hybrid Journal   (Followers: 30)
Aquatic Toxicology     Hybrid Journal   (Followers: 19)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 6)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 10)
Archives of Environmental Protection     Open Access   (Followers: 6)
Archives of Toxicology     Hybrid Journal   (Followers: 16)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 5)
Asian Journal of Rural Development     Open Access   (Followers: 7)
Asian Review of Environmental and Earth Sciences     Open Access   (Followers: 1)
Atas de Saúde Ambiental - ASA     Open Access  
ATBU Journal of Environmental Technology     Open Access   (Followers: 3)
Atmospheric and Climate Sciences     Open Access   (Followers: 28)
Atmospheric Environment     Hybrid Journal   (Followers: 66)
Austral Ecology     Hybrid Journal   (Followers: 12)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 11)
Australasian Journal of Human Security, The     Full-text available via subscription   (Followers: 3)
Avicenna Journal of Environmental Health Engineering     Open Access   (Followers: 2)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10)
Basic and Applied Ecology     Hybrid Journal   (Followers: 13)
Behavioral Ecology     Hybrid Journal   (Followers: 48)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 31)
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     Hybrid Journal   (Followers: 6)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 41)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 12)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 21)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 11)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 12)
Chain Reaction     Full-text available via subscription  
Challenges in Sustainability     Open Access   (Followers: 4)
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 15)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 61)
Civil and Environmental Engineering     Open Access   (Followers: 7)
Civil And Environmental Engineering Reports     Open Access   (Followers: 4)
Civil and Environmental Research     Open Access   (Followers: 18)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 20)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 6)
Cleanroom Technology     Full-text available via subscription   (Followers: 1)
Climate Change Economics     Hybrid Journal   (Followers: 12)
Climate Policy     Hybrid Journal   (Followers: 29)
Coastal Engineering Journal     Hybrid Journal   (Followers: 4)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 9)
Computational Ecology and Software     Open Access   (Followers: 8)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 4)
Conservation and Society     Open Access   (Followers: 11)
Conservation Letters     Open Access   (Followers: 32)
Conservation Science     Open Access   (Followers: 19)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 5)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 13)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 22)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 12)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 6)
Current Environmental Health Reports     Hybrid Journal  
Current Forestry Reports     Hybrid Journal  
Current Opinion in Environmental Sustainability     Hybrid Journal   (Followers: 13)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 7)
Current World Environment     Open Access   (Followers: 1)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 15)
Developments in Earth and Environmental Sciences     Full-text available via subscription   (Followers: 6)
Developments in Earth Surface Processes     Full-text available via subscription   (Followers: 3)
Developments in Environmental Modelling     Full-text available via subscription   (Followers: 7)
Developments in Environmental Science     Full-text available via subscription   (Followers: 5)
Developments in Integrated Environmental Assessment     Full-text available via subscription   (Followers: 6)
Disaster Prevention and Management     Hybrid Journal   (Followers: 20)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 14)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 6)
E3S Web of Conferences     Open Access  
Earth Interactions     Full-text available via subscription   (Followers: 11)
Earth Science Informatics     Hybrid Journal   (Followers: 3)
Earth System Science Data (ESSD)     Open Access   (Followers: 6)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 5)
Earthquake Science     Hybrid Journal   (Followers: 11)
EchoGéo     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 11)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 3)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 136)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecological Complexity     Hybrid Journal   (Followers: 7)
Ecological Indicators     Hybrid Journal   (Followers: 17)
Ecological Informatics     Hybrid Journal   (Followers: 5)
Ecological Management & Restoration     Hybrid Journal   (Followers: 14)
Ecological Modelling     Hybrid Journal   (Followers: 93)
Ecological Monographs     Full-text available via subscription   (Followers: 32)
Ecological Processes     Open Access   (Followers: 5)
Ecological Questions     Open Access   (Followers: 7)
Ecological Research     Hybrid Journal   (Followers: 10)
Ecological Restoration     Full-text available via subscription   (Followers: 23)
Ecologist, The     Full-text available via subscription   (Followers: 27)
Ecology     Full-text available via subscription   (Followers: 293)
Ecology and Evolution     Open Access   (Followers: 58)
Ecology Letters     Hybrid Journal   (Followers: 218)
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: 5)
Ecosystems     Hybrid Journal   (Followers: 28)
Ecotoxicology     Hybrid Journal   (Followers: 11)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 7)
Ecotrophic : Journal of Environmental Science     Open Access  
Ecozon@ : European Journal of Literature, Culture and Environment     Open Access   (Followers: 4)
Ekologija     Open Access  
Electronic Green Journal     Open Access   (Followers: 6)
Empowering Sustainability International Journal     Open Access   (Followers: 2)
Energy & Environmental Science     Full-text available via subscription   (Followers: 24)
Energy & Environment     Hybrid Journal   (Followers: 18)
Energy and Environment Focus     Free   (Followers: 6)
Energy and Environment Research     Open Access   (Followers: 11)
Energy and Environmental Engineering     Open Access   (Followers: 6)
Engenharia Sanitaria e Ambiental     Open Access  
Envigogika     Open Access  
Environment and Behavior     Hybrid Journal   (Followers: 20)
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: 49)
Environment and Planning B : Planning and Design     Full-text available via subscription   (Followers: 34)
Environment and Planning C : Government and Policy     Full-text available via subscription   (Followers: 36)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 49)
Environment and Pollution     Open Access   (Followers: 11)
Environment and Society     Full-text available via subscription   (Followers: 8)
Environment International     Hybrid Journal   (Followers: 11)
Environment of Care News     Full-text available via subscription   (Followers: 2)
Environment Systems & Decisions     Hybrid Journal   (Followers: 4)
Environment, Development and Sustainability     Hybrid Journal   (Followers: 33)
Environment, Space, Place     Full-text available via subscription   (Followers: 5)
Environment: Science and Policy for Sustainable Development     Hybrid Journal   (Followers: 42)
Environmental & Engineering Geoscience     Full-text available via subscription   (Followers: 4)
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: 9)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Claims Journal     Hybrid Journal   (Followers: 1)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 18)
Environmental Development     Hybrid Journal   (Followers: 3)
Environmental Disease     Open Access  
Environmental Education Research     Hybrid Journal   (Followers: 14)
Environmental Engineering Science     Hybrid Journal   (Followers: 8)
Environmental Ethics     Hybrid Journal   (Followers: 8)
Environmental Evidence     Open Access   (Followers: 1)
Environmental Fluid Mechanics     Hybrid Journal   (Followers: 5)
Environmental Forensics     Hybrid Journal   (Followers: 1)
Environmental Geosciences     Full-text available via subscription   (Followers: 4)
Environmental Geotechnics     Hybrid Journal   (Followers: 5)
Environmental Hazards     Hybrid Journal   (Followers: 2)
Environmental Health     Open Access   (Followers: 10)
Environmental Health Insights     Open Access   (Followers: 4)

        1 2 3 4 | Last

Journal Cover Basic & Clinical Pharmacology & Toxicology
  [SJR: 0.539]   [H-I: 70]   [10 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  [1584 journals]
  • Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung
           Cancer Patients with Bone Metastasis
    • Authors: Katalin Fábián; Rita Puskás, Tímea Kakuk, László Prés, Dorottya Fejes, Zsolt Szegedi, Lívia Rojkó, Zoltán Szállási, Balázs Döme, Orsolya Pipek, Judit Moldvay
      Abstract: Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Co-morbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 μmol/l, p
      PubDate: 2017-07-21T02:25:27.753067-05:
      DOI: 10.1111/bcpt.12854
  • Chitosan-Fe (III) Complex as a Phosphate Chelator in Uraemic Rats: A Novel
           Treatment Option
    • Authors: Wander Barros do Carmo; Bárbara Bruna Abreu Castro, Clóvis Antônio Rodrigues, Melani Ribeiro Custódio, Helady Sanders-Pinheiro
      Abstract: Phosphate retention and hyperphosphataemia are associated with increased mortality in chronic kidney disease (CKD) patients. We tested the use of cross-linked iron chitosan III (CH-FeCl) as a potential phosphate chelator in rats with CKD. We evaluated 96 animals, divided equally into 4 groups (control, CKD, CH-FeCl, and CKD/CH-FeCl), over 7 weeks. We induced CKD by feeding animals an adenine-enriched diet (0.75% in the first 4 weeks and 0.1% in the following 3 weeks). We administered 30 mg/kg daily of the test polymer, by gavage, from the third week until the end of the study. All animals received a diet supplemented with 1% phosphorus. Uraemia was confirmed by the increase in serum creatinine in week 4 (36.24 ± 18.56 versus 144.98 ± 22.1 μmol/L; p=0.0001) and week 7 (41.55 ± 22.1 versus 83.98 ± 18.56 μmol/L; p=0.001) in CKD animals. Rats from the CKD group treated with CH-FeCl had a 54.5% reduction in serum phosphate (6.10 ± 2.23 versus 2.78 ± 0.55 mmol/L) compared to a reduction of 25.6% in the untreated CKD group (4.75 ± 1.45 versus 3.52 ± 0.74 mmol/L, p=0.021), between week 4 and week 7. At week 7, renal function in both CKD groups was similar (serum creatinine: 83.98 ± 18.56 versus 83.10 ± 23.87 μmol/L, p=0.888); however, the CH-FeCl-treated rats had a reduction in phosphate overload measured by fractional phosphate excretion (FEPi) (0.71 ± 0.2 versus 0.4 ± 0.16, p=0.006) compared to the untreated CKD group. Our study demonstrated that CH-FeCl had an efficient chelating action on phosphate.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-20T06:20:54.960911-05:
      DOI: 10.1111/bcpt.12849
  • Gait and balance impairment after acute methanol poisoning
    • Authors: Kamila Peterová; Hana Brožová, Jiří Klempíř, Irena Lišková, Ondřej Bezdíček, Petr Ridzoň, Manuela Vaněčková, Sergej Zakharov, Daniela Pelclová, Michal Miovský, Evžen Růžička
      Abstract: Neurological sequelae including gait impairment were reported in survivors after methanol intoxication; however, no systematic study has been published so far. We aimed to analyse gait and balance impairment in a group of Czech methanol poisoning survivors.We examined 43 patients (age 46±13 years) 2-8 months after methanol poisoning and 43 healthy controls. Investigations contained a shortened version of Falls Efficacy Scale (FES), clinical tests of gait and balance including Timed Up and Go test (TUG) and gait analysis using GaitRite® system, neurological and neuropsychological examination, brain imaging, EMG and tests of alcohol consumption.Nineteen patients admitted balance and gait impairment according to FES. Mild to moderate parkinsonian signs showed 7 patients. Patients were slower (8.8 versus 5.7s, p
      PubDate: 2017-07-19T11:05:26.221356-05:
      DOI: 10.1111/bcpt.12853
  • Huprine X attenuates the neurotoxicity induced by kainic acid, especially
           brain inflammation
    • Authors: J. Relat; B. Pérez, P. Camps, D. Muñoz-Torrero, A. Badia, M.V. Clos
      Abstract: Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models in vivo and in vitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In the present study, we assessed the ability of HX (0.8 mg/kg, 21 days) to prevent the damage induced by kainic acid (KA; 28 mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain. KA administration significantly modified the levels of pAkt1, Bcl2, pGSK3β, p25/p35, increased the glial cell markers and reduced the neurogenesis process. We also observed that pre-treatment with HX significantly reduced the p25/p35 ratio and increased synaptophysin levels, which suggests a protective effect against apoptosis and an improvement of neuroplasticity. The increase in GFAP (88%) and Iba-1 (72%) induced by KA was totally prevented by HX pre-treatment, underlying a relevant anti-inflammatory action of the anticholinesterasic drug. Our findings highlight the potential of HX, in particular, and of AChEIs, in general, to treat a number of diseases that course with both cognitive deficits and chronic inflammatory processes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T11:00:32.814942-05:
      DOI: 10.1111/bcpt.12852
  • Role of the Long Non-Coding RNA GAS5 in Glucocorticoid Response in
           Children with Inflammatory Bowel Disease
    • Authors: Marianna Lucafò; Alessia Di Silvestre, Maurizio Romano, Alice Avian, Roberta Antonelli, Stefano Martelossi, Samuele Naviglio, Alberto Tommasini, Gabriele Stocco, Alessandro Ventura, M D Giuliana Decorti, Sara De Iudicibus
      Abstract: Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, in order to confirm the sensitivity and specificity of these lncRNA. These cells showed a different sensitivity to GCs, and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC-resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knockdown reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up-regultation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T10:15:56.792932-05:
      DOI: 10.1111/bcpt.12851
  • Effects of GIP, GLP-1 and GLP-1RAs on Bone Cell Metabolism
    • Authors: Morten S S Hansen; Michaela Terencova, Jacob Frølich, Moustapha Kassem, Morten Frost
      Abstract: The relationship between gut and skeleton is increasingly recognised as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism.We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify if similar effects are present and clinically relevant in humans.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T10:10:33.783209-05:
