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  Subjects -> ENVIRONMENTAL STUDIES (Total: 783 journals)
    - ENVIRONMENTAL STUDIES (712 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (39 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (712 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: 10)
Acta Regionalia et Environmentalica     Open Access  
Advances in Ecological Research     Full-text available via subscription   (Followers: 46)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 21)
Advances in Environmental Technology     Open Access  
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: 3)
Agricultura Tecnica     Open Access   (Followers: 5)
Agro-Science     Full-text available via subscription  
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10)
Amazon's Research and Environmental Law     Open Access   (Followers: 4)
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: 17)
American Journal of Environmental Protection     Open Access   (Followers: 8)
American Journal of Environmental Sciences     Open Access   (Followers: 16)
American Naturalist     Full-text available via subscription   (Followers: 73)
Annals of GIS     Hybrid Journal   (Followers: 24)
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: 62)
Annual Review of Environment and Resources     Full-text available via subscription   (Followers: 16)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 29)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 12)
Applied and Environmental Soil Science     Open Access   (Followers: 17)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 19)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 14)
Aquatic Ecology     Hybrid Journal   (Followers: 32)
Aquatic Toxicology     Hybrid Journal   (Followers: 20)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 8)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 12)
Archives of Environmental Protection     Open Access   (Followers: 5)
Archives of Toxicology     Hybrid Journal   (Followers: 17)
Asia Pacific Journal of Environment Ecology and Sustainable Development     Open Access   (Followers: 7)
Asian Journal of Rural Development     Open Access   (Followers: 7)
Asian Review of Environmental and Earth Sciences     Open Access   (Followers: 2)
Atas de Saúde Ambiental - ASA     Open Access  
ATBU Journal of Environmental Technology     Open Access   (Followers: 4)
Atmospheric and Climate Sciences     Open Access   (Followers: 28)
Atmospheric Environment     Hybrid Journal   (Followers: 66)
Austral Ecology     Hybrid Journal   (Followers: 15)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 12)
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: 11)
Basic and Applied Ecology     Hybrid Journal   (Followers: 17)
Behavioral Ecology     Hybrid Journal   (Followers: 51)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 32)
Biocenosis     Open Access  
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: 19)
Boletín Semillas Ambientales     Open Access  
Boston College Environmental Affairs Law Review     Open Access   (Followers: 8)
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: 12)
Bulletin of the American Meteorological Society     Open Access   (Followers: 37)
Business, Peace and Sustainable Development     Full-text available via subscription   (Followers: 3)
Canadian Journal of Earth Sciences     Hybrid Journal   (Followers: 19)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 44)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 13)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 22)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 16)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 13)
Chain Reaction     Full-text available via subscription  
Challenges in Sustainability     Open Access   (Followers: 6)
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 21)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 14)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 60)
China Population, Resources and Environment     Full-text available via subscription   (Followers: 2)
Civil and Environmental Engineering     Open Access   (Followers: 7)
Civil And Environmental Engineering Reports     Open Access   (Followers: 6)
Civil and Environmental Research     Open Access   (Followers: 19)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 20)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 5)
Cleanroom Technology     Full-text available via subscription   (Followers: 1)
Climate Change Economics     Hybrid Journal   (Followers: 13)
Climate Policy     Hybrid Journal   (Followers: 32)
Coastal Engineering Journal     Hybrid Journal   (Followers: 5)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Free   (Followers: 10)
Computational Ecology and Software     Open Access   (Followers: 9)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 4)
Conservation and Society     Open Access   (Followers: 12)
Conservation Letters     Open Access   (Followers: 37)
Conservation Science     Open Access   (Followers: 23)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 5)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 14)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 24)
Cuadernos de Investigación Geográfica / Geographical Research Letters     Open Access  
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 14)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 7)
Current Environmental Health Reports     Hybrid Journal  
Current Forestry Reports     Hybrid Journal  
Current Opinion in Environmental Sustainability     Hybrid Journal   (Followers: 13)
Current Research in Microbiology     Open Access   (Followers: 18)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 6)
Current World Environment     Open Access   (Followers: 3)
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: 8)
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: 22)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 15)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 7)
E3S Web of Conferences     Open Access  
Earth Interactions     Full-text available via subscription   (Followers: 13)
Earth Science Informatics     Hybrid Journal   (Followers: 4)
Earth System Science Data (ESSD)     Open Access   (Followers: 7)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 5)
Earthquake Science     Hybrid Journal   (Followers: 12)
EchoGéo     Open Access   (Followers: 1)
Ecocycles     Open Access   (Followers: 5)
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: 157)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecological Complexity     Hybrid Journal   (Followers: 7)
Ecological Indicators     Hybrid Journal   (Followers: 18)
Ecological Informatics     Hybrid Journal   (Followers: 4)
Ecological Management & Restoration     Hybrid Journal   (Followers: 14)
Ecological Modelling     Hybrid Journal   (Followers: 93)
Ecological Monographs     Full-text available via subscription   (Followers: 34)
Ecological Processes     Open Access   (Followers: 4)
Ecological Questions     Open Access   (Followers: 6)
Ecological Research     Hybrid Journal   (Followers: 9)
Ecological Restoration     Full-text available via subscription   (Followers: 24)
Ecologist, The     Full-text available via subscription   (Followers: 27)
Ecology     Full-text available via subscription   (Followers: 335)
Ecology and Evolution     Open Access   (Followers: 70)
Ecology Letters     Hybrid Journal   (Followers: 248)
Economics and Policy of Energy and the Environment     Full-text available via subscription   (Followers: 8)
Économie rurale     Open Access   (Followers: 2)
Ecoprint : An International Journal of Ecology     Open Access   (Followers: 2)
Ecopsychology     Hybrid Journal   (Followers: 7)
Ecosphere     Open Access   (Followers: 7)
Ecosystem Services     Hybrid Journal   (Followers: 7)
Ecosystems     Hybrid Journal   (Followers: 31)
Ecotoxicology     Hybrid Journal   (Followers: 11)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 9)
Ecotrophic : Journal of Environmental Science     Open Access   (Followers: 1)
Ecozon@ : European Journal of Literature, Culture and Environment     Open Access   (Followers: 4)
Ekologija     Open Access  
Electronic Green Journal     Open Access   (Followers: 5)
Energy & Environmental Science     Full-text available via subscription   (Followers: 27)
Energy & Environment     Hybrid Journal   (Followers: 20)
Energy and Environment Focus     Free   (Followers: 6)
Energy and Environment Research     Open Access   (Followers: 13)
Energy and Environmental Engineering     Open Access   (Followers: 7)
Engenharia Sanitaria e Ambiental     Open Access  
Envigogika     Open Access  
Environment and Behavior     Hybrid Journal   (Followers: 19)
Environment and Ecology Research     Open Access   (Followers: 7)
Environment and Natural Resources Research     Open Access   (Followers: 10)
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: 51)
Environment and Pollution     Open Access   (Followers: 11)
Environment and Society     Full-text available via subscription   (Followers: 8)
Environment International     Hybrid Journal   (Followers: 16)
Environment Systems & Decisions     Hybrid Journal   (Followers: 3)
Environment, Development and Sustainability     Hybrid Journal   (Followers: 34)
Environment, Space, Place     Full-text available via subscription   (Followers: 6)
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: 7)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 5)
Environmental Claims Journal     Hybrid Journal   (Followers: 2)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 19)
Environmental Development     Hybrid Journal   (Followers: 2)
Environmental Disease     Open Access   (Followers: 2)
Environmental Education Research     Hybrid Journal   (Followers: 14)
Environmental Engineering Science     Hybrid Journal   (Followers: 8)
Environmental Ethics     Hybrid Journal   (Followers: 9)
Environmental Evidence     Open Access   (Followers: 2)
Environmental Fluid Mechanics     Hybrid Journal   (Followers: 6)
Environmental Forensics     Hybrid Journal   (Followers: 2)
Environmental Geosciences     Full-text available via subscription   (Followers: 5)
Environmental Geotechnics     Hybrid Journal   (Followers: 5)

        1 2 3 4 | Last

Journal Cover Basic & Clinical Pharmacology & Toxicology
  [SJR: 0.539]   [H-I: 70]   [11 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  [1589 journals]
  • MiR-595 Suppresses the Cellular Uptake and Cytotoxic Effects of
           Methotrexate by Targeting SLC19A1 in CEM/C1 Cells
    • Authors: Shu-Mei Wang; Lu-Lu Sun, Wan-Shui Wu, Dan Yan
      Abstract: The human solute carrier family 19 member 1 (SLC19A1) is the gene coding for reduced folate carrier 1 (RFC1). In our previous work, we showed that the miR-595-related polymorphism, rs1051296 G>T, which was located in the 3’-untranslated region (3’-UTR) of SLC19A1, was associated with high methotrexate (MTX) plasma concentrations in pediatric acute lymphoblastic leukaemia (ALL) patients. The present study aimed to investigate the role of miR-595 in the regulation of SLC19A1 expression and its effects on the cellular uptake and cytotoxicity of MTX in ALL CEM/C1 cells. Luciferase reporter assay was performed to validate SLC19A1 as a miR-595 target. RFC1 protein expression was determined via western blotting. Intracellular MTX concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Cell viability and apoptosis were assessed using Cell Counting Kit-8 (CCK-8) assay and flow cytometer, respectively. Compared to the negative control, miR-595 mimics induced a significant decrease in the relative luciferase activity by binding to the 3’-UTR of SLC19A1 harbouring the rs1051296 T allele (P < 0.01). Treatment of CEM/C1 cells with miR-595 mimics substantially reduced RFC1 protein expression, intracellular MTX levels, MTX-induced cytotoxicity, and apoptosis rates compared to those of negative control. However, opposite results were observed in cells transfected with a miR-595 inhibitor. These findings suggested that miR-595 acts as a phenotypic regulator of MTX sensitivity in CEM/C1 cells by targeting SLC19A1. This study helped us to understand the mechanisms underlying the variable MTX responses observed in ALL patients.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-17T20:52:46.967543-05:
      DOI: 10.1111/bcpt.12966
       
  • Incidence of Common Cancers in Users of Antimuscarinic Medications for
           Overactive Bladder: A Danish Nationwide Cohort Study
    • Authors: Jesper Hallas; Andrea V. Margulis, Anton Pottegård, Nina Sahlertz Kristiansen, Willem Jan Atsma, Kwame Appenteng, Stefan de Vogel, James A. Kaye, Susana Perez-Gutthann, Alejandro Arana
      Abstract: The purpose of this study was to estimate the incidence rate (IR) of 10 common cancers in new users of antimuscarinic overactive bladder (OAB) medications.We conducted a cohort study using data recorded in Danish registers for patients newly exposed to the OAB drugs darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium in years 2004-2012, aged ≥18 years and without cancer before treatment initiation. We estimated IRs for each study cancer (bladder, breast, colorectal, lung, melanoma, non-Hodgkin lymphoma, pancreas, prostate, renal and uterine), standardised by age and sex and explored IR trends over time since treatment initiation. For all cancer analyses, only the first incident targeted cancer was considered.Of 72,917 patients (60% women; mean age at treatment start: 66 years), 3,475 developed a study cancer during 259,072 person-years of follow-up. The most common study cancers were prostate (48.1% of study cancers in men), breast (40.0% of study cancers in women) and lung (15.4% of all study cancers). The overall standardised study cancer IR was 5.4 per 1,000 person-years (95% confidence interval, 5.3-5.6); IRs were similar across individual OAB drugs. The standardised IRs for bladder and prostate cancers, which have symptoms in common with OAB, were highest in the first 6 months of treatment initiation and lower thereafter. In contrast, IRs for other study cancers were nearly constant during follow-up.Cancer IRs did not vary substantially by individual OAB drug. Protopathic bias is a plausible explanation for the higher rates of bladder and prostate cancers observed soon after starting OAB drug treatment.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-17T20:50:42.18234-05:0
      DOI: 10.1111/bcpt.12965
       
  • Preclinical Characterisation of Absorption, Distribution, Metabolism and
           Excretion Properties of TAK-063
    • Authors: Kimio Tohyama; Miyako Sudo, Akio Morohashi, Suguru Kato, Junzo Takahashi, Yoshihiko Tagawa
      Abstract: TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19, and P-gp with IC50 values of 8.4, 12, and 7.13 μM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020).This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-17T20:45:37.348025-05:
      DOI: 10.1111/bcpt.12964
       
  • Silica Nanoparticle-induced Cytokine Responses in BEAS-2B and HBEC3-KT
           Cells: Significance of Particle Size and Signalling Pathways in Different
           Lung Cell Cultures
    • Authors: Marit Låg; Tonje Skuland, Anna Godymchuk, Thu H. T. Nguyen, Hang L. T. Pham, Magne Refsnes
      Abstract: We have previously reported that silica nanoparticles (SiNPs) of nominal size 50 nm (Si50) induce the pro-inflammatory cytokines CXCL8 and IL-6 in BEAS-2B cells, via mechanisms involving MAPK p38, TACE-mediated TGFα release and the NFκB pathway. In the present study, we examined whether these findings are cell-specific or might be extended to another epithelial lung cell model, HBEC3-KT, and also to SiNPs of a smaller size (nominal size of 10 nm; Si10). The TEM average size of Si10 and Si50 was 10.9 nm and 34.7 nm, respectively. The surface area (BET) of Si10 was 3-fold higher than for Si50 per mass unit. With respect to hydrodynamic size (DLS), Si10 in exposure medium showed a higher z-average for the main peak than Si50, indicating more excessive agglomeration. Si10 strongly induced CXCL8 and IL-6, as assessed by ELISA and RT-PCR, and was markedly more potent than Si50, even when adjusted to equal surface area. Furthermore, Si10 was far more cytotoxic, measured as lactate dehydrogenase (LDH) release, than Si50 in both epithelial cell cultures. With respect to signalling pathways, western analysis and experiments with and without inhibition of MAPK, TACE and NFκB (synthetic inhibitors) revealed that p38-phosphorylation, TACE-mediated TGFα release and NFκB activation seem to be important triggering mechanisms both for Si50 and Si10 in the two different lung epithelial cell cultures. In conclusion, the identified signalling pathways are suggested to be important in inducing cytokine responses in different epithelial cell types and also for various sizes of silica nanoparticles.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-15T06:40:27.474747-05:
      DOI: 10.1111/bcpt.12963
       
  • The Prevalence of Cannabinoid Hyperemesis Syndrome Among Regular Marijuana
           Smokers in an Urban Public Hospital
    • Authors: Joseph Habboushe; Ada Rubin, Haoming Liu, Robert S. Hoffman
      Abstract: Epidemiological data, including prevalence, for cannabinoid hyperemesis syndrome (CHS) remain largely unknown. Without these data, clinicians often describe CHS as “rare” or “very rare” without supporting information. We seek to estimate the prevalence of CHS in a population of patients presenting to a socioeconomically and racially diverse urban Emergency Department of a public hospital.This study consisted of a questionnaire administered to a convenience sample of patients presenting to the ED of the oldest public hospital in the United States. Trained Research Associates (RAs) administered the questionnaire to patients between the ages of 18-49 years who reported smoking marijuana at least 20 days per month. The survey included questions related to CHS symptoms (nausea and vomiting) and Likert scale rankings on eleven symptom relief methods, including “hot showers.” Patients were classified as experiencing a phenomenon consistent with CHS if they reported smoking marijuana at least 20 days per month and also rated “hot showers” as five or more on the ten-point symptom relief method Likert scale for nausea and vomiting.Among 2,127 patients approached for participation, 155 met inclusion criteria as smoking 20 or more days per month. Among those surveyed, 32.9% (95% CI, 25.5% - 40.3%) met our criteria for having experienced CHS. If this is extractable to the general population, approximately 2.75 million (2.13 – 3.38 million) Americans may have suffered from a phenomenon similar to CHS.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-12T06:05:22.512373-05:
      DOI: 10.1111/bcpt.12962
       
  • No Impact of Pre-Existing Cardiovascular Disease on Prescribing Patterns
           of Sulphonylureas in Denmark - A Registry-based Nationwide Study
    • Authors: Malin Nilsson; Jørgen Rungby, Nathan Lassota, Andreas Daugaard Jørgensen, Rikke Ibsen, Jakob Kjellberg
      Abstract: Uncertainty exists regarding cardiovascular (CV) safety of sulphonylureas (SUs) as reflected in package labels and treatment guidelines. This study evaluated clinical treatment practice for SUs by analysing prescription patterns for SUs relative to patient history of CV disease (CVD).Patients in Denmark initiating treatment with SU or other anti-hyperglycaemic drugs during 2006-2012 were retrospectively identified using national health registries. Pre-existing (previous 12 years) overall CVD, coronary heart disease (CHD) and myocardial infarction (MI) were subsequently identified. Proportion of patients with pre-existing CVD was compared between new users of SU and new users of other anti-hyperglycaemic drugs.In total, 50,425 (42.2% females, mean±SD age 63.3±13.5 years) and 190,438 (46.5% females, age 60.3±15.0 years) patients initiated treatment with SU or other anti-hyperglycaemic drugs, respectively, during 2006-2012. The number of patients initiating SU treatment decreased by 63% during 2006-2012. The proportion of patients with pre-existing CVD varied between 46.9 and 49.8% among new SU users versus 39.9 and 44.8% among new users of other anti-hyperglycaemic drugs. Corresponding proportions for CHD (17.9-19.9% versus 15.4-16.9%) and MI (6.3-7.5% versus 5.8-6.2%) showed the same pattern. Excluding new gliclazide users (9.6% of all new SU users) from the SU definition did not alter the results.Despite a potentially increased CV risk associated with use of SUs, pre-existing CVD did not decrease clinicians’ relative prescriptions of SUs.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-12T06:05:21.461945-05:
      DOI: 10.1111/bcpt.12961
       