      DOI: 10.1111/bcpt.12850
  • Characterization of the Rabbit as an In Vitro and In Vivo Model to Assess
           the Effects of Fibrinogenolytic Activity of Snake Venom on Coagulation
    • Authors: Vance G. Nielsen; Elda E. Sánchez, Daniel T. Redford
      Abstract: Several in vitro investigations have demonstrated that anticoagulant effects of fibrinogenolytic snake venom metalloproteinases have been abrogated in human plasma by modifying fibrinogen with iron (Fe) and carbon monoxide (CO) to prevent catalysis or by directly inhibiting these enzymes with CO. In order to translate these findings, we chose to assess the rabbit as a model of envenomation with Crotalus atrox venom. It was determined with thrombelastography that 15-fold the concentration of venom noted to compromise coagulation in plasma in vitro was required to cause coagulopathy in vivo, likely secondary to venom binding to blood cells and being cleared from the circulation rapidly. Unlike human plasma, rabbit plasma pretreated with Fe/CO was not protected from fibrinogenolysis by venom. Consequently, the administration of purified human fibrinogen (with or without Fe/CO) would be required before venom administration to rabbits. Of greater interest, venom exposed to CO had complete loss of fibrinogenolytic effect in rabbit plasma and partial loss of activity in whole blood, indicative of unbinding of CO from venom and binding to hemoglobin. Thus, venom exposed to CO could remain partially or completely inhibited in whole blood long enough for clearance from the circulation, allowing rabbits to be a useful model to test the efficacy of regional CO administration to the bite site. Future investigations are planned to test these novel approaches to attenuate venom-mediated coagulopathy in the rabbit.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T09:25:42.666225-05:
      DOI: 10.1111/bcpt.12848
  • Severity of Baclofen Self-Poisoning Linked to Psychiatric Co-morbidity in
           Alcohol-Dependent Patients: Better Measurement of Risk and Benefit
    • Authors: Fanny Pelissier; Luc Haro, Benjamin Rolland, Nicolas Franchitto
      PubDate: 2017-07-10T18:50:32.001468-05:
      DOI: 10.1111/bcpt.12832
  • Tranexamic Acid in Total Knee Arthroplasty: Mixed Treatment Comparisons
           and Recursive Cumulative Meta-Analysis of Randomized, Controlled Trials
           and Cohort Studies
    • Authors: Kannan Sridharan; Gowri Sivaramakrishnan
      Abstract: Tranexamic acid (TXA) has been shown to be effective in patients with total knee arthroplasty (TKA) in clinical studies with no consensus with regard to the most appropriate route of administration. We conducted a network meta-analysis to compare the evidences available on efficacy and safety of TXA in TKA. Electronic databases were searched for randomized, clinical trials and cohort studies that evaluated TXA in TKA. Publication bias, risk of bias and inconsistencies were assessed. Direct and indirect comparisons were carried out for blood transfusion rate and incidence of thrombotic complications. Sensitivity analyses and grading of evidence was performed for key comparisons. A cumulative meta-analysis was conducted for comparisons that had a minimum of 10 included studies. A total of 19 studies with 8916 participants were pooled for this network meta-analysis. No inconsistencies and publication bias were observed. Low risk of bias was observed for the majority of the included studies. When compared to placebo, the pooled estimates for mixed treatment analyses favoured (in the order of higher ranking) the combined pre-operative oral and topical TXA, intra-operative intravenous TXA with topical TXA, pre-operative intravenous TXA, intra-operative and post-operative intravenous TXA, intra-operative intravenous bolus and topical TXA. Additionally, combined intravenous and topical TXA performed better than topical TXA alone. No significant changes were observed in the sensitivity analyses. No significant differences were observed in the risk of thrombotic complications between the interventions. TXA is efficacious and safe in patients with TKA. The combined topical and intra-operative intravenous TXA may perform better.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:17:01.423572-05:
      DOI: 10.1111/bcpt.12847
  • Statins and ACE Inhibitors are Associated with Reduced Mortality and
           Morbidity in Chronic Liver Disease
    • Authors: Knut Stokkeland; Christine Takami Lageborn, Anders Ekbom, Jonas Höijer, Matteo Bottai, Per Stål, Karin Söderberg-Löfdal
      Abstract: Liver fibrosis is a common response to many chronic liver diseases.The aim of our study was to explore whether pharmacotherapy for concurrent diseases affects overall mortality, liver-related mortality and liver-related morbidity in patients with chronic liver disease.We performed a register-based cohort study of all patients with a first-time diagnosis of chronic liver disease between 2005 and 2012 in Sweden (n=70 546). Data from the Patient Register, the Prescribed Drug Register and the Death Certificate Register were linked. We studied whether the use of statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and antibiotics affected the risk of total mortality, liver-specific mortality and morbidity.We found a reduction in mortality risk for statin users (n= 11 245) with hazard ratios from 0.57 (95%, CI 0.32-0.99) for patients with autoimmune hepatitis, to 0.84 (95%, CI 0.75-0.95) for alcoholic liver disease. There was a significant reduced liver-related mortality for patients with alcoholic liver disease who used angiotensin-converting enzyme inhibitors, 0.85 (95%, CI 0.65-0.96). There were increased overall mortality risks for antibiotic users (n=44 572), with hazard ratios up to 1.67 (95% CI, 1.55-1.80) for viral hepatitis.Statin use was associated with decreased risks of liver-specific mortality and morbidity, and reduced total mortality foremost among patients with alcoholic liver disease. Angiotensin-converting enzyme inhibitors was associated with reduced liver-related mortality among patients with alcoholic liver disease.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:11:16.801738-05:
      DOI: 10.1111/bcpt.12844
  • A Flow Cytometry-based Method for the Screening of Nanomaterial-induced
           Reactive Oxygen Species Production in Leukocyte Sub-Populations in Whole
    • Authors: Ali Kermanizadeh; Kim Jantzen, David M Brown, Peter Møller, Steffen Loft
      Abstract: To date, the use and translation of nanomedicine from the laboratory to the clinic has been relatively slow. Amongst other issues, one of the reasons for this tardiness is the lack of the availability of quick and reliable toxicity tools for the screening of nanomaterials (NMs). In the present investigation, we apply a flow cytometry-based method for the detection of nanomaterial-induced oxidative stress by measurement of reactive oxygen species production in specific leukocyte sub-populations in human whole blood. The screening of a panel of relevant nanomedical-associated materials (liposomes, silica, iron oxide and functionalised single-walled carbon nanotubes) demonstrated that only the carbon nanotubes induced oxidative stress in human circulating leukocytes. In summary, we apply and corroborate a flow cytometry based method for the simple and effective measurement of NM-induced oxidative stress in human blood sub-populations following realistic and relevant exposure scenarios which is extremely useful in future toxicological applications.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:11:15.229852-05:
      DOI: 10.1111/bcpt.12845
  • Crotalus atrox Venom Exposed to Carbon Monoxide Has Decreased
           Fibrinogenolytic Activity In Vivo in Rabbits
    • Authors: Vance G. Nielsen
      Abstract: Envenomation by hemotoxic enzymes remains a significant source of human morbidity and mortality worldwide, with administration of long-acting or multiple doses of antivenom first-line therapy. However, coagulopathy can still occur and recur. Of interest, it has been recently demonstrated that direct, isolated exposure of snake venom enzymes with fibrinogenolytic activity to carbon monoxide (CO) abrogates venom-mediated loss of coagulation in human plasma. These observations of CO inhibition of venom fibrinogenolytic activity were subsequently repeated in rabbit whole blood. The present study sought to translate these findings in an in vivo rabbit model of envenomation with fibrinogenolytic Crotalus atrox venom. Sedated rabbits were intravenously administered C. atrox venom (400 μg/kg) pre-exposed to 0 or 1000 μM carbon monoxide releasing molecule-2 (CORM-2) in vitro. Arterial whole-blood samples demonstrated that compared to pre-envenomation values, the CORM-2 naïve venom significantly prolonged the onset of coagulation, decreased the velocity of clot growth and decreased clot strength as determined by thrombelastography an hour after venom injection. In contrast, CORM-2 pre-exposure prevented or attenuated C. atrox venom effects on coagulation kinetics. Future studies to determine if rabbits injected with such venom subcutaneously/intramuscularly can have consequent coagulopathy abrogated by injection of carbon monoxide releasing molecules into the “bite site” are justified.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:11:08.501134-05:
      DOI: 10.1111/bcpt.12846
  • Relaxing Responses to Hydrogen Peroxide and Nitric Oxide in Human
           Pericardial Resistance Arteries Stimulated with Endothelin-1
    • Authors: Thomas M. Leurgans; Maria Bloksgaard, Akhmadjon Irmukhamedov, Lars P. Riber, Jo G. R. De Mey
      Abstract: In human pericardial resistance arteries, effects of the endothelium-dependent vasodilator bradykinin are mediated by NO during contraction induced by K+ or the TxA2 analogue U46619 and by H2O2 during contraction by endothelin-1 (ET-1), respectively. We tested the hypotheses that ET-1 reduces relaxing effects of NO and increases those of H2O2 in resistance artery smooth muscle of patients with cardiovascular disease.Arterial segments, dissected from the parietal pericardium of 39 cardiothoracic surgery patients, were studied by myography during amplitude-matched contractions induced by K+, the TXA2 analogue U46619 or ET-1. Effects of the NO-donor Na-nitroprusside (SNP) and of exogenous H2O2 were recorded in absence and presence of inhibitors of cyclooxygenases, NO-synthases and small and intermediate conductance calcium-activated K+ channels.During contractions induced by either of the three stimuli, the potency of SNP did not differ and was not modified by the inhibitors. In vessels contracted with ET-1, the potency of H2O2 was on average and in terms of inter-individual variability considerably larger than in K+-contracted vessels. Both differences were not statistically significant in presence of inhibitors of mechanisms of endothelium-dependent vasodilatation.In resistance arteries from patients with cardiovascular disease, ET-1 does not selectively modify smooth muscle relaxing responses to NO or H2O2. Furthermore, the candidate endothelium-derived relaxing factor H2O2 also acts as an endothelium-dependent vasodilator.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-07T10:15:23.489656-05:
      DOI: 10.1111/bcpt.12843
  • GSTP1 c.313A>G, XPD c.934G>A, XPF c.2505T>C and CASP9 c.-1339A>G
           Polymorphisms and Severity of Vomiting in Head and Neck Cancer Patients
           treated with Cisplatin Chemoradiation
    • Authors: Juliana Carron; Leisa Lopes-Aguiar, Ericka Francislaine Dias Costa, Guilherme Augusto Silva Nogueira, Tathiane Regine Penna Lima, Eder Carvalho Pincinato, Marilia Berlofa Visacri, Júlia Coelho França Quintanilha, Patrícia Moriel, Gustavo Jacob Lourenço, Carmen Silvia Passos Lima
      Abstract: Cisplatin (CDDP) chemotherapy associated with radiation (RT) has been used in advanced head and neck squamous cell carcinoma (HNSCC) patients, and vomiting is a common side effect during treatment. This prospective study aimed to identify the roles of GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.−93G>A, MSH2 c.211+9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-1168G>T, CASP9 c.-1339A>G, CASP8 c.-937_-932delAGTAAG, FAS c.-1378G>A and c.-671A>G, and FASL c.-157-687C>T single nucleotide polymorphisms, involved in CDDP metabolism, in vomiting severity in 88 HNSCC patients treated with CDDP and RT. Ondansetron and dexamethasone were administered as antiemetic therapy. Patients with GSTP1 c.313AG or GG genotype alone and combined with XPD c.934GA or AA, XPF c.2505TC or CC, and CASP9 c.-1339AG or GG genotypes had 4.28, 5.00, 5.45, and 5.38 more chances of presenting moderate/severe vomiting than patients with others genotypes. Our data suggest, for the first time, that inherited abnormality in apoptosis pathway alone or combined with inherited abnormalities in DNA repair pathway, are capable of modulating emesis in HNSCC patients under CDDP chemoradiation and may be used for selecting patients who should receive preemptive antiemetic therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-07T08:40:20.992785-05:
      DOI: 10.1111/bcpt.12842
  • Global Trends in Aspirin Resistance-Related Research from 1990 to 2015: A
           Bibliometric Analysis
    • Authors: Samah W. Al-Jabi
      Abstract: Aspirin resistance can be defined as the inability of the usual dose of aspirin medication to produce its antithrombotic effect. Patients with diabetes or cardiovascular disease are at higher risk of stroke, myocardial infarction or cardiovascular death due to aspirin resistance. The aim of this bibliometric study was to identify and analyse the status and trends of aspirin resistance research production at global level through publications indexed in Scopus database; this will shed new light on future research trends and help researchers predict dynamic direction of research. Literature search using Scopus database was conducted to assess publications related to aspirin resistance. The selected publications included the terms related to aspirin resistance in the title, abstract or keywords. The searching was accomplished on 20 March 2016 and can be considered to include all publications up to 31 December 2015. Global cumulative publication output on aspirin resistance consists of 986 papers during 1990–2015. Among the 986 documents, 19 (1.9%) were published before 2000, 567 (57.5%) were published from 2000 to 2009 and 400 (40.6%) were published from 2010-2015, with peak of publications on this topic in 2008. The leading country in the field of aspirin resistance was the USA, which had the greatest counts of independent articles (165) and international collaboration articles (44). Turkey was in the second rank with 78 articles, followed by Italy (68), the UK (62) and Poland (60). The total number of citations for all documents was 26,342, and the average citations per document were 26.7. The h-index for all aspirin resistance publications was 82. This study presents the results of the first bibliometric study (including quantitative and qualitative analysis) of scientific publications in the field of aspirin renitence at global level. Aspirin resistance-related researches have notably increased in the last years, especially from 2000 to 2015. The USA is the most prolific country, not only in research quantity but also in quality. Furthermore, Turkey and European countries provided more research related to aspirin resistance than other regions such as the developing countries.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-01T09:25:24.188738-05:
      DOI: 10.1111/bcpt.12840
  • Oral Administration of Polaprezinc Attenuates Fluorouracil-induced
           Intestinal Mucositis in a Mouse Model
    • Authors: Zhaoyang Liu; Wenbo Xie, Mingru Li, Nan Teng, Xiao Liang, Ziqiang Zhang, Zhaogang Yang, Xiaobing Wang
      Abstract: 5-fluorouracil (5-FU) has broadly been applied to treat colorectal cancer as one of the most effective chemotherapeutic agents. However, it frequently causes intestinal mucosal injury and related side effects, such as abdominal pain and diarrhoea, which limit the use of 5-FU in a clinic setting. Polaprezinc has gradually become known as a mucosal protective agent for the management of gastric ulcer. This study aimed to investigate the prophylactic efficacy of Polaprezinc administered orally against intestinal mucositis induced by 5-FU in mice on the condition that the anti-tumour effect could not be compromised. We induced intestinal mucositis in SPF grade ICR mice with 5-FU, and evaluated intestinal damage in the absence or presence of Polaprezinc. We examined the score of diarrhoea and the loss of weight following the 5-FU treatment, and assessed the integrity of villus and the proliferation of small intestine crypt cells by Hematoxylin&Eosin staining and PCNA immunohistochemical detection. The anti-tumour effect of 5-FU on colorectal cancer was assessed with or without Polaprezinc in a xenograft model. The result showed that Polaprezinc significantly reduced the elevated diarrhoea score and the body weight loss caused by 5-FU, abolished histological abnormality and crypt cell hypoproliferation in a dose-dependent manner, without affecting 5-FU efficacy on colon xenograft tumour in mice. We conclude that Polaprezinc could inhibit 5-FU-induced diarrhoea and alleviate the weight loss during 5-FU chemotherapy, as a possible candidate for treatment and prevention of intestinal mucositis, through protecting intestinal mucosa and improving the quality of life following chemotherapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-01T09:25:21.76578-05:0
      DOI: 10.1111/bcpt.12841
  • Haloperidol Decreases Hyperalgesia and Allodynia Induced by Chronic
           Constriction Injury
    • Authors: Josué Vidal Espinosa-Juárez; Osmar Antonio Jaramillo-Morales, Francisco Javier López-Muñoz
      Abstract: Neuropathic pain has proven to be a difficult condition to treat, so investigational therapy has been sought that may prove useful, such as the use of sigma-1 antagonists. Haloperidol (HAL) is a compound that shows a high affinity with these receptors, acting as an antagonist. Therefore, the objective of this study was to demonstrate its effect in an experimental model of neuropathic pain and corroborate its antagonistic action of the sigma-1 receptors under these conditions. BD-1063 was used as a sigma-1 antagonist control and gabapentin was used as a positive control. The anti-hyperalgesic and anti-allodynic effects of the drugs were determined after single-dose trials. In every case, the effects increased in a dose-dependent manner. HAL had the same efficacy as both BD-1063 and gabapentin. In the analysis of pharmacological potency, in which the ED50 were compared, HAL was the most potent drug of all. The effect of HAL on chronic constriction injury (CCI) rats was reversed by the sigma-1 agonist (PRE-084). HAL reversed the hyperalgesic and allodynic effects of PRE-084 in naïve rats. The dopamine antagonist, (-)-sulpiride, showed no effect in CCl rats. These results suggest that HAL presents an antinociceptive effect via sigma-1 receptor antagonism at the spinal level in the CCl model.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-27T10:45:20.529354-05:
      DOI: 10.1111/bcpt.12839
  • Sensitivity and Reliability of Halothane-Anaesthetized Microminipigs to
           Assess Risk of Drug-induced Long QT Syndrome
    • Authors: Xin Cao; Takeshi Wada, Yuji Nakamura, Suchitra Matsukura, Hiroko Izumi-Nakaseko, Kentaro Ando, Atsuhiko T. Naito, Atsushi Sugiyama
      Abstract: Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n=4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 μg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane-anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT-interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-27T10:45:19.13994-05:0
      DOI: 10.1111/bcpt.12838
  • Physicians’ Non-Uniform Approach to Prescribing Drugs to Older Patients
           – A Qualitative Study
    • Authors: Line Due Christensen; Janne Petersen, Ove Andersen, Susanne Kaae
      Abstract: Multi-morbidity and polypharmacy are common in older patients and increase their susceptibility to adverse drug events and hospitalizations. Rational drug prescription is critical, however, little is known about physicians’ perspectives on how to prescribe drugs for older patients. The aim of this study was to explore physicians’ approach to prescribe drugs to older patients, including identifying the drugs that physicians perceive to be risk drugs for older patients and comparing them with established lists of potentially inappropriate medications. Short semi-structured interviews were conducted with 50 medical specialists in 23 different specialities throughout Denmark who had contact with older patients. Content analysis was performed to identify the relevant themes. Regardless of their medical or surgical background and how often they prescribed drugs for older patients in daily work, all physicians expressed a cautious approach when prescribing risk drugs. Despite their shared caution, physicians had different strategies for prescribing drugs to older patients. The following strategies were identified: 1) “Start low, go slow”, 2) “Trial and error”, 3) “Dose reduction”, and 4) “Never prescribe”. The most frequently mentioned risk drugs considered to cause hospitalization were vitamin K antagonists, opioids and diuretics; these drugs are relatively highly consistent with established lists of PIMs.Physicians were relatively knowledgeable about risk drugs. Although the physicians agreed that a cautious approach was needed when prescribing drugs for older people, there was no consensus about how to best accomplish this in practice.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T12:10:22.010742-05:
      DOI: 10.1111/bcpt.12837
  • Reply to ‘Multiple and Opposite Effects of Angiotensin II Receptor
           Blockers on the Bioavailability of Epoxyeicosatrienoic Acids’
    • Authors: Asuna Senda; Yuji Mukai, Toru Hayakawa, Yuka Kato, Erik Eliasson, Anders Rane, Takaki Toda, Nobuo Inotsume
      PubDate: 2017-06-22T02:00:22.349371-05:
      DOI: 10.1111/bcpt.12811
  • Multiple and Opposite Effects of Angiotensin II Receptor Blockers on the
           Bioavailability of Epoxyeicosatrienoic Acids
    • Authors: Jeremy Bellien; Matthieu Leuillier, Safa Louhichi, Thomas Duflot, Robinson Joannides
      PubDate: 2017-06-22T01:50:55.631634-05:
      DOI: 10.1111/bcpt.12810
  • A High HASBLED Score Identifies Poor Warfarin Control in Patients treated
           for Non-Valvular Atrial Fibrillation in Australia and Singapore
    • Authors: Nijole Bernaitis; Ching Chi Keong, Chen Liping, Hon Jin Shing, Teo Siew Chong, Tony Badrick, Andrew K. Davey, Shailendra Anoopkumar-Dukie
      Abstract: Warfarin reduces stroke risk in atrial fibrillation (AF) patients. The quality of warfarin control, measured by time in therapeutic range (TTR), impacts outcomes and adverse events. One tool evaluating risk of adverse events and potential warfarin control would simplify risk-benefit assessment of warfarin. Recently, HASBLED was demonstrated effective for this purpose but this was in well-controlled patients with deep vein thrombosis. HASBLED as a predictor of warfarin control has not been validated in other populations including differing indications, warfarin control levels and ethnicities. The aim of this study was to determine if HASBLED can predict warfarin control in patients with AF in Australia and Singapore.Retrospective data were collected for patients receiving warfarin between January and June 2014 in Australia and Singapore. Patient data were used to calculate HASBLED at the start and end of the study period. TTR was calculated for each patient, and mean TTR used for analysis to stratified HASBLED scores.Of the 4370 patients, there were 3199 in Australia and 1171 in Singapore with mean TTRs of 82% and 58%, respectively. At the start of the study, a HASBLED score ≥3 predicted significantly lower TTR in Singapore, whilst at the end of the study, this score identified patients with poor control in both Australia and Singapore.A HASBLED score ≥3 in patients treated with warfarin can differentiate significantly lower TTRs in Australian and Singapore patients with AF. HASBLED may assess bleed risk and warfarin control, identifying patients at high risk of poor warfarin outcomes requiring additional INR monitoring or alternative anticoagulation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:35:24.92709-05:0
      DOI: 10.1111/bcpt.12836
  • The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy
           Danish Volunteers
    • Authors: Claus Stage; Gesche Jürgens, Louise Schow Guski, Ragnar Thomsen, Ditte Bjerre, Laura Ferrero-Miliani, Yassine Kamal Lyauk, Henrik Berg Rasmussen, Kim Dalhoff,
      Abstract: The present study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: Group 1 (controls, n=16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n=5) with four copies of CES1; group 3 (n=6) harbouring the G143E polymorphism; group 4 (n=2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n=4) harbouring the CES1A1c variant; and group 6 (n=10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 μg/l x h in the control group versus 310, 282, 294, 344 and 306 μg/l x h in group 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared to the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:32:48.074534-05:
      DOI: 10.1111/bcpt.12835
  • Vascular Calcification, Vitamin K and Warfarin Therapy – Possible or
           Plausible Connection'
    • Authors: Aino Siltari; Heikki Vapaatalo
      Abstract: Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long-term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma-carboxylation, is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K–dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:32:44.369507-05:
      DOI: 10.1111/bcpt.12834
  • Decrease in Oxidative Stress Parameters after Post-Ischaemic Recombinant
           Human Erythropoietin Administration in the Hippocampus of Rats Exposed to
           Focal Cerebral Ischaemia
    • Authors: Jasenka Mršić-Pelčić; Kristina Pilipović, Goran Pelčić, Dinko Vitezić, Gordana Župan
      Abstract: Recombinant human erythropoietin (rhEpo) is a multifunctional drug with antioxidant potential. However, the underlying molecular mechanisms of its action are still unclear. The purpose of this study was to investigate the effects of rhEpo on the brain infarct volume as well as on the levels of the neuronal damage, oxidative stress parameters and active caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expressions in the hippocampi of rats exposed to the right middle cerebral artery occlusion (MCAO) for 1 hr. Ischaemic animals received either vehicle or rhEpo (5000 IU/kg, i.p.) immediately or 3 hr after the induction of ischaemia. Sham-operated, vehicle-treated animals served as the control group. Rats were killed 24 hr after the onset of the ischaemic or sham experimental procedure. MCAO caused ipsilateral brain infarction within the striatum and cortex. In the CA1 region of the hippocampi, we did not find significant neuronal loss but a statistically significant rise in the active caspase-3 and Nrf2 protein expressions was registered. We detected also significant increases in the hippocampal levels of oxidative stress parameters (thiobarbituric acid-reactive substances, superoxide dismutase, glutathione peroxidase). Post-ischaemic administration of rhEpo significantly reduced the brain infarct volume, decreased levels of all tested oxidative stress parameters and increased the Nrf2 expression level. These findings suggest that decrease in oxidative stress parameters in the hippocampus could be an early indicator of post-ischaemic neuroprotective effect of rhEpo in rats exposed to focal cerebral ischaemia, and that this effect could be attributable to additional post-ischaemic activation of Nrf2 endogenous antioxidant system.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:32:21.324049-05:
      DOI: 10.1111/bcpt.12833
  • Suspected Methadone Toxicity; from Hospital to Autopsy Bed
    • Authors: Jaber Gharehdaghi; Asieh Takalloo-Bakhtiari, Hossein Hassanian-Moghaddam, Nasim Zamani, Mohammad-Javad Hedayatshode
      Abstract: High mortality rates have been reported for methadone in both adults and children. We aimed to determine the pattern of toxicity, possible underlying diseases and treatment challenges in patients referred to our center with early diagnosis of methadone toxicity and who later died. Medical files of all methadone-poisoned patients who had been admitted to a referral center of toxicology between March 2011 and March 2016, died during the hospital stay and sent for autopsy to Legal Medicine Organization were retrospectively evaluated. In a total of 94 patients, autopsy findings and laboratory evaluations showed that cause of death was pure methadone toxicity in 57 (60.6%). Other causes of death were ischaemic heart disease in ten, co-ingestions (toxicities including methadone) in eight, brain haemorrhage, multi organ failure, and pneumosepsis (each in four), meningitis/encephalitis in three, and head trauma and other toxicities (other than methadone but including an opioid, each in two) patients. Time of cardiopulmonary arrest was significantly different between those with pure methadone toxicity and those who died due to other causes (p=0.01). Patients who had died due to co-ingestions and other toxicities were younger (p=0.029) and took more bolus doses of naloxone (p=0.042). In methadone users, especially in older ages and those with trivial response to naloxone administration, loss of consciousness should not be strictly attributed to methadone toxicity. In such patients, thorough evaluation for other possible causes of loss of consciousness is mandatory.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T07:01:03.409213-05:
      DOI: 10.1111/bcpt.12831
  • The Acute Effect of Loperamide on Ileostomy Output: A Randomized,
           Double-blinded, Placebo-controlled, Cross-over Study
    • Authors: Katrine Kristensen; Niels Qvist
      Abstract: High stoma output is a common problem in patients with ileostomy and can lead to dehydration and electrolyte disturbances. The first drug of choice to reduce stoma output is often loperamide.The aim was to assess the acute effect of loperamide on (a) ileostomy output in g/day, (b) gastrointestinal transit time and (c) patient-reported effects.A total of 12 patients completed this double-blinded, randomized, placebo-controlled, cross-over study, consisting of a 3-day treatment period with loperamide 12 mg/day or placebo followed by the reverse after a washout period of 5-7 days. Patients collected stoma output and noted food and fluid intake over 48 hr and swallowed a capsule with radiopaque markers for the determination of gastrointestinal transit time over 24 hr. At the end of the study, patients were asked to report their treatment sequence.Ileostomy output was significantly reduced during loperamide treatment (P
      PubDate: 2017-06-19T07:00:42.571229-05:
      DOI: 10.1111/bcpt.12830
  • Clinical Experience with the Integrase Inhibitors Dolutegravir and
           Elvitegravir in HIV-infected Patients: Efficacy, Safety and Tolerance
    • Authors: Purificación Cid-Silva; Josep María Llibre, Noelia Fernández-Bargiela, Luis Margusino-Framiñán, Vanesa Balboa-Barreiro, Berta Pernas-Souto, Isabel Martín-Herranz, Ángeles Castro-Iglesias, Eva Poveda-López
      Abstract: Two integrase inhibitors (INSTIs), Dolutegravir (DTG) and Elvitegravir/Cobicistat (EVG/COBI) have joined recently the pharmacotherapy arsenal against HIV. This study evaluated the efficacy and tolerability of these INSTIs in the last two years. A retrospective observational study in patients who started DTG or EVG/COBI from January 2015 to January 2017 at a reference hospital in Northwestern Spain was done. Epidemiological, clinical and immunovirological data were recorded. A statistical analysis was performed using SPSS software. A total of 542 DTG (n=275) or EVG/COBI (n=267) based therapies were initiated during the study period. Overall,>90% of naïve and pre-treated patients had virological suppression in both groups after 48 weeks of treatment initiation per-protocol snapshot analysis. During follow-up, 10.2% of patients treated with DTG and 4.5% of those treated with EVG discontinued due to adverse events (AE). In the case of DTG mainly related to neuropsychiatric disturbances (70.4%) and for EVG/COBI with gastrointestinal discomfort (50%). Female sex (HR 2.255 [95%CI 1.121-4.535], p=0.023) and DTG treatment (HR 2.453 [95%CI 1.221-4.931], p=0.012) were associated with AE discontinuations. Specifically for neuropsychiatric events, DTG treatment (HR 5.906 [95%CI 1.954-17.846], p=0.002) and receiving abacavir/lamivudine/DTG (HR 4.380 [95%CI 1.348-14.233], p=0.014) were identified as predictive risk factors for treatment discontinuations in two different multivariate analysis. A high percentage of AE discontinuations not previously described in clinical trials has been observed, especially with DTG. Female gender and DTG treatment were identified as risk factors for AEs discontinuation. DTG-based therapies, especially in combination with abacavir/lamivudine, were associated with an increased risk of treatment discontinuation due to neuropsychiatric AE.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T06:55:40.993935-05:
      DOI: 10.1111/bcpt.12828
  • Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias
    • Authors: Gerrit Frommeyer; Jan Weller, Christian Ellermann, Nils Bögeholz, Patrick Leitz, Dirk G. Dechering, Simon Kochhäuser, Kristina Wasmer, Lars Eckardt
      Abstract: The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of the present study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias.Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34ms,p
      PubDate: 2017-06-19T06:55:35.371747-05:
      DOI: 10.1111/bcpt.12829
  • The COMT Val(108/158)Met Genetic Polymorphism can not be Recommended as a
           Biomarker of Prediction of Venlafaxine Efficacy in Patients treated in
           Psychiatric settings
    • Authors: Adela Taranu; Khalil El Asmar, Romain Colle, Florian Ferreri, Mircea Polosan, Denis David, Laurent Becquemont, Emmanuelle Corruble, Céline Verstuyft
      Abstract: The antidepressant venlafaxine is known to increase the turn-over of cerebral monoamines, which are catabolized by the cathecol-O-methyltransferase (COMT). The COMT (Val108/158Met, rs4680) genetic polymorphism affects the cerebral COMT activity. But whether this genetic polymorphism is associated with response to venlafaxine remains unclear. We assessed the impact of the COMT Val(108/158)Met, rs4680 genetic polymorphism on the efficacy of venlafaxine in depressed patients. This study was nested in the METADAP cohort, a real-world naturalistic treatment study in psychiatric settings. 206 Caucasian patients with a unipolar Major Depressive Episode (DSM-IVTR) treated with venlafaxine and evaluated with the Hamilton Depression Rating Scale (HDRS) were studied. 180 patients were genotyped for the COMT Val(108/158)Met, rs4680 genetic polymorphism and classified into 3 genotype subgroups: Val/Val, Val/Met, Met/Met. The COMT genotype was the explanatory variable and the variables to be explained were the HDRS score, the HDRS score improvement over time, response and remission rates. Venlafaxine had a trend to higher efficacy in the Val/Val patients as compared to Met/Met carriers, as shown by the HDRS score improvement after 3 months of treatment but this result was not significant in mixed models (Val/Val: 59.78% (±22.4); Val/Met: 51.64% (±26.3); Met/Met: 39.52% (±27.6). The percentage of responders and remitters after 3 months of treatment were not significantly different in the 3 genotype groups, although coherent trends were shown. The COMT Val(108/158)Met, rs4680 genetic polymorphism can not be recommended as a biomarker of prediction of venlafaxine efficacy in patients treated in psychiatric settings.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T06:50:31.234945-05:
      DOI: 10.1111/bcpt.12827
  • The Effect of Genetic Polymorphisms in SLCO2B1 on the Lipid-lowering
           Efficacy of Rosuvastatin in Healthy Adults with Elevated Low-density
    • Authors: Tae-Eun Kim; Dong-Seong Shin, Namyi Gu, Byung Hwa Jung, Jayoun Kim, Young Min Cho, Kyung-Sang Yu, Joo-Youn Cho
      Abstract: Rosuvastatin is an HMG-CoA reductase inhibitor widely used for treating hypercholesterolaemia. We investigated whether genetic polymorphisms in solute carrier organic anion transporter 2B1 (SLCO2B1) affect the lipid-lowering effect of rosuvastatin in healthy adults with elevated low-density lipoprotein (LDL).This study included 18 volunteers with LDL levels above 130 mg/dL. Rosuvastatin (20 mg) was administered once a day for 8 weeks. Blood samples were drawn before and after the 8-week treatment to measure changes in lipid levels. The presence of single nucleotide polymorphisms (SNPs) of SLCO2B1 (c.935G>A and c.1457C>T), SLCO1B1 (c.521C>T, c.388A>G, and c.-11187G>A) and ABCG2 (c.421C>A) were determined by genotyping. Responses to rosuvastatin were compared between wild-type and variant genotypes using permutation test on each polymorphism.In volunteers with SLCO2B1 c.935G>A (rs12422149) variant, rosuvastatin was less effective at lowering LDL (mean % decrease: GG 62.8% GA 50.6% AA 49.3%, p=0.012) and apoprotein B (mean % decrease: GG 52.1% GA 42.8% AA 42.8%, p=0.036). Regarding SLCO2B1 c.1457C>T (rs2306168) SNP, there was no significant difference between wild-type and variant genotypes.This study demonstrated that SLCO2B1 c.935G>A (rs12422149) polymorphism influenced the lipid-lowering effects of rosuvastatin in volunteers with hypercholesterolaemia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T06:50:18.699953-05:
      DOI: 10.1111/bcpt.12826
  • Study of the Cytotoxic and Bactericidal Effects of Sila-substituted
           Thioalkyne and Mercapto-thionecompounds based on 1,2,3-Triazole Scaffold
    • Authors: Hanieh Mousazadeh; Mortaza Milani, Nosratollah Zarghami, Effat Alizadeh, Kazem D. Safa
      Abstract: A series of sila-organosulfur compounds containing 1,2,3-triazole cores were screened for their cytotoxic activity on human breast cancer cell line MCF-7. Most of the tested compounds exhibited moderate to good activity against the cancer cells. Especially, the compound 4-((2-(trimethylsilyl)ethynylthio)methyl)-1-benzyl-1H-1,2,3-triazole 3a from series of sila-substituted thioalkyne 1,2,3-triazoles (STATs) and the compounds 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-mercapto-1,1-bis(trimethylsilyl)propane-2-thione 4a and 1-Mercapto-1,1-bis(trimethylsilyl)-3-(1-phenethyl-1H-1,2,3-triazol-4-yl)propane-2-thione 4e from series of sila-substituted mercapto-thione 1,2,3-triazoles (SMTTs)exhibited promising cytotoxicity against MCF-7 with IC50 values of 35.17, 32.63 and 30.3 μg/mL, respectively. In addition, the possible mechanisms for inhibition of cell growth and induction of apoptotic cell death were explored by DAPI staining, cell cycle analysis and qRT-PCR.The synthetic compounds were evaluated for their in vitro anti-bacterial activities, and as a result the most prominent effects were observed for 3e and 4e. Especially, 3e was found to be quite active against all the tested strains with the MIC values ranging from 15 to 62 μg/mL, except P. aeruginosa. The results of the time-kill assay suggested that the compound of 3e completely inhibited the growth of both gram-negative bacteria A. baumannii and gram-positive bacteria S. aureus. In addition, SEM analysis confirmed morphostructural damage of the bacteria. Our findings could be applicable for developing dual targeting anti-cancer/anti-bacterial therapeutics.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-14T09:45:20.968194-05:
      DOI: 10.1111/bcpt.12822
  • Could Modafinil Prevent Psychostimulant Addiction' An Experimental
           Study in Rats
    • Authors: Verônica Tironi Dias; Luciana Taschetto Vey, Higor Zuquetto Rosa, Lívia Ferraz D'avila, Raquel Cristine Silva Barcelos, Marilise Escobar Burger
      Abstract: Addiction is a serious health problem which leads to general social impairment. The period of adolescence plays a significant role in drug abuse liability. Psychostimulants, such as modafinil (MOD), are majorly used by teenagers seeking improvements in cognition, which contributes to its indiscriminate use. The present study aimed to investigate the influence of MOD (64 mg/kg by gavage, once a day) treatment during adolescence (PND 28-42) on amphetamine (AMPH, 4 mg/kg i.p.) conditioned place preference (CPP) in early adulthood (PND 60). Our findings showed that AMPH increased CPP for the drug and anxiety-like behaviours; on the other hand, AMPH decreased the number of crossings and recognition index. In addition, AMPH decreased catalase activity and increased reactive species, malondialdehyde and carbonyl protein levels in the hippocampus. AMPH also increased pro-BDNF, Trk-B, DAT, D1R and decreased BDNF and D2R immunoreactivity. Contrarily, animals pre-exposed to MOD showed reduced AMPH-CPP, no locomotor impairment, less anxiety-like behaviours and no memory deficits. In addition, MOD showed antioxidant activity by preventing AMPH-induced oxidative damage in the hippocampus. Moreover, molecular analysis showed that MOD was able to modulate the hippocampal dopaminergic system, thus preventing AMPH-induced impairments. Animals that received MOD during adolescence showed reduced AMPH-CPP in early adulthood. These unexpected behavioural effects of MOD on CPP could be due to its hippocampal dopaminergic system modulation, mainly by its action on D1R, which is closely linked to drug addiction. Nevertheless, further studies are necessary.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-14T03:45:21.238069-05:
      DOI: 10.1111/bcpt.12821
  • Voriconazole Concentrations in Plasma and Epithelial Lining Fluid after
           Inhalation and Oral Treatment
    • Authors: Charlotte U. Andersen; Lene Dahl Sønderskov, Elisabeth Bendstrup, Nina Voldby, Lindsey Cass, John Ayrton, Ole Hilberg
      Abstract: Adverse effects can compromise oral voriconazole treatment of pulmonary aspergillosis. Inhaled low-dose voriconazole may be an alternative treatment.In this study, six patients inhaled 40 mg voriconazole b.i.d. for two days, and six patients ingested 400 and 200 mg orally b.i.d. on day one and two, respectively. Blood samples were collected after the first inhalation, and bronchial alveolar lavage fluids and blood samples were collected for measurements of voriconazole 12 hr after the last administration. The concentration of voriconazole in epithelial lining fluid (ELF) was calculated by the urea dilution method.Voriconazole concentrations were detectable in plasma 15 min. after inhalation, and declined at 30 and 60 min. Twelve hours after the last dose, median (95%CI) plasma voriconazole concentration was 8 (4-26) ng/mL in the inhalation group, and 1224 (535-2341) ng/mL in the oral group (p
      PubDate: 2017-06-13T13:15:26.017874-05:
      DOI: 10.1111/bcpt.12820
  • Chemogenetic Modulation of G Protein-Coupled Receptor Signalling in Visual
           Attention Research
    • Authors: Søren H. Jørgensen; Ciarán Martin Fitzpatrick, Ulrik Gether, David D.P. Woldbye, Andreas T. Sørensen
      Abstract: Attention is a fundamental cognitive process involved in nearly all aspects of life. Abnormal attention control is a symptom of many neurological disorders, most notably recognized in ADHD (attention deficit hyperactivity disorder). Although attentional performance and its malfunction has been a major area of investigation, it has proven difficult to accurately associate specific neuronal projections, cell types, neurotransmitter systems and receptors with distinct phenotypes owing to its complexity. In this MiniReview, we present a recently invented technology known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). The DREADD technology is an emerging and transformative method that allows selective manipulation of G protein-coupled receptor (GPCR) signalling, and its broad-ranging usefulness in attention research is now beginning to emerge. We first describe the different DREADDs available and explain how unprecedented specificity of neuronal signalling can be achieved using DREADDs. We next discuss various studies performed in animal models of visual attention, where different brain regions and neuronal populations have been probed by DREADDs. We highlight the interplay between the dopamine (DA) and noradrenaline (NA) catecholamine systems in visual attention, and explain why DREADD technology can untangle and help us better understand such complex systems in normal and malfunctioning conditions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-13T13:10:23.293584-05:
      DOI: 10.1111/bcpt.12819
  • Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental
           Chronic Kidney Disease
    • Authors: Badreldin H. Ali; Suhail Al-Salam, Yousuf Al Suleimani, Jamila Al Kalbani, Shadia Al Bahlani, Mohammed Ashique, Priyadarsini Manoj, Buthaina Al Zhili, Nadia Al Abri, Heba T. Naser, Javed Yasin, Abderrahim Nemmar, Mohamed Al Za'abi, Christina Hartmann, Nicole Schupp
      Abstract: Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong anti-oxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD.Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue.Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-β-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced the adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1β, IL-6 and TNFα, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level.In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-31T07:25:30.445982-05:
      DOI: 10.1111/bcpt.12817
  • Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy
    • Authors: Sara Drago; Roger Imboden, Philipp Schlatter, Mirabel Buylaert, Stephan Krähenbühl, Juergen Drewe
      Abstract: Little is known about the course of the plasma concentration and the bioavailability of non-steroidal anti-inflammatory drugs (NSAIDs) contained in dermal patches. We compared an etofenamate prototype patch (patent EP 1833471) and a commercially available diclofenac epolamine patch regarding the bioavailability of the active ingredients relative to respective i.m. applications and regarding their plasma concentration-time course. Twenty-four healthy human volunteers were treated using a parallel group design (n=12 per group) with a single dermal patch (removed after 12 hr) followed (after a latency of 48 hr) by 8 consecutive dermal patches every 12 hr to reach steady-state conditions. The patches were generally well tolerated, but one volunteer treated with etofenamate developed an allergic contact dermatitis. After the first patch, Cmax was 0.81±0.11 (mean±SEM) ng/mL (reached 12 hr after patch removal) for diclofenac and 31.3±3.8 ng/mL for flufenamic acid (reached at patch removal), the main metabolite of etofenamate. Etofenamate was not detectable. After repetitive dosing, trough plasma concentrations after the eighth dose were 1.72±0.32 ng/mL for diclofenac and 48.7±6.6 ng/mL for flufenamic acid. Bioavailabilities (single dose) relative to i.m. applications were 0.22±0.04% for diclofenac and 1.15±0.06% for flufenamic acid. In conclusion, the relative bioavailability (compared to the respective i.m. application) of both drugs is low. The maximal plasma concentrations after topical administration of these drugs are well below the IC50 values for COX-1 and COX-2, explaining the absence of dose-dependent toxicities.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-31T07:25:24.92033-05:0
      DOI: 10.1111/bcpt.12818
  • Pharmacokinetic Properties of Memantine Following a Single Intraperitoneal
           Administration and Multiple Oral Doses in Euploid Mice and in the Ts65Dn
           Mouse Model of Down's Syndrome
    • Authors: Daniella B. Victorino; Ilya R. Bederman, Alberto C. S. Costa
      Abstract: Memantine is a drug approved for the treatment of moderate-to-severe Alzheimer's disease (AD), and there is ongoing research on the potential expansion of its clinical applicability. Published data on the pharmacokinetics of memantine in the mouse is still incomplete, particularly for chronic administration regimens and mouse models of specific genetic disorders. Down's syndrome (DS) is a genetic disorder known to affect multiple organs and systems, with the potential to alter significantly drug pharmacokinetics. Here, we describe a simple, efficient and sensitive GC/MS-based procedure for the determination of memantine concentrations in murine blood and tissue samples. We analysed pharmacokinetic properties of memantine, particularly its distribution in blood, brain and liver in the Ts65Dn mouse model of DS and euploid F1 hybrid mice after single intraperitoneal administrations of increasing doses of this drug. We also determined steady-state memantine concentrations in plasma, brain and liver following chronic oral administration of this drug in adult male Ts65Dn mice, euploid littermate controls and nursing or pregnant Ts65Dn mice. Our results revalidated the acute dose of memantine used in previously published work, determined the appropriate amount of memantine to be mixed into mouse chow to achieve steady and pharmacologically relevant plasma and tissue levels of this drug, and demonstrated that memantine can be transferred from mother to offspring via maternal milk and placenta. Most of these findings are potentially applicable not only to the study of DS but also to other neurodevelopmental and neurodegenerative disorders.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-30T07:07:50.461312-05:
      DOI: 10.1111/bcpt.12816
  • Safety, Pharmacokinetics and Pharmacodynamics of Hetrombopag Olamine, a
           Novel TPO-R Agonist, in Healthy Subjects
    • Authors: Li Zheng; Mao-zhi Liang, Xiao-ling Zeng, Cai-zheng Li, Yi-fan Zhang, Xiao-yan Chen, Xi Zhu, An-bo Xiang
      Abstract: Hetrombopag olamine (hetrombopag) is a novel small-molecule, orally bioavailable, non-peptide thrombopoietin (TPO) receptor agonist that is being developed as the treatment for thrombocytopenia. Two randomized, placebo-controlled phase I studies were conducted in 72 healthy subjects to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of hetrombopag. Hetrombopag was orally administered with a single dose in 5 dose cohorts (5 mg, 10 mg, 20 mg, 30 mg or 40 mg) in the first study, and given once daily for 10 days in 3 dose cohorts (2.5 mg, 5.0 mg or 7.5 mg) in the second study, respectively. Hetrombopag was well tolerated, and the majority of adverse events associated with medicine were platelet elevations significantly above the normal range in healthy subjects. The single dose escalation study revealed a Tmax of approximate 8 hr, and a t1/2 of 11.9 hr to 40.1 hr in a dose-prolonged manner. A dose-proportional increase in maximum concentration (Cmax) of hetrombopag was observed, with area under the curve (AUC) increasing in a greater-than-dose-proportional manner. The plasma concentration of hetrombopag reached the steady state after 7 days. The steady-state AUC0-24hr and Cmax were dose-proportionally elevated from the 5.0 mg to 7.5 mg dose level. The potent pharmacological effect of the hetrombopag-induced platelet elevation was observed in a time- and dose-dependent manner. Furthermore, the thrombopoietic response was significantly (p
      PubDate: 2017-05-24T18:20:27.95253-05:0
      DOI: 10.1111/bcpt.12815
  • A Critical Note on Treatment of a Severe Diltiazem Intoxication; High-Dose
           Calcium and Glucagon Infusions
    • Authors: N M Van Veggel; G J Van der Veen, T C Jansen, E M Westerman
      Abstract: The morbidity and mortality of a severe calcium channel blocker intoxication is high due to serious toxic cardiac effects. Its treatment is supported by low-quality evidence from heterogeneous literature. We describe a case of a severe diltiazem intoxication and critically appraise the efficacy and role of high-dose calcium and glucagon infusions.A 53-year-old woman was admitted to the emergency department with a cardiogenic shock with complete AV block, not responding to atropine, isoprenaline and an external pacemaker. Later on, it became clear that she had a severe diltiazem intoxication which was successfully treated with isotone fluids, inotropics, vasopressors and continuous infusion of high-dose calcium and glucagon. The patient developed, however, an acute, necrotizing pancreatitis, probably related to iatrogenic high calcium levels.This case demonstrates lack of consensus regarding target levels of serum calcium for treatment of a severe diltiazem intoxication. Goal-directed tapering of calcium should prevent side-effects of iatrogenic hypercalcaemia. The contribution of glucagon infusions is doubtful due to the instability of solubilized glucagon. This might explain why the effect of glucagon is variable in the literature.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-15T02:30:33.304554-05:
      DOI: 10.1111/bcpt.12809
  • Analysis of National Pharmacovigilance Data Associated with Statin Use in
           Korea. Adverse Drug Reactions with Statins
    • Authors: Hyunah Kim; Namhyo Kim, Da Hee Lee, Hun-Sung Kim
      Abstract: The aim of this study was to evaluate clinical manifestations, age distribution and risk factors of adverse drug reactions (ADRs) of statins.Korean Adverse Event Reporting System (KAERS) database records (July 2009 – June 2014) on statin-treated adults were used. ADRs classified as “certain,” “probable” and “possible” based on the WHO-Uppsala Monitoring Centre criteria were analysed. The frequency of ADRs was compared between adults (18-64 years) and older people (age ≥ 65 years) groups.In total, 2161 ADRs from 1690 patients (579, 34.3% older people) were included for analysis. Mean patient age and ADRs per patient were 60.46 ± 12.72 years and 1.28, respectively. ADRs were reported with atorvastatin (48.4%), rosuvastatin (23.0%), pitavastatin (10.4%) and simvastatin (9.1%). The frequent ADRs were gastrointestinal (421 events, 19.5%), musculoskeletal (331, 15.3%), skin (312, 14.4%) and hepatobiliary disorders (286, 13.2%). Skin disorders were significantly more frequent in adults compared to those in older patients (16.3% versus 12.4%, p = 0.021). Common clinical symptoms were myalgia (263 events, 12.2%), dyspepsia (133, 6.2%) and pruritus (103, 4.8%). Myalgia was more frequently reported in adults (12.7% versus 9.5%, p = 0.039) and dizziness was more frequent in older people (3.4% versus 5.8%, p = 0.015).According to KAERS data, leading statin ADRs were gastrointestinal and musculoskeletal disorders. Myalgia and dyspepsia were the common clinical symptoms.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-13T09:45:27.076062-05:
      DOI: 10.1111/bcpt.12808
  • Severe Acute Valproic Acid Intoxication Successfully Treated with Liver
           Support Therapy
    • Authors: Yongchun Ge; Bin Xu, Chuan Li, Qunpeng He, Tingting Zhu, Rong Fan, Dehua Gong
      Abstract: Valproic acid (VPA) is widely used for treatment of epilepsy. However, its overdose can cause intoxication and could be life-threatening. Due to lack of specific antidote and poorness of endogenous clearance, extracorporeal treatment for severe intoxication cases is indicated. Here, we report a case of severe intoxication of VPA which was successfully treated with liver support therapy. A previously healthy woman was admitted due to coma and hypotension after intentional ingestion of 20 g of sodium valproate. Her serum concentration of VPA measured on admission was 420.84 mg/L. In addition to standard therapy, she received two sessions of extracorporeal blood purification using a system based on fractionated plasma separation and adsorption mode integrated with continuous veno-venous hemofiltration (FPSA-CVVH), which is usually used for liver support therapy at our hospital. Her serum concentration of VPA decreased dramatically to 40.18 mg/L and her consciousness recovered completely within 24 hr after admission. Therefore, although hemodialysis has been reported to be effective in treatment of VPA poisoning, FPSA-CVVH may provide an option for patients who require bedside therapy but have an unstable haemodynamic status or other conditions that result in inability to endure hemodialysis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-08T10:35:24.144751-05:
      DOI: 10.1111/bcpt.12807
  • The Pig-a Gene Mutation Assay in Mice and Human Cells: A Review
    • Authors: Ann-Karin Olsen; Stephen D. Dertinger, Christopher T. Krüger, Dag M. Eide, Christine Instanes, Gunnar Brunborg, Andrea Hartwig, Anne Graupner
      Abstract: This MiniReview describes the principle of mutation assays based on the endogenous Pig-a gene and summarizes results for two species of toxicological interest, mice and humans. The work summarized here largely avoids rat-based studies, as are summarized elsewhere. The Pig-a gene mutation assay has emerged as a valuable tool for quantifying in vivo and in vitro mutational events. The Pig-a locus is located at the X-chromosome, giving the advantage that one inactivated allele can give rise to a mutated phenotype, detectable by multi-colour flow cytometry. For in vivo studies, only minute blood volumes are required, making it easily incorporated into on-going studies or experiments with limited biological materials. Low blood volumes also allows subjects to serve as their own controls, providing temporal information of the mutagenic process, and/or outcome of intervention. These characteristics make it a promising exposure marker. To date, the Pig-a gene mutation assay has been most commonly performed in rats, while reports regarding its usefulness in other species are accumulating. Besides its applicability to in vivo studies, it holds promise for genotoxicity testing using cultured cells, as shown in recent studies. In addition to safety assessment roles, it is becoming a valuable tool in basic research to identify mutagenic effects of different interventions or to understand implications of various gene defects by investigating modified mouse models or cell systems. Human blood-based assays are also being developed that may be able to identify genotoxic environmental exposures, treatment- and life-style-related factors, or endogenous host factors that contribute to mutagenesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-08T10:30:29.180343-05:
      DOI: 10.1111/bcpt.12806
  • Evolution of Novel 3D Culture Systems for Studies of Human Liver Function
           and Assessments of the Hepatotoxicity of Drugs and Drug Candidates
    • Authors: Tommy B. Andersson
      Abstract: The pharmaceutical industry urgently needs reliable pre-clinical models to evaluate the efficacy and safety of new chemical entities before they enter the clinical trials. Development of in vitro model systems that emulate the functions of the human liver organ has been an elusive task. Cell lines exhibit a low drug-metabolizing capacity and primary liver cells rapidly de-differentiate in culture, which restrict their usefulness substantially. Recently, the development of hepatocyte spheroid cultures has shown promising results. The proteome and transcriptome in the spheroids were similar to the liver tissue, and hepatotoxicity of selected substances was detected at in vivo-relevant concentrations.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T03:40:28.917744-05:
      DOI: 10.1111/bcpt.12804
  • Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai
           Autistic Children and Adolescents
    • Authors: Nopphadol Nuntamool; Nattawat Ngamsamut, Natchaya Vanwong, Apichaya Puangpetch, Monpat Chamnanphon, Yaowaluck Hongkaew, Penkhae Limsila, Chuthamanee Suthisisang, Bob Wilffert, Chonlaphat Sukasem