  • ITPA Activity in Children treated by Azathioprine: Relationship to the
           Occurrence of Adverse Drug Reactions and Inflammatory Response
    • Authors: Antony Citterio-Quentin; Mustapha Moulsma, Marie-Paule Gustin, Alain Lachaux, Roselyne Boulieu
      Abstract: Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological disease such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reaction (ADRs) and drug response is observed. This study investigated 1) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, 2) the relationship between ITPA activity and the inflammatory activity observed in children with IBD.ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits.No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flu-like symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV) (P=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase of gamma globulin level reflecting inflammation (P=0.005).In our study, ITPA activity was not associated with occurrence of ADRs but a relationship between high ITPA activity and gamma globulin, a marker of inflammation, was found in children with IBD. Thereby, measurement of ITPA activity may help to identify IBD children predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-11T21:05:37.034854-05:
      DOI: 10.1111/bcpt.12958
       
  • Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 polymorphisms on
           pharmacokinetics and safety of aripiprazole in healthy volunteers
    • Authors: Carmen Belmonte; Dolores Ochoa, Manuel Román, Miriam Saiz-Rodríguez, Aneta Wojnicz, Clara Isabel Gómez-Sánchez, Samuel Martín-Vilchez, Francisco Abad-Santos
      Abstract: The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from 6 bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC0-t, Cmax and t1/2 of aripiprazole were higher and clearance of aripiprazole, AUC0-t of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC0-t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM) and AUC0-t of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p=0.023) and AUC0-t (p=0.039) and Cmax of dehydro-aripiprazole (p=0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p=0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC0-t of aripiprazole (p=0.001), especially nausea/vomiting, which were more common in women (p=0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p=0.034; p=0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-11T19:00:22.719352-05:
      DOI: 10.1111/bcpt.12960
       
  • Availability of Paracetamol Sold Over-the-Counter in Europe: A Descriptive
           Cross-Sectional International Survey of Pack Size Restriction
    • Authors: Britt Reuter Morthorst; Annette Erlangsen, Merete Nordentoft, Keith Hawton, Lotte Christine Groth Hoegberg, Kim Peder Dalhoff
      Abstract: Due to the risk of hepatotoxicity when excessive amounts of paracetamol are consumed, Poisons Information Centers (PICs) frequently receive paracetamol-related enquiries. This study examined how widely pack size restrictions of paracetamol sold over-the-counter have been implemented in Europe and also availability of paracetamol through non-pharmacy outlets and their possible associations with frequency of poisoning enquiries.A cross-sectional European multicentre questionnaire study was performed using a questionnaire to identify the extent and nature of paracetamol pack size restrictions, non-pharmacy outlet sales and the frequency of paracetamol-related enquiries to PICs.In total, 21 European countries participated. All PICs provided telephone hotline services.In 14 (67%) countries, pack size restrictions had been implemented in pharmacies (range: 8-30 grams). No significant difference (median difference 0.7%, p-value=0.36) was found when comparing median frequencies of paracetamol-related enquiries in countries with pack size restriction to countries without restrictions. A significantly lower median frequency of paracetamol-related enquiries was found in countries without non-pharmacy outlet sales compared to those with such sales (median difference 2.2%, p = 0.02).Pack size restrictions on pharmacy sales of paracetamol have been implemented in two thirds of examined countries. There was no difference in the proportion of paracetamol-related enquiries to PICs among countries with and without pack size restrictions. However, a lower rate of paracetamol-related enquiries was noted in countries where paracetamol was not available in non-pharmacy outlets.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-10T07:45:19.333152-05:
      DOI: 10.1111/bcpt.12959
       
  • A Systematic Review on Insulin Overdose Cases: Clinical Course,
           Complications and Novel Treatment Options
    • Authors: Nicklas Järvelä Johansen; Mikkel Bring Christensen
      Abstract: A large overdose of insulin is a serious health matter. Information concerning administration and duration of intravenous (IV) glucose, other treatment options or complications beside hypoglycaemia following large insulin overdoses is not readily apparent from the literature.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-09T11:10:46.613576-05:
      DOI: 10.1111/bcpt.12957
       
  • Integrated approaches to testing and assessment (IATA): OECD activities on
           the development and use of adverse outcome pathways and case studies
    • Authors: Yuki Sakuratani; Masashi Horie, Eeva Leinala
      Abstract: The Organisation for Economic Co-operation and Development (OECD) works with member countries and other stakeholders to improve and harmonise chemical assessment methods. In 2012, the OECD Adverse Outcome Pathways (AOPs) Development Programme started. The Programme has published six AOPs thus far and more than 60 AOPs are under various stages of development under the Programme. This paper reviews recent OECD activities on the use of AOPs in developing Integrated Approaches to Testing and Assessments (IATAs). The guidance document for the use of AOPs in developing IATA, published in 2016, provides a framework for developing and using IATA and describes how IATA can be based on an AOP. The guidance document on the reporting of defined approaches to be used within IATA, also published in 2016, provides a set of principles for reporting defined approaches to testing and assessment to facilitate their evaluation. In the guidance documents, the AOP concept plays an important role for building IATA approaches in a science-based and transparent way. In 2015, the IATA Case Studies Project was launched to increase experience with the use of IATA and novel hazard methodologies by developing case studies, which constitute examples of predictions that are fit for regulatory use. This activity highlights the importance of international collaboration for harmonizing and improving chemical safety assessment methods.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-09T07:00:29.337398-05:
      DOI: 10.1111/bcpt.12955
       
  • Improving the Safety Assessment of Chemicals and Drug Candidates by the
           Integration of Bio-informatics and Chemoinformatics Data
    • Authors: Thomas Steger-Hartmann; Francois Pognan
      Abstract: The application of read-across and in silico tools for regulatory decision-making has been limited for pharmaceutical compounds to the assessment of genotoxic impurity. In contrast, the broad availability of toxicity data for industrial chemicals has triggered regulatory frameworks for read-across (e.g. ECHA read-across assessment framework), software tools and public databases for an automated process of gap filling for safety assessment framework. This MiniReview provides an overview of the currently existing in silico and read-across approaches for chemicals together with recent developments for pharmaceutical compounds in these areas. It also highlights the differences and commonalities in the in silico safety assessment of industrial chemicals and drug candidates.Whereas toxicity data collection and sharing is now common practice for chemicals falling under the European REACH regulation (Registration, Evaluation, Authorisation and Restriction of Chemicals), the biggest hurdle for establishing preclinical safety databases for pharmaceutical compounds is the unwillingness to share proprietary data and lack of published datasets. In a recent consortium approach, thirteen pharmaceutical companies, eleven academic partners and six small to medium size enterprises (SMEs) of the bioinformatics sector joined forces over the last seven years within the European Innovative Medicines Initiative project eTOX (“electronic toxicity”) to design and implement a strategy for leveraging these preclinical data for small molecules and sharing them across project partners. The eTOX database has evolved as the largest preclinical toxicity database for drugs and drug candidates and currently contains more than 1900 different chemical structures and more than 8000 in vivo toxicity study datasets. It can be foreseen that the development and application of such databases for drugs or drug candidates will in the future also cross-fertilize the read-across and the in silico assessment of industrial or consumer chemicals particularly as soon as human safety data from clinical trials are integrated, too.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-07T22:45:28.428354-05:
      DOI: 10.1111/bcpt.12956
       
  • Issue Information
    • Pages: 189 - 190
      PubDate: 2018-01-15T02:42:55.065904-05:
      DOI: 10.1111/bcpt.12883
       
  • A Comparison of the Effectiveness of Silibinin and Resveratrol in
           Preventing Alpha-Amanitin-Induced Hepatotoxicity
    • Authors: Aynur Sahin; M. Aylin Arici, Yeliz Yılmaz, Sule Kalkan, Nergiz Durmus, Bekir Ugur Ergur, İlkay Aksu, Neşe Atabey, Yesim Tuncok
      Abstract: Amanita phalloides species mushrooms containing alpha amanitin (α-AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of α-AMA-induced hepatotoxicity. We investigated the effects of resveratrol on α-AMA-induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with α-AMA (α-AMA +SR) or 12 (α-AMA +12R) or 24 (α-AMA +24R) hr after α-AMA administration. Silibinin (5 mg/kg) (α-AMA +Sil) and normal saline (α-AMA+NS) were given simultaneously with α-AMA. We found that liver transaminase levels in α-AMA+SR and α-AMA+12R groups and histomorphologic injury score in the α-AMA+SR, α-AMA+12R, α-AMA+24R and α-AMA+Sil groups were significantly lower than that of the α-AMA+NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase-3 immunopositivity in liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in reduction in cell viability induced by α-AMA in THLE-2 and THLE-3 hepatocytes. Neither resveratrol nor silibinin were found to be effective in increasing cell viability decreased by α-AMA+NS.As a conclusion, resveratrol was found to be effective in α-AMA-induced hepatotoxicity with its anti-inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-29T02:35:37.084624-05:
      DOI: 10.1111/bcpt.12954
       
  • The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients
           Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants
           
    • Authors: K S Valeur; S A Hertel, K E Lundstrøm, H Holst
      Abstract: Poly-medicated neonates and young infants may be at risk of harmful cumulative exposure to toxic excipients like ethanol, propylene glycol and benzyl alcohol during routine clinical care. The aim of this study was to calculate the cumulative daily alcohol exposure (mg/kg/day) in poly-medicated neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA).As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received ≥two medicinal products/day and infants ≥three medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA.In total, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products. In total, 45% (n=288) of patients were exposed to an alcohol of interest; 2% (n=14) were exposed to benzyl alcohol (BA), 38% (n=237) to ethanol and 23% (n=146) to propylene glycol (PG). Of the total number of prescriptions involving ethanol-containing medicinal products (n=334), 51% would alone exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n=174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563mg/kg/day) or PG (954mg/kg/day) exceeded the tolerance limits recommended by EMA 260.5 and 19.1 times, respectively.Tolerance limits for ethanol and PG as proposed by the EMA are frequently exceeded in poly-medicated neonates and infants due to the cumulative effect of these alcohols. Alternative formulations may minimize excipient exposure.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-27T08:30:40.778159-05:
      DOI: 10.1111/bcpt.12950
       
  • The Effect of 7-Hydroxycoumarin on Dextran Sulfate Sodium-induced
           Ulcerative Colitis
    • Authors: Chengzheng Wang; Jing Liu, Yingchun Zhou, Gao Feng
      Abstract: 7-Hydroxycoumarin (HC) or Umbelliferone exerts many beneficial effects, ie. antioxidant, anti-tumour, anti-inflammatory and immunomodulatory activities. We hypothesized that HC had mitigating properties on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice, via suppression of inflammation. The induction of UC in mice was achieved by the administration of 3.5% DSS in drinking water for 7 consecutive days. Administration of HC to DSS-induced mice ameliorated the loss of body weight, reduced diarrhoea and gross bleeding and showed a significant reduction in the disease activity index (DAI). Further, it alleviated the DSS-induced shortening of colon length. Also, HC ameliorated mucosal damage, colonic oedema and infiltration of neutrophil into colonic intestinal tissue in response to damage caused by DSS. The increased expressions of inflammatory factors such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-17, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and decreased expression of anti-inflammatory marker IL-10. Administration of HC reduced the above said inflammatory factors significantly. In addition, HC reduced the level ofTBARS, increased the activities of antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD). We also analysed the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) expression in the experimental mice. It was found that HC could activate the Nrf2 and its downstream targets. In conclusion, HC treatment protects the colon from DSS-induced pathology, which is associated with enhanced enzymatic antioxidants and the activation of Nrf2 signalling. Thus, dietary HC can be beneficial to UC patients as a complementary therapeutic agent.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-26T09:50:44.654554-05:
      DOI: 10.1111/bcpt.12948
       
  • β-adrenergic Receptor Blocker ICI 118,551 Selectively Increases
           Intermediate-Conductance Calcium-Activated Potassium Channel
           (IKCa)-Mediated Relaxations in Rat Main Mesenteric Artery
    • Authors: Melike Hacer Ozkan; Serdar Uma
      Abstract: Endothelial IKCa and/or SKCa channels play an important role in the control of vascular tone by participating in endothelium-dependent relaxation. Whether β-AR antagonists, mainly used in hypertension, affect endothelial KCa channel function is unknown. In this study, we examined the effect of the β2-AR antagonist and inverse agonist ICI 118,551 on the IKCa/SKCa channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Spraque-Dawley mounted to organ baths. Acetylcholine elicited IKCa- and SKCa-mediated relaxations that were abolished by TRAM-34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IKCa-mediated relaxations, whereas SKCa-mediated relaxations remained unaltered. Same potentiating effect was also detected on the IKCa-mediated relaxations to carbachol and A 23187, but not to NS309. Neither acetylcholine-induced nitric oxide-mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT-5720, the selective β2-AR agonist salbutamol, the selective β2-AR antagonist butoxamine, the non-selective β-AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IKCa-mediated relaxations. ICI 118,551-induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium-induced relaxations in endothelium-removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IKCa channel-mediated vasodilation, through a mechanism independent of β2-AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-26T09:50:21.791702-05:
      DOI: 10.1111/bcpt.12949
       
  • Disproportionality Analysis Used to Identify Patterns in Medication Error
           Reports involving Hospitalized Children
    • Authors: Rikke Mie Rishoej; Henrik Thybo Christesen, Lene Juel Kjeldsen, Anna Birna Almarsdóttir, Jesper Hallas
      Abstract: Medication errors (MEs) in children are frequent and associated with increased risk of harm (1,2). Incident reporting of errors is considered a key element in strategies to reduce MEs (3). Traditionally, analyses of ME reports involve narrative descriptions and frequency counts which may cause important errors to be overlooked or may entail an element of subjectivism (2,4). A formal approach to analysis of ME reports could involve disproportionality principles used in pharmacovigilance, for example the proportional reporting ratio (PRR) (5). In large databases, PRRs may help identify potential safety targets which would go unnoticed when using frequency counts (6).This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-18T23:55:30.252708-05:
      DOI: 10.1111/bcpt.12947
       
  • Considerations for Pharmacoepidemiological Studies of Drug-Cancer
           Associations
    • Authors: Anton Pottegård; Søren Friis, Til Stürmer, Jesper Hallas, Shahram Bahmanyar
      Abstract: In this MiniReview, we provide general considerations for the planning and conduct of pharmacoepidemiological studies of associations between drug use and cancer development. We address data sources, study design, assessment of drug exposure, ascertainment of cancer outcomes, confounder adjustment and future perspectives.Aspects of data sources include assessment of complete history of drug use and data on dose and duration of drug use, allowing estimates of cumulative exposure. Outcome data from formal cancer registries are preferable, but cancer data from other sources, e.g., patient or pathology registries, medical records or claims are also suitable. The two principal designs for observational studies evaluating drug-cancer associations are the cohort and case-control designs. A key challenge in studies of drug-cancer associations is the exposure assessment due to the typically long period of cancer development. We present methods to examine early and late effects of drug use on cancer development and discuss the need for employing ‘lag-time’ in order to avoid reverse causation. We emphasize that a new user study design should always be considered. We also underline the need for ‘dose-response’ analyses, as drug-cancer associations are likely to be dose-dependent. Generally, studies of drug-cancer associations should explore risk of site-specific cancer, rather than cancer overall. Additional differentiation may also be crucial for organ-specific cancer with various distinct histological subtypes (e.g., lung or ovary cancer). We also highlight the influence of confounding factors and discuss various methods to address confounding, while emphasizing that the choices of methods depend on the design and specific objectives of the individual study. In some studies, use of active comparator(s) may be preferable.Pharmacoepidemiological studies of drug-cancer associations are expected to evolve considerably in the coming years, due to the increasing availability of long-term data on drug exposures and cancer outcomes, the increasing conduct of multinational studies, allowing studies of rare cancers and subtypes of cancer, and methodological improvements specifically addressing cancer and other long-term outcomes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-18T23:55:22.011862-05:
      DOI: 10.1111/bcpt.12946
       
  • Regulated Cell Death of Lymphoma Cells after Graded Mitochondrial Damage
           is differentially affected by Drugs Targeting Cell Stress Responses
    • Authors: Tomás Lombardo; Martín Gil Folgar, Luciana Salaverry, Estela Rey-Roldán, Elida M. Alvarez, María C Carreras, Laura Kornblihtt, Guillermo A. Blanco
      Abstract: Collapse of the mitochondrial membrane potential (MMP) is often considered the initiation of regulated cell death (RCD). Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) is an uncoupler of the electron transport chain (ETC) that facilitates the translocation of protons into the mitochondrial matrix leading to the collapse of the MMP. Several cell stress responses such as mitophagy, mitochondrial biogenesis and the ubiquitin proteasome system, may differentially contribute to restrain the initiation of RCD depending on the extent of mitochondrial damage. We induced graded mitochondrial damage after collapse of MMP with the mitochondrial uncoupler CCCP in Burkitt's lymphoma cells, and we evaluated the effect of several drugs targeting cell stress responses over RCD at 72 hr, using a multiparametric flow cytometry approach. CCCP caused collapse of MMP after 30 min., massive mitochondrial fission, oxidative stress and increased mitophagy within the 5-15 μM low-dose range (LDR) of CCCP. Within the 20-50 μM high-dose range (HDR), CCCP caused lysosomal destabilization and rupture, thus precluding mitophagy and autophagy. Cell death after 72 hr was below 20%, with increased mitochondrial mass (MM). The inhibitors of mitophagy Mdivi-1 and vincristine increased cell death from CCCP within the LDR, while valproic acid (an inducer of mitochondrial biogenesis) also increased MM and cell death within the LDR. The proteasome inhibitor, MG132, increased cell death only in the HDR. Doxycycline, an antibiotic that disrupts mitochondrial biogenesis, had no effect on cell survival, while iodoacetamide, an inhibitor of glycolysis, increased cell death at the HDR. We conclude that mitophagy influenced RCD of lymphoma cells after MMP collapse by CCCP only within the LDR, while proteasome activity and glycolysis contributed to survival in the HDR under extensive mitochondria and lysosome damage.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-04T09:15:47.400952-05:
      DOI: 10.1111/bcpt.12945
       