      Abstract: The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcomes in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI-I, aggressive, over-activity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), over-activity (71.95%), repetitive (70.89%) behavior and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI-I score. Patients in the non-stable symptom group had DRD2 Taq1A non-wildtype (TT and CT) frequencies higher than the clinically stable group (P = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non-stable clinical outcome (χ2 = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcomes. On the other hand, risperidone dose, 9-OH Risperidone levels and prolactin levels were significantly higher in the non-stable compared to the stable symptom group (P = 0.013, P = 0.044, P = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body weight, whereas it was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long-term treatment. However, Taq1A T – carrier of dopamine2 receptor gene is associated with non-stable response in risperidone-treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T02:55:35.678686-05:
      DOI: 10.1111/bcpt.12803
  • Clinical Effects of a Pharmacist Intervention in Acute Wards- A
           Randomised, Controlled Trial
    • Authors: Trine R. H. Nielsen; Per H. Honoré, Mette Rasmussen, Stig E. Andersen
      Abstract: The purpose of the study was to investigate the clinical effect of a clinical pharmacist (CP) intervention upon admission to hospital on in-patient harm and to assess a potential educational bias.Over16 months, 593 adult patients taking ≥ 4 medications daily were included from three Danish acute medicine wards. Patients were randomised to 'either the CP intervention or the usual care (prospective control). To assess a potential educational bias or educational bias, a retrospective control group was formed by randomisation. The CP intervention comprised medication history, medication reconciliation, medication review and entry of proposed prescriptions into the electronic prescribing system. The primary outcome of in-patient harm was identified by using triggers from the IHI Global Trigger Tool. Harms were validated and rated for severity by two independent and blinded outcome panels. Secondary endpoints were harms per patient, length of hospital stay, readmissions and one-year mortality.Harm affected 11% of the patients in the intervention group compared to 17% in the combined control group, odds ratio (OR) 0.57 (CI 0.32 to 1.02, p=0.06). The incidence of harm was similar in the intervention and prospective control groups, OR 0.80 (CI 0.40 to 1.59, p=0.52) but occurred less frequently in the intervention than in the retrospective control group OR 0.46 (CI 0.25 to 0.85, p=0.01). An educational bias from the intervention to the control group might have contributed to this negative outcome. In conclusion, the CP intervention at admission to hospital had no statistically significant effect on in-patient harm.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-29T09:28:31.310133-05:
      DOI: 10.1111/bcpt.12802
  • Azilsartan Medoxomil, an Angiotensin II Receptor Antagonist for the
           Treatment of Hypertension
    • Authors: Marie Harthøj Hjermitslev; Daniela Grimm, Markus Wehland, Ulf Simonsen, Marcus Krüger
      Abstract: Azilsartan medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both in blood pressure (BP) reduction and in tolerability, but has not yet been taken into practice to the same extent as other angiotensin-II receptor blockers (ARBs) that have been on the market for a longer period.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-26T10:35:43.714962-05:
      DOI: 10.1111/bcpt.12800
  • Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced
           Non-Small-Cell Lung Cancer (NSCLC) Receiving Erlotinib Treatment
    • Authors: Zinnia P. Parra-Guillen; Peter B. Berger, Manuel Haschke, Massimiliano Donzelli, Daria Winogradova, Bogumila Pfister, Martin Früh, Charlotte Kloft, Stephan Krähenbühl, Silke Gillessen, Markus Joerger
      Abstract: Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD. was initiated, and the 2 oral probe drugs midazolam (2mg) and caffeine (100mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R2 = 0.960, P < 0.0001), OSI-420 (R2 = 0.971, P < 0.0001), midazolam (R2 = 0.995, P < 0.0001) and caffeine (R2 = 0.968, P < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R2 = 0.33, P = 0.048), while midazolam clearance was not (R2 = -0.09, P = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, P = 0.086 for Student's T). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in cancer patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-26T10:35:40.21372-05:0
      DOI: 10.1111/bcpt.12801
  • Autonomic Receptor-Mediated Regulation of Production and Release of Nitric
           Oxide in Normal and Malignant Human Urothelial Cells
    • Authors: Michael Winder; Renata Vesela, Patrik Aronsson, Bhavik Patel, Thomas Carlsson
      Abstract: In the urinary bladder, the main source of NO seems to be the urothelium and the underlying suburothelium. In this study, we aimed to characterize how receptors in the human urothelium regulate the production and release of NO. For this, we cultured two human urothelial cell lines - the normal immortalized cell line UROtsa and the malignant cell line T24. These were treated with an array of agonists and antagonists with affinity for adrenergic, muscarinic and purinergic receptors. The production of NO and expression of nitric oxide synthase (NOS) was studied by immunocytochemistry and western blotting. The amount of released NO was measured indirectly by detecting nitrite using amperometry and a Griess reaction kit. The results showed that NO, endothelial NOS and inducible NOS were predominantly produced and expressed in the close vicinity of the nucleus in untreated human urothelial cells. Upon treatment with a beta-adrenoceptor agonist, but not any of the other agonists or antagonists, the pattern of NO production changed, showing a more even production throughout the cytosol. The pattern of expression of endothelial NOS changed in a similar way upon dobutamine treatment. The release of nitrite, as a measurement of NO, increased following treatment with dobutamine from 0.31±0.029 to 1.97±0.18 nmol and 0.80±0.12 to 3.27±0.24 nmol in UROtsa and T24, respectively. In conclusion, our results show that the expression of NOS and production of NO as well as the release of NO from human urothelial cells is regulated by beta-adrenoceptor activation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-24T10:21:16.194567-05:
      DOI: 10.1111/bcpt.12799
  • Effects of Aluminium on long-term Memory in Rats and on SIRT1 Mediating
           the Transcription of CREB-Dependent Gene in Hippocampus
    • Authors: Dongying Yan; Cuihong Jin, Yang Cao, Lulu Wang, Xiaobo Lu, Jinghua Yang, Shengwen Wu, Yuan Cai
      Abstract: Epidemiological investigations have shown that aluminium (Al) is an important neurotoxicant which can be absorbed by organisms via various routes. Previous studies have confirmed that exposure to Al could cause neurodegenerative diseases, decline CREB phosphorylation and then down-regulate the transcription and protein expression of its target genes including BDNF. However, recent studies revealed that CREB activation alone was far from enough to activate the expression of long-term memory (LTM) related genes; there might be other regulatory factors involved in this process. Several studies showed that TORC1 might be involved in regulating the transcription of downstream target genes as well. Also, TORC1 could be mediated by SIRT1 during the formation of LTM. However, the role of CREB regulating system in Al-induced LTM impairment was still not utterly elucidated till now. This study was designed to establish the rat model of subchronic Al exposure to observe the neuroethology, regulatory factor levels and molecular biological alterations in hippocampal cells. The results showed that, with the increasing AlCl3 dose, blood Al content increased gradually; morphology of the hippocampus and neuronal ultrastructure were aberrant; in the Morris water maze test, the escape latency and distance travelled became longer, swimming traces turned more complicated in the place navigation test; intracellular Ca2+, cAMP levels declined significantly in AlCl3-treated rats, followed by abated nuclear translocation of TORC1 and decreased SIRT1, TORC1 and pCREB levels. These results indicate that SIRT1 and TORC1 might play an important mediating role in Al-induced LTM impairment.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-21T04:15:40.848701-05:
      DOI: 10.1111/bcpt.12798
  • A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in
           a Hospital-wide Population of Patients Receiving Conventional Dosing: Is
    • Authors: Federico Pea; Pier Giorgio Cojutti, Massimo Baraldo
      Abstract: A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (Cmin) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of Cmin was set between 2 and 7 mg/L (under-exposure, Cmin < 2 mg/L; over-exposure, Cmin > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid Cmin. One thousand forty-nine patients had 2484 linezolid Cmin assessed during treatment with conventional doses. Median (IQR) linezolid Cmin was 5.08 mg/L (2.78 – 8.52 mg/L). Linezolid Cmin were within the desired range in 50.8% of cases (1262/2484). Over-exposure (n=821; 33%) occurred much more frequently than under-exposure (n=401;16.2%), and was severe (> 20 mg/L) in 3.9% of cases (98/2484). Linezolid over-exposure was significantly associated with CrCLC-G estimates ≤ 40 mL/min (OR 1.463; 95% CI 1.124 – 1.904, P = 0.005). Linezolid under-exposure resulted significantly associated with CrCLC-G estimates > 100 mL/min (OR 3.046; 95% CI 2.234 – 4.152, P < 0.001. Linezolid Cmin was not correlated linearly to CrCLC-G (R2 = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid Cmin variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-17T03:05:52.007671-05:
      DOI: 10.1111/bcpt.12797
  • Therapeutic Drug Monitoring of Venlafaxine in an Everyday Clinical
           Setting: Analysis of Age, Sex and Dose Concentration Relationships
    • Authors: Morten Rix Hansen; Ida Berglund Kuhlmann, Anton Pottegård, Per Damkier
      Abstract: Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we identified all adults for whom the treating physician had requested clinical advice on the TDM result for venlafaxine between 2002 and 2012. We identified 1,077 TDM samples of venlafaxine from 334 males and 743 females (median age 45 years), and the median daily dose was 225 mg. Median plasma concentration of venlafaxine and o-desmethyvenlafaxine (ODV) were 306 nmol/L and 861 nmol/L, respectively. The median dose-corrected serum level for venlafaxine was 1.49 nmol/L/mg., while the dose-corrected serum level of men and women were 1.21 nmol/L/mg and 1.60 nmol/L/mg, respectively. The dose-corrected sum of venlafaxine and ODV was 8.91 nmol/L/mg (IQR 6.56-12.26) versus 5.52 nmol/L/mg (IQR 4.16-7.52) for patients above 64 years and below the age of 65 years, respectively. Dose-corrected plasma concentrations of venlafaxine and ODV are increased to a clinically significant degree in patients above the age of 64, and initiation of venlafaxine therapy in the elderly should be made cautiously and supported by drug measurements.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-11T02:25:28.363702-05:
      DOI: 10.1111/bcpt.12796
  • Matrix Metalloproteinase (MMP)-2 Activity is Associated with Divergent
           Regulation of Calponin-1 in Conductance and Resistance Arteries in
           Hypertension-Induced Early Vascular Dysfunction and Remodelling
    • Authors: Juliana M. Parente; Camila A. Pereira, Gustavo H. Oliveira-Paula, José Eduardo Tanus-Santos, Rita C. Tostes, Michele M. Castro
      Abstract: Matrix metalloproteinase (MMP)-2 participates in hypertension-induced maladaptive vascular remodelling by degrading extra and intracellular proteins. The consequent extracellular matrix rearrangement and phenotype switch of vascular smooth muscle cells (VSMC) lead to increased cellular migration and proliferation. As calponin-1 degradation by MMP-2 may lead to VSMC proliferation during hypertension, the hypothesis of this study is that increased MMP-2 activity contributes to early hypertension-induced maladaptive remodelling in conductance and resistance arteries via regulation of calponin-1. The main objective was to analyse whether MMP-2 exerts similar effects on the structure and function of the resistance and conductance arteries during early hypertension. Two-kidney, one-clip (2K-1C) hypertensive male rats and corresponding controls were treated with doxycycline (30 mg/kg/day) or water until reaching one week of hypertension. Systolic blood pressure (SBP) was increased in 2K-1C rats and doxycycline did not reduce it. Aortas and mesenteric arteries were analysed. MMP-2 activity and expression were increased in both arteries and doxycycline reduced it. Significant hypertrophic remodelling and VSMC proliferation were observed in aortas but not in mesenteric arteries of 2K-1C rats. The contractility of mesenteric arteries to phenylephrine was increased in 2K-1C rats and doxycycline prevented this alteration. The potency of phenylephrine to contract aortas of 2K-1C rats was increased and doxycycline decreased it. Whereas calponin-1 expression was increased in 2K-1C mesenteric arteries, calponin-1 was reduced in aortas. Doxycycline treatment reverted changes in calponin-1 expression. MMP-2 contributes to hypertrophic remodelling in aortas by decreasing calponin-1 levels, which may result in VSMC proliferation. On the other hand, MMP-2-dependent increased calponin-1 in mesenteric arteries may contribute to vascular hypercontractility in 2K-1C rats. Divergent regulation of calponin-1 by MMP-2 may be an important mechanism that leads to maladaptive vascular effects in hypertension.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T07:06:05.206976-05:
      DOI: 10.1111/bcpt.12787
  • Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling
           Pathway in Autoimmune Hepatitis with Failure of Standard Treatment
    • Authors: Peter Lykke Eriksen; Martin Kreutzfeldt, Henning Grønbæk, Kasper Thorsen, Søren Vang, Niels Jessen, Hendrik Vilstrup