  • Gender-specific Association between ABCC2 -24C>T SNP and Reduction in
           Triglycerides in Chilean Patients treated with Atorvastatin
    • Authors: Y Prado; A Arancibia, T Zambrano, L A Salazar
      Abstract: Statins are the first-line therapy prescribed to lower plasma cholesterol levels. Although being safe and showing several beneficial cholesterol-independent pleiotropic effects, a significant variability regarding statin's therapeutic goals has been abundantly documented, but less understood. We aimed to investigate the influence of the ABCC2 -24C>T single nucleotide polymorphism on Chilean hypercholesterolaemic subjects treated for 4 weeks with 10 mg/day atorvastatin. A total of 127 individuals medicated with atorvastatin 10 mg/day/4 weeks were included. Lipid profiles were determined before and after drug administration by conventional assays. Genotyping of the ABCC2 rs717620 SNP (-24C>T) was performed using TaqMan® Drug Metabolism Genotyping Assays. As expected, atorvastatin reduced TC, LDL-C and TG concentrations (p
      PubDate: 2017-11-27T09:25:19.585147-05:
      DOI: 10.1111/bcpt.12943
       
  • Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite
           of (R,S)-Ketamine, with Morphine
    • Authors: Tuomas O. Lilius; Hanna Viisanen, Viljami Jokinen, Mikko Niemi, Eija A. Kalso, Pekka V. Rauhala
      Abstract: Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-D-aspartate (NMDA) receptors. Ketamine is extensively metabolised to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings.Male Sprague-Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a co-treatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure, and rotarod tests were used. Brain and serum drug concentrations were quantified with high performance liquid chromatography-tandem mass spectrometry.Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pretreatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance.Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-24T00:55:42.457059-05:
      DOI: 10.1111/bcpt.12941
       
  • Variation in the Response of Clozapine Biotransformation Pathways in Human
           Hepatic Microsomes to CYP1A2 and CYP3A4-selective Inhibitors
    • Authors: Michael Murray; Wei V. Zhang, Robert J. Edwards
      Abstract: The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidise CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterise the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0.2 and 2 μM) and fluvoxamine (1 and 10 μM). The CYP3A4-selective inhibitor ketoconazole (2 μM) impaired CLZ N-oxide formation in all 14 of the livers used in inhibition studies (≥50% inhibition) while the CYP1A2-selective inhibitor fluvoxamine (10 μM) decreased norCLZ formation in nine. Ketoconazole effectively inhibited CLZ metabolism in 5 of 7 livers that catalysed CYP3A4-dependent testosterone 6β-hydroxylation at or above the median rate and in four other livers with lower intrinsic CYP3A4 activity. Similarly, fluvoxamine (10 μM) readily inhibited CLZ oxidation in seven livers with high CYP1A2-mediated 7-ethoxyresorufin O-deethylation activity (at or above the median) and three livers with lower intrinsic CYP1A2 activity. In three livers CLZ biotransformation was impaired by both ketoconazole and fluvoxamine, consistent with a major role for both CYPs. These findings suggest that the intrinsic activities of CYPs 1A2 and 3A4 are unrelated to the response to CYP-selective inhibitors and that assessment of the activities in vivo may not assist the prediction of drug-drug interactions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-20T10:15:25.17735-05:0
      DOI: 10.1111/bcpt.12933
       
  • Post-Treatment with Methylene Blue is Effective against Delayed
           Encephalopathy after Acute Carbon Monoxide Poisoning
    • Authors: Ningjun Zhao; Pengchong Liang, Xiaoying Zhuo, Chenglei Su, Xuemei Zong, Bingnan Guo, Han Dong, Xianliang Yan, Shuqun Hu, Quanguang Zhang, Xu Tie
      Abstract: Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is the most severe and clinically intractable complication that occurs following acute carbon monoxide poisoning. Unfortunately, the mechanism of DEACMP is still vague. Growing evidence indicates that delayed cerebral damage following CO poisoning is related to oxidative stress, abnormal neuro-inflammation, apoptosis and immune-mediated injury. Our recent report indicated that methylene blue (MB) may be a promising therapeutic agent in the prevention of neuronal cell death and cognitive deficits following transient global cerebral ischaemia (GCI). In the present study, we aimed to investigate the potential of MB therapy to ameliorate the signs and symptoms of DEACMP. Rats were exposed to 1000 ppm CO for 40 min. in the first step; CO was then increased to 3000 ppm, which was maintained for another 20 min. The rats were implanted with 7-day release Alzet osmotic mini-pumps subcutaneously under the back skin, which provided MB at a dose of 0.5 mg/kg/day 1 hr after CO exposure. The results showed that MB significantly suppressed oxidative damage and expression of pro-inflammatory factors, including tumour necrosis factor-α and interleukin (IL)-1β. MB treatment also suitably modulated mitochondrial fission and fusion, which is helpful in the preservation of mitochondrial function. Furthermore, MB dramatically attenuated apoptosis and neuronal death. Lastly, behavioural studies revealed that MB treatment preserved spatial learning and memory in the Barnes maze test. Our findings indicated that MB may have protective effects against delayed encephalopathy after acute carbon monoxide poisoning.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-19T08:10:22.87196-05:0
      DOI: 10.1111/bcpt.12940
       
  • High Prevalence of Drug-Drug Interactions in Primary Health Care is Caused
           by Prescriptions from other Health Care Units
    • Authors: Marine L. Andersson; Ylva Böttiger, Henrik Kockum, Birgit Eiermann
      Abstract: Drug-drug interactions are increasingly common, as patients are getting older and the number of drugs per patient is increasing. In this study, we investigated to which extent potential drug-drug interactions originated from single or multiple prescribers. All patients attending any of 20 primary health care centres were included in a retrospective observational cohort study. Data on all prescriptions to these patients, irrespectively of the prescriber, were collected for two 4-month periods. Potential drug interactions were identified using the drug-drug interaction database SFINX. Interactions were classified with respect to the workplace of the prescriber and the prevalence of interactions according to origin was analysed. We found that the drug interactions were significantly more common when the drugs were prescribed from different health care centres, compared with drugs prescribed from the patients’ primary health care centre only. One explanation for this increased risk of drug interactions could be that the prescribers at different primary health care centres do not share the same information concerning the total medication list of the patient.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-15T21:50:42.178804-05:
      DOI: 10.1111/bcpt.12939
       
  • SII Ang II Potentiates Insulin Receptor Signalling and Glycogen Synthesis
           in Hepatocytes
    • Authors: Samra Joke Sanni; Christina Lyngsø, Steen Gammeltoft, Jakob Lerche Hansen
      Abstract: The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue that only activates a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes.We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-14T12:10:57.716714-05:
      DOI: 10.1111/bcpt.12937
       
  • Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and
           Safety of Sertraline in Healthy Volunteers
    • Authors: Miriam Saiz-Rodríguez; Carmen Belmonte, Manuel Román, Dolores Ochoa, Dora Koller, María Talegón, María C. Ovejero-Benito, Rosario López-Rodríguez, Teresa Cabaleiro, Francisco Abad-Santos
      Abstract: Sertraline is a selective serotonin reuptake inhibitor (SSRI) widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of the present study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP binding cassette subfamily B member 1 (ABCB1), Solute carrier family 6 member 4 (SLC6A4), 5-Hydroxytryptamine receptor 2A (HTR2A) and 5-Hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Subjects carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2. No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and subjects with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T subjects.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-14T12:10:52.901825-05:
      DOI: 10.1111/bcpt.12938
       
  • Functional Characterization of 22 CYP3A4 Protein Variants to Metabolize
           Ibrutinib In Vitro
    • Authors: Ren-ai Xu; Jian Wen, Pengfei Tang, Chenchen Wang, Saili Xie, Bo-wen Zhang, Quan Zhou, Jian-ping Cai, Guo-xin Hu
      Abstract: Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in humans. Ibrutinib is an anti-cancer drug and primarily metabolized by CYP3A4. The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild-type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4.10, .11, .18, .23 and .33) exhibited no significant differences; another five variants (CYP3A4.3, .4, .9, .19 and .34) showed increased intrinsic clearance values, while the remaining nine variants (CYP3A4.2, .5, .14, .15, .16, .28, .29, .31 and .32) displayed decreased enzymatic activities in different degrees. As the first study of 22 CYP3A4 protein variants in ibrutinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism and elimination of ibrutinib, and also offer a reference to the personalized treatment of ibrutinib in clinic.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T19:00:24.312615-05:
      DOI: 10.1111/bcpt.12934
       
  • Evaluation of the Influence of Three Newly Developed Bispyridinium
           Anti-Nicotinic Compounds (MB408, MB442, MB444) on the Efficacy of
           Antidotal Treatment of Nerve Agent Poisoning in Mice
    • Authors: Jiri Kassa; Christopher M. Timperley, Mike Bird, Rebecca L. Williams, A. Christopher Green, John E. H. Tattersall
      Abstract: The influence of three newly-developed bispyridinium antinicotinic compounds (the non-oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning. Addition of all the tested non-oximes increased significantly the therapeutic efficacy of atropine in combination with an oxime against tabun poisoning. They also positively influenced the number of surviving mice 6 hr after supralethal poisoning with tabun. However, they were only slightly effective for the treatment of soman poisoning. The benefit of the tested bispyridinium non-oximes was dose-dependent. To conclude, the addition of bispyridinium non-oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T19:00:22.766803-05:
      DOI: 10.1111/bcpt.12935
       
  • Policy Change and the National Essential Medicines List Development
           Process in Brazil between 2000 and 2014: Has the Essential Medicine
           Concept been Abandoned'
    • Authors: Claudia Garcia Serpa Osorio-de-Castro; Thiago Botelho Azeredo, Vera Lúcia Edais Pepe, Luciane Cruz Lopes, Sueli Yamauti, Brian Godman, Lars L. Gustafsson
      Abstract: Brazil has had a National Essential Medicines List (EML) since 1964. From 2000 to 2010, five consecutive evidence-based editions were produced, building on the essential medicines concept. In 2012, the government changed course to establish a new paradigm, introducing adoption of new medicines as the main aim within the recommendation process. The objective of the paper is to report efforts to develop Brazil's national EML, policy changes from 2000 to 2014, discussing results, challenges and perspectives. Brazilian EML history and development process were collected from legislation, minutes, reports and legal ordinances, from 2000 to 2014. The Brazilian EML and the WHO Model lists were compared using the Anatomical Therapeutic Chemical system. Overlap between lists was verified and linear trends were produced. Type of membership, inclusion criteria, procedures, flow and listed medicines varied greatly between the selection committees acting before and after 2012. Paradigm-changing legislation aiming at linking list compliance to public financing in 2012 produced (i) greater importance given to political and administrative stakeholders, (ii) increasing trends in number of medicines over the years, (iii) decrease in use of WHO Model List as a reference, (iv) substitution of an essential medicines list review and update process by an adoption decision output. Other issues remained unchanged. Insufficient efforts for list implementation, such as lack of physician education, presented consequences to the health system. Substantial efforts were made to produce and update the list from 2000 to 2014. However, continuous and intense health litigation disproves process outcome effectiveness.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T19:00:21.085783-05:
      DOI: 10.1111/bcpt.12932
       
  • Advanced Electrocardiogram (ECG) analysis in the Amitriptyline poisoned
           pig treated with Activated Charcoal Hemoperfusion (CAC-HP)
    • Authors: Tejs Jansen; Lotte C.G. Hoegberg, Thomas Eriksen, Christian Haarmark, Kim Dalhoff, Bo Belhage
      Abstract: Coated Activated Charcoal Hemoperfusion (CAC-HP) does not reduce the plasma concentration in amitriptyline (AT)-poisoned pigs. The aim of this non-blinded, randomised, controlled animal trial was to determine if CAC-HP reduces the pathological ECG changes caused by AT poisoning. Fourteen female Danish Land Race pigs (mean weight 27.7 kg, range 20-35 kg (CAC-HP) and 24.4 kg, range 18-30 kg (control group, CG), n=7 in each group were included. After randomisation, the pigs were anaesthetised and intravenously poisoned with AT. The intervention group underwent 4 hr of CAC-HP plus standard care (oral activated charcoal). Intervention was compared to standard care alone. From each pig, a 12-lead ECG and haemodynamic variables were obtained at baseline, at full AT loading dose, before and during CAC-HP. Baseline ECG variables (RR, PR, QRS, QTc, QTp, QTe, TpTe, and TpTe/QT) for lead II, v2 and v5 were not significantly different (F=0.035 to 0.297, p-values 0.421 to 0.919). Differences within groups over time and between groups were tested by ANOVA repeated measures. For all variables, the time-plus-group level of significance revealed a p-value>0.05. Severe cardiovascular dysrhythmias occurred in both groups with 3 in the CAC-HP group versus 1 incident with premature death in the CG. The attenuating effect of CAC-HP to orally instilled activated charcoal alone on AT-induced ECG alterations did not differ significantly. We conclude that the use of modern CAC-HP as an adjunctive treatment modality in AT-poisoned pigs is inadequate.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T18:55:31.023221-05:
      DOI: 10.1111/bcpt.12931
       
  • Forensic Toxicology Perspectives of Methadone-associated Deaths in Tehran,
           Iran, a Seven-year Overview
    • Authors: Maryam Akhgari; Noushin Amini-Shirazi, Fariba Sardari Iravani
      Abstract: Methadone has a long history of pain relief and successful substitute for maintenance treatment in heroin and narcotic addiction. The aim of the study was to assess the trends of methadone-associated deaths in Tehran, Iran, in 2009-2015, from a forensic toxicology point of view. All methadone-associated deaths during this 7-year study period were evaluated according to demographic parameters and forensic toxicology analysis results. Results showed that 1274 cases of methadone-associated deaths were investigated during the study period. The incidence rate of methadone-associated deaths had risen 7.7 times in 2015 in comparison to 2009 (p
      PubDate: 2017-10-27T07:26:15.504526-05:
      DOI: 10.1111/bcpt.12930
       
  • New Insights into SN-38 Glucuronidation: Evidence for the Important Role
           of UDP Glucuronosyltranseferase 1A9
    • Authors: Ling Xiao; Liangliang Zhu, Wenjuan Li, Conghu Li, Yunfeng Cao, Guangbo Ge, Xiaoyu Sun
      Abstract: Glucuronidation of SN-38 serves as an important metabolism pathway in determining the toxic effects of irinotecan. The role of UDP-glucoronosyltransferases (UGT) 1A9 in SN-38 glucuronidation pathway is very confusing. This study re-investigates the pathway through testing effects of bovine serum albumin (BSA) and the selective inhibitor on SN-38 glucuronidation in pooled human liver microsomes (HLM) and recombinant UGT1A1/1A9. For UGT1A1, SN-38 glucuronidation was little affected by BSA. Whether in the presence of BSA or not, the reactions both obey Michaelis-Menten kinetics with closed Vmax/Km values. For UGT1A9 and HLM, BSA can significantly accelerate SN-38 glucuronidation activities and similar effects are fatherly observed on kinetic patterns. In the absence of BSA, reactions by HLM and UGT1A9 both display substrate inhibition kinetics. When BSA is included in the incubations, the reactions exhibit Michaelis-Menten kinetics. To get the true contribution of UGT1A9 in SN-38 glucuronidation, a relative activity factor (RAF) approach was additionally used. It is suggested that UGT1A9 and 1A1 contribute equally to SN-38 glucuronidation in HLM. Furthermore, in the presence of BSA, magnolol, a selective UGT1A9 inhibitor, displays moderate inhibition against HLM. Results together conclude that UGT1A9 serves as an additional important contributor to hepatic SN-38 glucuronidation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-27T07:20:28.834959-05:
      DOI: 10.1111/bcpt.12929
       
  • Antidote Availability in Saudi Arabia Hospitals in the Riyadh Province
    • Authors: Abdullah AlTamimi; Nidal K. Malhis, Najla M. Khojah, Saleh A. Manea, Abdulrahman AlTamimi, Sami Ayed AlShammary
      Abstract: Inadequate antidote stocking is a global problem in hospitals. Insufficient supplies and delays in the administration of antidotes could lead to death and additional potentially negative clinical consequences. Our objective was to determine the availability of antidotes in hospitals listed on the Saudi Ministry of Health website in the Riyadh Province and to evaluate the leading poison in Saudi Arabia. A cross-sectional study was conducted using questionnaires. The questionnaires were distributed to pharmacist directors and emergency room-treating physicians in 17 public hospitals throughout the Riyadh Province. None (0/17) of the pharmacies contained the 24 recommended essential antidotes by the expert consensus guidelines for stocking of antidotes in hospitals. Polyvalent scorpion antivenom, atropine sulphate, calcium gluconate, flumazenil and naloxone hydrochloride were stocked in 94.12% (16/17) of hospitals. 66.67% of patients presented with osmolality, and 55.56% of referral patients with opiates, barbiturates, acetaminophen and salicylate. Our findings have important implications for healthcare institutions and pharmaceutical practices. National practice guidelines are needed to assist pharmacists in selecting appropriate antidotes based on the local pattern of poisoning incidents. Therefore, further study in the Kingdom of Saudi Arabia needs to be completed to fully evaluate the availability of antidotes throughout the country.
      PubDate: 2017-10-25T04:45:26.204056-05:
      DOI: 10.1111/bcpt.12897
       