      Abstract: The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants.Fifty-six consecutive patients with AIH (41 female and 15 male; median age 42 years (12-76)) were retrospectively stratified according to being responders to standard therapy (n=33) or patients with failure of standard therapy (n=23). Their blood DNA was exome-captured and sequenced. Genomic variants were filtered and compared between the groups using Ingenuity Variant Analysis (3.1.20150407)The exome sequencing and data processing revealed glucocorticoid receptor signalling to be the most prominently affected pathway among the patients with failure of standard therapy (highly significant). Standard treatment failure was not associated with thiopurine S-methyltransferase variants or the HLA-DRB1*03 genotype.In conclusion, enrichment of variants related to glucocorticoid receptor signalling was a particular genomic trait of the AIH patients in whom standard treatment failed and alternative immunosuppression was required. If confirmed, a future application of this finding may be to identify prospective cases of failure of standard treatment already at diagnosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T06:55:46.924306-05:
      DOI: 10.1111/bcpt.12788
  • Apoptosis, Dysbiosis and Expression of Inflammatory Cytokines are
           Sequential Events in the Development of 5-Fluorouracil-induced Intestinal
           Mucositis in Mice
    • Authors: Nahla Hamouda; Tatsushi Sano, Yosuke Oikawa, Toru Ozaki, Masaki Shimakawa, Kenjiro Matsumoto, Kikuko Amagase, Kazuhide Higuchi, Shinichi Kato
      Abstract: The chemotherapeutic agent 5-fluorouracil (5-FU) causes intestinal mucositis with severe diarrhoea but the pathogenesis is not fully understood. In the present study, we investigated the pathogenic effects of 5-FU in mice, focusing on apoptosis, enterobacteria and inflammatory cytokines. Repeated administration of 5-FU caused severe intestinal mucositis on day 6, accompanied by diarrhoea and body weight loss. TNF-α expression increased one day after exposure to the drug, and spiked a second time on day 4, at which point myeloperoxidase activity and IL-1β expression also increased. Apoptotic cells were observed in intestinal crypts only on day 1. 5-FU also induced dysbiosis, notably decreasing the abundance of intestinal Firmicutes while increasing the abundance of Bacteroidetes and Verrucomicrobia. Twice-daily co-administration of oral antibiotics significantly reduced the severity of intestinal mucositis and dysbiosis, and blocked the increase in myeloperoxidase activity and cytokine expression on day 6, without affecting apoptosis and TNF-α upregulation on day 1. In cultured colonic epithelial cells, exposure to 5-FU also upregulated TNF-α expression. Collectively, the data suggest that crypt apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of intestinal mucositis after exposure to 5-FU. In particular, 5-FU appears to directly induce apoptosis via TNF-α and to suppress intestinal cell proliferation, thereby resulting in degradation of the epithelial barrier, as well as in secondary inflammation mediated by inflammatory cytokines.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:31:05.911109-05:
      DOI: 10.1111/bcpt.12793
  • PPARα Activation Suppresses Cytochrome P450 Induction Potential in Mice
           Treated with Gemfibrozil
    • Authors: Cunzhong Shi; Luo Min, Julin Yang, Manyun Dai, Danjun Song, Huiying Hua, Gangming Xu, Frank J. Gonzalez, Aiming Liu
      Abstract: Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in Cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than that in wild-type mice. So, gemfibrozil induced CYP and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:31:00.285252-05:
      DOI: 10.1111/bcpt.12794
  • Mathematical Modelling of Glucose-Dependent Insulinotropic Polypeptide and
           Glucagon-like Peptide-1 following Ingestion of Glucose
    • Authors: Rikke M. Røge; Jonatan I. Bagger, Oskar Alskär, Niels R. Kristensen, Søren Klim, Jens J. Holst, Steen H. Ingwersen, Mats O. Karlsson, Filip K. Knop, Tina Vilsbøll, Maria C. Kjellsson
      Abstract: The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semi-mechanistic model describing the release of GIP and GLP-1 following ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:15:38.245696-05:
      DOI: 10.1111/bcpt.12792
  • Angiotensin II Receptor Blockers Inhibit the Generation of
           Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9,
           CYP2J2 and Human Liver Microsomes
    • Authors: Asuna Senda; Yuji Mukai, Toru Hayakawa, Yuka Kato, Erik Eliasson, Anders Rane, Takaki Toda, Nobuo Inotsume
      Abstract: Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), have cardioprotective effects including anti-inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2, and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50) of AA metabolism was losartan < telmisartan < irbesartan < candesartan < olmesartan < valsartan via CYP2C9, and telmisartan < irbesartan < olmesartan < losartan < candesartan and valsartan via CYP2J2. The order for the HLMs was losartan < telmisartan < irbesartan < olmesartan < candesartan < valsartan. Some ARBs having lower concentration of IC50 indicate that these ARBs might inhibit the AA metabolism in the liver.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:11:02.808987-05:
      DOI: 10.1111/bcpt.12789
  • Comparative Analysis of the Suspected Heparin-Induced Thrombocytopenia
           Level in Korea
    • Authors: Hun-Sung Kim; Hyunah Kim, Yoo Jin Jeong, Hyunyong Lee, Hyeon Woo Yim, Ji il Kim, In Sung Moon, Jang-Yong Kim
      Abstract: The primary objective of our study was to evaluate the frequency of suspected heparin-induced thrombocytopenia (HIT) among patients treated with different formulations of heparin and investigate the factors that affect the incidence of HIT. This study is an electronic medical record (EMR)-based large-scale retrospective cohort study conducted from 2009 to 2014 in Korea. After hospitalization, patient platelet count was determined before heparin was prescribed, and all platelet count values obtained during hospitalization were extracted. Suspected HIT was estimated by three 4Ts scores (acute thrombocytopenia, timing onset and other possible causes), which when combined yielded a high probability of HIT. Among 6046 patients enrolled in this study, HIT was suspected in 641 cases (10.6%) and a statistically significant increase in HIT incidence rate was observed for three heparins used (p < 0.001). Dalteparin (HR=0.55, p=0.036) and enoxaparin (HR=0.40, p
      PubDate: 2017-04-04T05:10:38.563688-05:
      DOI: 10.1111/bcpt.12791
  • Human BJ Fibroblasts is an Alternative to Mouse BALB/c 3T3 Cells in In
           Vitro Neutral Red Uptake Assay
    • Authors: Marika Mannerström; Tarja Toimela, Jertta-Riina Sarkanen, Tuula Heinonen
      Abstract: The OECD GD 129 BALB/c 3T3 Neutral Red Uptake (NRU) assay is a standardized test method for estimating starting dose for an acute oral systemic toxicity test in rodents. Mouse BALB/c 3T3 fibroblasts are the most commonly used cells in the NRU assay. We have previously transferred and validated BALB/c 3T3 NRU assay in our GLP laboratory. Subsequently, in order to obtain more human relevant cytotoxicity data, we performed an intra-laboratory validation using human BJ fibroblasts in the NRU assay instead of mouse BALB/c 3T3 fibroblasts. Here, we present comparative cytotoxicity data of 26 different test chemicals (pharmaceuticals, industrial chemicals, pesticides and food additives) produced with both BALB/c 3T3 NRU and BJ NRU assays.There were marked differences between these two fibroblasts in their sensitivity to predict cytotoxicity. 46% of the chemicals studied (acetone, acetyl salicylic acid, boric acid, carbamazepine, cupric sulfate pentahydrate, dichlorvos, mercury II chloride, octyl gallate, 2-propranol, sorbic acid and valporic acid) were more toxic to mouse BALB/c 3T3 than to human BJ fibroblasts, 19% (acryl amide, amitriptyline HCl, digoxin, oxytetracycline and propranol) were more toxic to human than to mouse fibroblasts and 23% (sodium selenite, sodium fluoride, sodium dichromate dehydrate, sodium arsenite, nicotine, lithium carbonate and bishenol A) showed equal toxicity to both cells types. Lindane and acetaminophen were only toxic to mouse fibroblasts whereas potassium cyanide exhibited toxicity only to human fibroblasts. The IC50 values of test chemicals in the BJ NRU assay correlated much better with the literature human data (r=0.882 and r=0.788, for TDLo and LDLo, respectively) than did the IC50 values of the same test chemicals in the BALB/c 3T3 assay (r=0.428) proposing that human BJ fibroblast assay could be a potential test to be used to predict acute cytotoxicity of chemicals in humans.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T05:10:36.997945-05:
      DOI: 10.1111/bcpt.12790
  • Inhibitory Effects of Urothelium-related Factors
    • Authors: Na N. Guan; Lars E. Gustafsson, Karl Svennersten
      Abstract: The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium-derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor, cyclo-oxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD2 from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD2 was found to have an inhibitory influence on nerve-induced contractions in guinea pig urinary bladder and on spontaneous contractions in the outflow region.An altered release of excitatory and inhibitory factors is likely to play an important part of bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-02T20:20:26.144637-05:
      DOI: 10.1111/bcpt.12785
  • Essential Medicines List Implementation Dynamics: A Case Study using
           Brazilian Federal Medicines Expenditures
    • Authors: Rachel Magarinos-Torres; Larry David Lynd, Tatiana Chama Borges Luz, Paulo Eduardo Potyguara Coutinho Marques, Claudia Garcia Serpa Osorio-de-Castro
      Abstract: The aim was to analyse the implementation dynamics of the Essential Medicines List (EML). We used the government expenditures on medicines and Brazil as a case study. Drug purchases were considered as a proxy for utilization. The essential medicines (EMs) expenditures were followed over time by Brazilian National EMLs lifetime and defined by broad therapeutic categories and by specific medicines. Brazil increased the number of the EMs during the last four editions of your Brazilian National EMLs and the federal government expenditures on them. The EML implementation dynamics changed the distribution of expenditures on EMs. We identified a common set of 404 EMs present in all four editions of the Brazilian National EMLs. There was a proportional decrease in expenditures on anti-infectives for systemic use, blood and blood-forming organs and alimentary tract and metabolism, and increase in expenditures on antineoplastic and immunomodulating agents. The expenditures distribution per specific medicines revealed that a small set of essential medicines was responsible for 50% or more of expenditures considering Brazilian National EML lifetime for all four periods. The increase in expenditures on EMs in Brazil was a consequence of the newer medicines incorporated over time in the Brazilian National EMLs. The use of the medicines expenditures as a source of data and the definition of an EML lifetime permitted follow-up of the implementation dynamics of different versions of the Brazilian National EMLs. Our results have implications for policy-makers and stakeholders to gain a better understanding of the role EMLs play in health system sustainability and in the provision of the most beneficial heath care.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T12:14:30.284597-05:
      DOI: 10.1111/bcpt.12783
  • Effects of Nano-Graphene Oxide on Testis, Epididymis and Fertility of
           Wistar Rats
    • Authors: Naresh Kumar Nirmal; Kumud Kant Awasthi, Placheril Joseph John
      Abstract: Nanoscale graphene oxide (NGO) has great potential in biomedicine by the virtue of its facile functionalization and tunable characteristics. Toxicity assessments have, therefore, become essential prior to its biomedical applications. The present study examined the effects of NGO exposure on male reproductive function of adult Wistar rats. Rats were exposed intraperitoneally to three increasing doses, namely low (0.4 mg/kg BW), mid (2.0 mg/kg BW) and high (10.0 mg/kg BW) dose of NGO. Repeated exposure of NGO for 15 and 30 days resulted in decreased epididymal sperm counts and elevated sperm abnormalities. Percentage of motile sperms was also significantly reduced due to the exposure. Activities of SOD, GPx and malondialdehyde concentration in testes increased in a dose-specific manner. Results of the study demonstrated that high-dose NGO (10.0 mg/kg BW) resulted in considerable histological damage to testicular tissue which included atrophy of seminiferous tubules with reduction in germinal epithelium, germ cell loss and vacuolization. Low and mid doses of NGO were not associated with sperm dysfunction or testis damage. Withdrawal of treatment for 30 days demonstrated significant recovery potential. Histology of epididymis and male fertility potential were not affected due to the NGO exposure. These findings are important for assessment of the risk involved in manufacturing, use and processing of the graphene oxide-based materials towards male reproductive function.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T12:14:27.931488-05:
      DOI: 10.1111/bcpt.12782
  • Population Exposure to Phthalate-Containing Drugs
    • Authors: Anne Broe; Zandra Nymand Ennis, Anton Pottegård, Jesper Hallas, Thomas Ahern, Per Damkier
      Abstract: Phthalates are known endocrine disruptors. Not commonly recognised, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate-containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the ‘defined daily dose’ (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1,000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethylphthalate (DEP) and dibutylphthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate-containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low-molecular-weight phthalates and three high-molecular-weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1,000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multienzymes (24.6-32.8 mg per DDD) and mesalazine (12.5-26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate-containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T07:36:06.239346-05:
      DOI: 10.1111/bcpt.12781
  • The Effect of Desmopressin on the Amount of Bleeding and Transfusion
           Requirements in Patients undergoing Heart Transplant Surgery
    • Authors: Alireza Jahangirifard; Mohammad Reza Razavi, Zargham Hosein Ahmadi, Mohammad Forozeshfard
      Abstract: One of the most common risks after a heart transplant is bleeding. In this study, the effect of desmopressin administration on the amount of bleeding and transfusion requirements following heart transplant surgery was investigated.In a double-blind clinical trial, 48 patients who were candidates for heart transplant surgery were randomly assigned to two groups. In the intervention group, patients received desmopressin 0.3 μg/kg, 30 min. before surgery. Patients in the control group received normal saline at the same amount and time. Homeostasis was evaluated using activated clotting time (ACT), PT, PTT and PLT before, 12 and 24 hr after surgery, and also, chest tube drainage, blood products transfusion requirements during the first day in both groups.No significant differences were found between the groups in terms of ACT, PT, PTT and PLT at all times. Transfusion of packed red blood cells and the mean drainages of chest tube during the first 24 hr after surgery were significantly lower in the desmopressin group compared to the saline group.Desmopressin may reduce postoperative bleeding in patients undergoing heart transplant surgery. Further studies are required to confirm the potential effect of desmopressin on establishing hemostasis following heart transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-22T02:55:44.616845-05:
      DOI: 10.1111/bcpt.12780
  • Baclofen and Alcohol-dependent Patients: A Real Risk of Severe
    • Authors: David Boels; Caroline Victorri-Vigneau, Marie Grall-Bronnec, Ali Touré, Anais Garnier, Alain Turcant, Gaël Le Roux
      Abstract: Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, since baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders and psychiatric illnesses determine predictors of severity.This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014.111 cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39±12). Poisoning severities were: “null” (9 cases), “minor” (37 cases), “moderate” (19 cases) and “high” (46 cases, including 4 deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR=2.9; p=0.03).Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-19T20:16:07.669889-05:
      DOI: 10.1111/bcpt.12779
  • 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
  • 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
  • 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 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
  • Cis-Nerolidol Induces Endoplasmic Reticulum Stress and Cell Death in Human
           Hepatocellular Carcinoma Cells through Extensive CYP2C19 and CYP1A2
    • Authors: Bruna Isabela Biazi; Thalita Alves Zanetti, Adrivanio Baranoski, Amanda Cristina Corveloni, Mário Sérgio Mantovani
      Abstract: Of late, many studies are attempting to find new molecules with anti-cancer properties, especially those with the capability to inhibit cell growth. The aim of this work was to evaluate nerolidol, a plant-based compound, as its cytotoxicity, genotoxicity, antiproliferative and apoptotic induction, cell cycle, mitochondrial membrane potential, and RT-qPCR of transcripts related to those pathways in the human hepatocellular carcinoma cell line (HepG2/C3A). Only cis-nerolidol (C-NER) demonstrated cytotoxicity (100 to 250 μM) activity and was selected to conduct the following experiments. C-NER did not show genotoxic activity, but altered the mitochondrial membrane potential, reduced cell proliferation by arresting cell cycle in G1 phase and induced cell death. RT-qPCR showed that C-NER down-regulated genes related to apoptosis (BAK1, BAX, CAPN1, CASP8, CASP9, PARP1 and TP53), cell cycle (CCND1, CCNE1, CDK1 and CDK2), xenobiotic metabolism (CYP2D6 and CYP3A4) and paraptosis (IGF1R receptor). Up-regulation was seen in case of genes related to cell survival (BBC3 and MYC) and reticulum stress protein response (EIF2AK3 and ERN1) and xenobiotic metabolism (CYP1A2 and CYP2C19). We deduced that the antiproliferative activity of C-NER is attributable to its modulation of the cyclins and cyclin-dependent kinases as these proteins are necessary for G1/S phase transition. EIF2AK3, ERN1, CYP2C19 and CYP1A2 up-regulation suggests that endoplasmic reticulum stress was induced owing to the increased activity of cytochrome P450 enzymes. Caspase-independent cell death was also observed, indicating that another type of cell death, paraptosis, was triggered. Our results indicate that C-NER has considerable potential in anti-cancer therapy because it modulates important molecular targets of cell survival and proliferation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-02T20:30:25.399702-05:
      DOI: 10.1111/bcpt.12772
  • 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
  • Efficacy and Tolerability of an Inhaled Selective Glucocorticoid Receptor
           modulator - AZD5423 - in COPD Patients: Phase II Study Results
    • Authors: Piotr Kuna; Magnus Aurivillius, Carin Jorup, Susanne Prothon, Ziad Taib, Staffan Edsbäcker
      Abstract: AZD5423 is a novel, inhaled, selective glucocorticoid receptor modulator (SGRM), which in an allergen challenge model in asthmatics improved lung function and airway hyper-reactivity. In the current trial, AZD5423 was for the first time tested in patients with chronic obstructive pulmonary disease (COPD).In this double-blind, randomised and parallel group study, we examined airway and systemic effects of two doses of AZD5423, inhaled via Turbuhaler for 12 weeks, in 353 symptomatic COPD patients (average pre-bronchodilator forced expiratory volume in one second (FEV1) at screening was 50-52% of predicted normal). Pre-bronchodilator FEV1 was primary variable, with other lung function parameters plus symptoms and 24-hr plasma cortisol being secondary variables. Plasma concentrations of AZD5423 were also measured. Effects were compared against placebo and a reference glucocorticoid receptor agonist control.Neither AZD5423, at doses which have shown to be efficacious in allergen-induced asthma, nor the reference control, at double the approved dose, had any clinically meaningful effect in the patient population studied in regard to lung function or markers of inflammation. Both GR modulators were well tolerated and did suppress 24-hr cortisol.The present study suggests that the selected population of COPD patients does not respond to treatment with AZD5423 as regards lung function, whilst showing the expected systemic effects. It cannot be ruled out that a favourable lung function response of AZD5423 can be evoked using another experimental setting and/or within a different population of COPD patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-17T13:01:11.925661-05:
      DOI: 10.1111/bcpt.12768
  • Salivary DNA Methylation Profiling: Aspects to Consider for Biomarker
    • Authors: Sabine A. S. Langie; Matthieu Moisse, Ken Declerck, Gudrun Koppen, Lode Godderis, Wim Vanden Berghe, Stacy Drury, Patrick De Boever
      Abstract: Is it not more comfortable to spit saliva in a tube than to be pricked with a needle to draw blood to analyse your health and disease risk' Many patients, study participants and (parents of) young children undoubtedly prefer non-invasive and convenient procedures. Such procedures increase compliance rates especially for longitudinal prospective studies. Saliva is an attractive biofluid providing good quality DNA to study epigenetic mechanisms underlying disease across development. In this MiniReview, we will describe the different applications of saliva in the field of epigenetics, focusing on genomewide methylation analysis. Advantages of the use of saliva and its comparability with blood will be discussed, as will the challenges in data processing and interpretation. Knowledge gaps will be identified and suggestions given on how to improve the analysis, making saliva ‘the’ biofluid of choice for future biomarker initiatives in many different epidemiological and public health studies.
      PubDate: 2017-02-10T04:11:46.263571-05:
      DOI: 10.1111/bcpt.12721
  • Use of Moderate-Intensity Statins for Low-Density Lipoprotein Cholesterol
           Level above 190 mg/dL at Baseline in Koreans
    • Authors: Hun-Sung Kim; Hyeseon Lee, Sue Hyun Lee, Yoo Jin Jeong, Tong Min Kim, So Jung Yang, Sun Jung Baik, Hyunah Kim, Seung-Hwan Lee, Jae Hyoung Cho, In-Young Choi, Kun-Ho Yoon, Ju Han Kim
      Abstract: The ACC/AHA 2013 guideline recommends high-intensity statin therapy for a decrease in low-density lipoprotein cholesterol (LDL-C) level by>50% among patients with baseline values of ≥190 mg/dL (approximately 4.872 mmol/L); however, this value should be modified before applying it to Korean populations. We investigated the statin-specific LDL-C-lowering effects in Korean patients with baseline LDL-C value ≥ 4.872 mmol/L. Data of patients prescribed a statin for the first time from January 2009 to December 2013 were assessed. In patients with baseline LDL-C value ≥ 4.872 mmol/L, laboratory data for a maximum of 6 months from the date of first statin prescription were collected. Among 33,721 patients who were prescribed a statin for the first time, 655 patients had a baseline LDL-C value ≥ 4.872 mmol/L (1.9%). Of these, 179 patients were analysed. Patients receiving moderate-intensity statins were divided into 2 groups based on LDL-C reduction rate (p=0.0002), defined as moderate-high- (atorvastatin 20 mg, rosuvastatin 10 mg, simvastatin 20 mg) and moderate-low-intensity (atorvastatin 10 mg, pitavastatin 2 mg, pravastatin 40 mg) statin groups. LDL-C reduction rates did not significantly differ between the moderate-high- and high-intensity statin groups (p=0.4895). We found that some moderate-intensity statins demonstrated a LDL-C lowering effect of more than 50% in Korean patients with a baseline LDL-C value ≥ 4.872 mmol/L. Our results reflect the need of a large-scale, randomized, controlled trial on partial reclassification of statins for patients with baseline LDL-C value ≥ 4.872 mmol/L before adopting ACC/AHC guidelines in Korea.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-06T09:46:26.685007-05:
      DOI: 10.1111/bcpt.12765
  • Modelling Mutation Spectra of Human Carcinogens Using Experimental Systems
    • Authors: Maria Zhivagui; Michael Korenjak, Jiri Zavadil
      Abstract: Mutation spectra in cancer genomes provide information on the disease aetiology and the causality underlying the evolution and progression of cancer. Genome-wide mutation patterns reflect the effects of mutagenic insults and can thus reveal past carcinogen-specific exposures and inform hypotheses on the causative factors for specific cancer types. To identify mutation profiles in human cancers, single-gene studies were first employed, focusing mainly on the tumour suppressor gene TP53. Furthermore, experimental studies had been developed in model organisms. They allowed the characterization of the mutation patterns specific to known human carcinogens, such as polycyclic aromatic hydrocarbons or ultraviolet light. With the advent of massively parallel sequencing, mutation landscapes become revealed on a large scale, in human primary tumours and in experimental models, enabling deeper investigations of the functional and structural impact of mutations on the genome, including exposure-specific base-change fingerprints known as mutational signatures. These studies can now accelerate the identification of aetiological factors, contribute to carcinogen evaluation and classification and ultimately inform cancer prevention measures.
      PubDate: 2017-02-03T03:30:27.970513-05:
      DOI: 10.1111/bcpt.12690
  • An Adductomic Approach to Identify Electrophiles In Vivo
    • Authors: Henrik Carlsson; Margareta Törnqvist
      Abstract: Human beings are exposed to many reactive electrophiles, both formed endogenously and from exogenous exposures. Such compounds could react with cellular biomolecules and form stable reaction products, adducts, at nucleophilic sites in proteins and DNA, constituting a risk for toxic effects. Adductomic approaches aim to study the totality of adducts, to specific biomolecules, by mass spectrometric screening. This Mini-Review focuses on the development and application of an adductomic approach for the screening of unknown adducts to N-terminal valine (Val) in haemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC-MS/MS). The approach is based on the FIRE procedure, a modified Edman procedure for the analysis of adducts to N-terminal Val in Hb by LC-MS/MS. In the first application of the approach, samples from 12 smokers/non-smokers were screened for Hb adducts, and six previously identified adducts and 20 unknown adducts were detected. To confirm the observation of the detected unknown adducts, targeted screenings were performed in larger sets of blood samples (n = 50–120) from human cohorts. The majority of the previously detected unknown adducts was found in all analysed samples, with large interindividual variations in adduct levels. For structural identification of unknown adducts, a strategy using adductome LC-MS/MS data was formulated and applied. Six identified adducts correspond to ethylation and the precursor electrophiles ethyl vinyl ketone, glyoxal, methylglyoxal, acrylic acid and 1-octen-3-one. The observation of these adducts in human blood motivate further studies to evaluate possible contributions to health risks, as well as their potential as biomarkers of exposure.
      PubDate: 2017-01-11T00:55:30.184559-05:
      DOI: 10.1111/bcpt.12715
  • DNA Damage Potential of Engine Emissions Measured In Vitro by Micronucleus
           Test in Human Bronchial Epithelial Cells
    • Authors: Tereza Cervena; Andrea Rossnerova, Jitka Sikorova, Vit Beranek, Michal Vojtisek-Lom, Miroslav Ciganek, Jan Topinka, Pavel Rossner
      Abstract: Internal combustion engine emissions belong among the major anthropogenic sources of air pollution in urban areas. According to the International Agency for Research on Cancer, there is sufficient evidence of the carcinogenicity of diesel exhaust in human beings. Although alternative fuels, mainly biodiesel, have recently become popular, little is still known about the genotoxicity of emissions from these fuels. We analysed DNA damage expressed as the frequency of micronuclei (MN) in human bronchial epithelial cells (BEAS-2B), induced by extractable organic matter (EOM; tested concentrations: 1, 10 and 25 μg/ml) obtained from particle emissions from various blends of biodiesel with diesel fuels (including neat diesel fuel (B0), a blend of 70% B0 and 30% biodiesel (B30) and neat biodiesel (B100)). We also tested the effect of selected diesel exhaust organic/genotoxic components [benzo[a]pyrene (B[a]P) concentrations: 25, 100 and 200 μM; 1-nitropyrene (1-NP) concentrations: 1, 5 and 10 μM; 3-nitrobenzanthrone (3-NBA) concentrations: 1, 5 and 50 μM]. The cells were treated with the compounds for 28 and 48 hr. Our results showed that most of the tested compounds (except for the 25 μM B[a]P, 28-hr treatment) significantly increased MN frequency. The genotoxicity of EOMs from the engine emissions of diesel and biodiesel engines was comparable. Both nitro-PAH compounds demonstrated higher genotoxic potential in comparison with B[a]P. Considering our results and due to increasing popularity of alternative fuels, it is prudent that the potential genotoxic effects of various fuels are investigated across engine technologies and operating conditions in a relevant model system.
      PubDate: 2017-01-06T03:35:40.115409-05:
      DOI: 10.1111/bcpt.12693
  • Issue Information
    • Pages: 1 - 2
      PubDate: 2017-06-13T02:00:27.579879-05:
      DOI: 10.1111/bcpt.12812
  • Abstracts
    • Pages: 3 - 55
      PubDate: 2017-06-13T02:00:25.801513-05:
      DOI: 10.1111/bcpt.12813
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