  • Identification of the Molecular Determinants of the Antibacterial Activity
           of LmutTX, a Lys49 Phospholipase A2 Homologue Isolated from Lachesis muta
           muta Snake Venom (Linnaeus, 1766)
    • Authors: Rafaela Diniz-Sousa; Cleópatra A. S. Caldeira, Anderson M. Kayano, Mauro V. Paloschi, Daniel. C. Pimenta, Rodrigo Simões-Silva, Amália S. Ferreira, Fernando B. Zanchi, Najla B. Matos, Fernando P. Grabner, Leonardo A. Calderon, Juliana P. Zuliani, Andreimar M. Soares
      Abstract: Snake venom phospholipases A2 (PLA2s) are responsible for numerous pathophysiological effects in snakebites; however, their biochemical properties favour antimicrobial actions against different pathogens, thus constituting a true source of potential microbicidal agents. This study describes the isolation of a Lys49 PLA2 homologue from Lachesis muta muta venom using two chromatographic steps: Size Exclusion and Reverse Phase. The protein showed a molecular mass of 13,889 Da and was devoid of phospholipase activity on an artificial substrate. The primary structure made it possible to identify an unpublished protein from L. m. muta venom, named LmutTX, that presented high identity with other Lys49 PLA2s from bothropic venoms. Synthetic peptides designed from LmutTX were evaluated for their cytotoxic and antimicrobial activities. LmutTX was cytotoxic against C2C12 myotubes at concentrations of at least 200 μg/mL, whereas the peptides showed a low cytolytic effect. LmutTX showed antibacterial activity against Gram-positive and Gram-negative bacteria; however, S. aureus ATCC 29213 and MRSA strains were more sensitive to the toxin's action. Synthetic peptides were tested on S. aureus, MRSA and P. aeruginosa ATCC 27853 strains, showing promising results. This study describes for the first time the isolation of a Lys49 PLA2 from Lachesis snake venom and shows that peptides from specific regions of the sequence may constitute new sources of molecules with biotechnological potential.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-25T02:05:38.743694-05:
      DOI: 10.1111/bcpt.12921
       
  • The New Acetylcholinesterase Inhibitors PC-37 and PC-48
           (7-MEOTA-Donepezil-like Compounds): Characterization of Their Metabolites
           in Human Liver Microsomes; Pharmacokinetics and In Vivo Formation of the
           Major Metabolites in Rats
    • Authors: Jana Zdarova Karasova; Martin Mzik, Milos Hroch, Jan Korabecny, Eugenie Nepovimova, Viktor Vorisek, Vladimir Palicka, Kamil Kuca
      Abstract: The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer disease patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principle metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions.Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavaibility expressed as AUCtotal was 28179 ± 4691 min.ng/mL for PC-37 and 23374 ± 4045 min.ng/mL for PC-48.Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile).All these characteristics are crucial for new candidates intended for Alzheimer's disease treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites but this needs to be confirmed by further studies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-25T02:05:23.489422-05:
      DOI: 10.1111/bcpt.12922
       
  • Higher Levels of CYSTATIN C in HIV/AIDS Patients with Metabolic Syndrome
    • Authors: Gordana Dragović; Danica Srdić, Khawla Al Musalhi, Ivan Soldatović, Jovana Kušić, Djordje Jevtović, Devaki Nair
      Abstract: Data about Cystatin-C levels in HIV-infected patients with metabolic syndrome (MetS) are still limited. Therefore, the aim of this study was to evaluate the possible correlations of serum levels of Cystatin-C in HIV/AIDS patients treated with combined antiretroviral therapy (cART) with or without MetS. This cross-sectional study included 89 HIV/AIDS Caucasian patients receiving cART at the HIV/AIDS Centre Belgrade, Serbia, divided into two groups according to the presence of MetS. Cystatin-C and other biochemical parameters were measured using Cytokine-Array-I, Metabolic-Array-I and Metabolic-Array-II, at the Department of Clinical Biochemistry, Royal Free Hospital and University College London, United Kingdom. A linear regression model was performed in order to evaluate which clinical and laboratory variables had an independent effect on Cystatin-C levels in HIV/AIDS patients. There were 33 (37%) patients with MetS and 56 (63%) without MetS. Patients with and without MetS were homogenous for age, duration of cART, number of cART combinations and CD4+T-cell count. Statistically increased Cystatin-C levels were observed in HIV/AIDS patients with MetS (p = 0.017), when compared to patients without MetS. Data showed a positive correlation of Cystatin-C and C-reactive protein (r = 0.349, p = 0.001). Using linear regression modelling, significant correlations were obtained between Cystatin-C and MetS in univariate analysis (p < 0.001). Cystatin-C levels were significantly higher in HIV/AIDS patients with MetS versus without MetS. Early assessment of metabolic syndrome using Cystatin-C as a marker, may ultimately help increase the lifespan of HIV/AIDS patients, since these patients appear to be at high risk of cardiovascular diseases.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-11T10:55:24.992291-05:
      DOI: 10.1111/bcpt.12919
       
  • Activation of Group II Metabotropic Glutamate Receptors Increases
           Proliferation but does not Influence Neuronal Differentiation of a Human
           Neural Stem Cell Line
    • Authors: Anne Dindler; Morten Blaabjerg, Morad Kamand, Helle Bogetofte, Morten Meyer
      Abstract: The multiple functions of glutamate include regulation of neural development and stem cells. While the importance of the ionotropic glutamate receptors is well established, less is known about the role of metabotropic glutamate receptors (mGluRs).In this study, we examined the effects of pharmacological activation and inhibition of mGluR2/3 on proliferation, differentiation and viability of a human neural stem cell line.Immunofluorescence staining revealed the presence of mGluR2/3 receptors on both proliferating and differentiating stem cells, including cells differentiated into β-tubulin III-positive immature neurons and glial fibrillary acidic protein-positive astrocytes. Stimulation of mGluR2/3 receptors during cell propagation using the agonist (2S,2'R,3'R)-2-(2’,3’-dicarboxycyclopropyl) glycine (DCG-IV) increased total cell numbers significantly (60% compared to untreated controls). This effect could be inhibited by the specific antagonist (2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). The antagonist alone had no effect. No significant decrease in cell death was found following mGluR2/3 stimulation, suggesting that the observed elevation in cell number was not related to cell viability. Subsequent differentiation of the cells resulted in a slight decrease in beta-tubulin III-positive neurons (5.2% to 3.2% of total cells) for DCG-IV pre-treated cultures. Treatment with DCG-IV and LY342495 during cell differentiation alone had no such effect. Western blot analysis revealed that the active, dimeric form of mGluR2/3 was mainly present on the proliferating cells, which may explain our findings.The present study emphasises the importance of glutamate and mGluRs on regulation of human neural stem cells and suggests a significant role of mGluR2/3 during cell proliferation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-11T10:55:18.77207-05:0
      DOI: 10.1111/bcpt.12920
       
  • Next-Generation Magnetic Nanocomposites: Cytotoxic and Genotoxic Effects
           
    • Authors: Katharina Netzer; Galateja Jordakieva, Angelika M. Girard, Alexandra C. Budinsky, Alexander Pilger, Lukas Richter, Nadezhda Kataeva, Joerg Schotter, Jasminka Godnic-Cvar, Peter Ertl
      Abstract: Metal nanoparticles (NPs) have unique physicochemical properties and a widespread application scope depending on their composition and surface characteristics. Potential biomedical applications and the growing diversity of novel nanocomposites highlight the need for toxicological hazard assessment of next-generation magnetic nanomaterials. Our study aimed to evaluate the cytotoxic and genotoxic properties of coated and uncoated ferric cobalt boron (FeCoB) NPs (5-15 nm particle size) in cultured human dermal fibroblasts (NHDFs). Cell proliferation was assessed via ATP bioluminescence kit, DNA breakage and chromosomal damage were measured by alkaline comet assay and micronucleus test.Polyacryl acid-coated FeCoB NPs (PAA-FeCoB NPs) and uncoated FeCoB NPs inhibited cell proliferation at 10 μg ml-1. DNA strand breaks were significantly increased by PAA-coated FeCoB NPs, uncoated FeCoB NPs and l-cysteine-coated FeCoB NPs (Cys-FeCoB NPs), although high concentrations (10 μg ml-1) of coated NPs (Cys- and PAA-FeCoB NPs) showed significantly more DNA breakage when compared to uncoated ones. Uncoated FeCoB NPs and coated NPs (PAA-FeCoB NPs) also induced the formation of micronuclei. Additionally, PAA coated NPs and uncoated FeCoB NPs showed a negative correlation between cell proliferation and DNA strand breaks, suggesting a common pathomechanism, possibly by oxidation-induced DNA damage.We conclude that uncoated FeCoB NPs are cytotoxic and genotoxic at in vitro conditions. Surface coating of FeCoB NPs with Cys and PAA does not prevent but rather aggravates DNA damage. Further safety assessment and a well-considered choice of surface coating are needed prior to application of FeCoB nanocomposites in biomedicine.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-09T01:45:25.95734-05:0
      DOI: 10.1111/bcpt.12918
       
  • Valproate Plays a Protective Role against Migraine by Inhibiting Protein
           Kinase C Signalling in Nitroglycerin-treated Mice
    • Authors: Lian Yi; Qiong Wu, Nan Chen, Ge Song, Chao Wang, Qiaoge Zou, Zhongling Zhang
      Abstract: Migraine is a common disease with a high morbidity. Valproate (VP) is used as an anti-epilepsy drug in clinic. This study aimed to investigate the role of VP in nitroglycerin (NTG)-induced migraine using a mouse model. NTG was employed by intraperitoneal injection to induce a migraine model in mice. The NTG administration caused mouse head discomforts, decreased tolerance to cold or hot stimulation and increased content of nitric oxide (NO), calcitonin gene related peptide (CGRP) and Neuropeptide Y (NPY) in serum, which were ameliorated by intraperitoneal injection of VP. The levels of two inflammatory factors, interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), in dura mater were increased by NTG treatment, while the increase was attenuated by application of VP. In addition, the phosphorylation levels of protein kinase C (PKC) α, γ, δ and ε were increased by NTG and decreased by VP. However, their total expression at the transcriptional and translational levels did not change significantly. Two substrates of PKC, cAMP-response element binding protein (CREB) 1 and signal transducer and activator of transcription (STAT) 1 were also phosphorylated by NTG application, and the phosphorylation level was attenuated by VP, consistent with the change of PKC informs. Together, we demonstrated that VP prevented damage due to migraine by inhibiting PKC signalling in NTG-injected mice, which may provide a basis for investigating the clinical treatment of migraine.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-08T21:00:37.852718-05:
      DOI: 10.1111/bcpt.12915
       
  • Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and
           Clopidogrel Pharmacokinetics and Antiplatelet Effects
    • Authors: Mikko Neuvonen; E Katriina Tarkiainen, Aleksi Tornio, Päivi Hirvensalo, Tuija Tapaninen, Maria Paile-Hyvärinen, Matti K. Itkonen, Mikko T. Holmberg, Vesa Kärjä, Ville T. Männistö, Pertti J. Neuvonen, Jussi Pihlajamäki, Janne T. Backman, Mikko Niemi
      Abstract: Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n=106) and pharmacodynamics (n=46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (P=4.0 x 10-13) and 31% (P=2.5 x 10-8) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-08T21:00:31.207947-05:
      DOI: 10.1111/bcpt.12916
       
  • Prediction of Drug-Drug Interaction between Tacrolimus and Principal
           Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using
           Physiologically-based Pharmacokinetic Modelling
    • Authors: Hongyan Zhang; Fengjiao Bu, Lei Li, Zheng Jiao, Guo Ma, Weimin Cai, Xiaomei Zhuang, Hai-Shu Lin, Jae-Gook Shin, Xiaoqiang Xiang
      Abstract: Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug-drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 were investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus wereestablished. Finally, tacrolimus pharmacokinetic were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-25T06:30:18.8254-05:00
      DOI: 10.1111/bcpt.12914
       
  • Evaluation of Prolonged Exposure to Varenicline in Adult Rats:
           Hematological, Biochemical and Anatomopathological Studies
    • Authors: Julia Zaccarelli-Magalhães; Natalia Moreira, Thaisa Meira Sandini, Gabriel Ramos Abreu, Angélica Maria Sánchez-Sarmiento, Esther Lopes Ricci, André Rinaldi Fukushima, Helenice Souza Spinosa
      Abstract: Varenicline is a synthetic chemical substance produced from the alkaloid cytisine, used for smoking treatment, which acts as a partial agonist for α4β2 and α3β4 nicotinic cholinergic receptors and as a total agonist for α7 receptor. While there are studies regarding varenicline's non-smoking-related effects, as in treatment for drug dependence, there are no studies in the literature evaluating the long-term toxicity of varenicline through a physiological approach. Thus, the aim of this study was to evaluate possible toxicity through hematological, biochemical and anatomopathological parameters of prolonged exposure (30 days) to varenicline in rats. Three doses of varenicline were used: 0.03 (therapeutic dose for humans), 0.1 and 0.3 mg/kg orally (gavage). Body weight, water and food intake were measured weekly during treatment. On the 30th treatment day, blood and various organs were collected for hematological, biochemical and anatomopathological evaluation. The results show a decrease in some biochemical parameters in animals from the 0.1 and 0.3 mg/kg group, although the values are within the normal range of the species. There were no changes in the other evaluations performed. Together, these data indicate that prolonged exposure of rats to different doses of varenicline was not able to alter hematological, biochemical and anatomopathological parameters.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-25T06:25:18.561294-05:
      DOI: 10.1111/bcpt.12913
       
  • Rho Kinase Inhibitor, Fasudil, Attenuates Contrast-induced Acute Kidney
           Injury
    • Authors: Yiming Wang; Hao Zhang, Zhijian Yang, Dengshun Miao, Dingguo Zhang
      Abstract: In this study, we tested the hypothesis that fasudil, a Rho kinase inhibitor, would protect against contrast-induced acute kidney injury (CI-AKI) in a mouse model and attempted to elucidate the mechanism involved. Mice subjected to unilateral ligation of the left anterior renal pedicle were divided into four groups: (1) control group, (2) CI-AKI induced by contrast media (CM group), (3) CI-AKI plus low-dose fasudil (LD group) and (4) CI-AKI plus high-dose fasudil (HD group). Animals from groups 2–4 received iodixanol (4.0 g iodine/kg), and the control group received saline. At 12, 2 hr before iodixanol injection and 4 hr after iodixanol administration, the animals in groups 3–4 received 3 or 10 mg/kg fasudil, respectively. Renal blood flow, renal function parameters, kidney histology and the expression of proteins that regulates apoptosis and inflammation were determined 24 hr later. Fasudil treatment notably ameliorated contrast medium-induced medullary damage, restored renal function, suppressed renal tubular apoptosis, ameliorated redox imbalance and DNA damage. Fasudil had a nephroprotective effect that was partially attributed to its anti-inflammatory, anti-apoptotic and antioxidant effects of inhibiting the Rho/ROCK pathway.
      PubDate: 2017-09-19T19:45:45.426138-05:
      DOI: 10.1111/bcpt.12895
       
  • Relationship between Optimum Mini-doses of Glucagon and Insulin Levels
           when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes - A
           Simulation Study
    • Authors: Ajenthen Ranjan; Sabrina L. Wendt, Signe Schmidt, Sten Madsbad, Jens J. Holst, Henrik Madsen, Carsten B. Knudsen, John B Jørgensen, Kirsten Nørgaard
      Abstract: Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualised subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG≥3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses>500 μg were needed when se/ba-insulin>2.5, IOB>2.0U or IOB/TDD>6%. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-18T09:50:27.347356-05:
      DOI: 10.1111/bcpt.12907
       
  • Correlation of Recommendations of Treatment Guidelines and Frequently
           Prescribed Antibiotics: Evaluation of Their Pharmaceutical Pack Size
    • Authors: Shoma Mukherjee; Nilanjan Saha
      Abstract: There are various factors that contribute to development of antimicrobial resistance. Overuse, inappropriate prescribing and extensive agricultural use of antibiotics are some of the factors which have been identified. Antibiotics are almost always universally packaged by manufacturers in packs that are heavily driven by cost of economies and convenience rather than by any scientific basis or duration of therapy. So, in the present study, the correlation of the treatment guidelines with the choice of antibiotics and whether packing size contributes to left-over dosing units when used according to guideline recommendations were assessed.The Standard Treatment Guidelines by DSPRUD 2015, Clinical Guidelines by MSF (Oct, 2016 Updated) and the Infectious Disease Society of America Guidelines 2007-2014 recommendations for various infections were compared and evaluated against the commonly prescribed antibiotics identified by prescription research. Number of branded generic products and their most commonly available pack size was also defined. For many antibiotics, multiple packs are required to complete a recommended course of therapy and these are likely to produce left-over medicines in case of 100% compliance or short-falls when patients buy inadequate supply to complete the recommended regime of antibiotics. A simplified guideline on antibiotic use is required based on national data of antimicrobial resistance in different pathogens in the country. Pharmaceutical packing of antibiotics should be reviewed jointly by health policy makers and infectious disease physicians with representatives of the pharmaceutical industry to devise steps to reduce left-over antibiotic medications.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-10T06:35:25.465465-05:
      DOI: 10.1111/bcpt.12905
       
  • Salidroside, a Chemopreventive Glycoside, Diminishes Cytotoxic Effect of
           Cisplatin in vitro
    • Authors: Martina Zduriencikova; Dana Cholujova, Jozef Duraj, Maria Mastihubova, Vladimir Mastihuba, Elena Karnisova Potocka, Eliska Galova, Andrea Sevcovicova, Martina Klapakova, Eva Horvathova
      Abstract: Natural products represent the source or the inspiration for the majority of the active ingredients of medicines because of their structural diversity and a wide range of biological effects. Our aims in this study were (i) to synthesize enzymatically salidroside (SAL), the most effective phenylethanoid glycoside in Rhodiola species; (ii) to examine its antioxidant capacity using cell-free assays (reducing power, DPPH radicals scavenging and Fe2+-chelating assays); (iii) to assess its DNA-protective potential on plasmid DNA (DNA topology assay) and in HepG2 cells (comet assay) damaged by Fe2+ ions and hydrogen peroxide, respectively; and (iv) to investigate the effects of SAL, cisplatin (CDDP) and combined treatments of SAL + CDDP on cell viability (MTT test), level of DNA damage (comet assay), proliferation, cell cycle (flow cytometry) and the expression of signalling molecules associated with cell growth and apoptotic pathways (western immunoblotting). We found out that SAL manifested low antioxidant and DNA-protective capacity in all assays used. In both parental A2780 and CDDP-resistant A2780/CP human ovarian carcinoma cells SAL itself exerted in fact no impact on the viability, while in combination with CDDP it showed antagonistic effect supporting the chemopreventive activity on the CDDP-induced cell damage. These results were confirmed by the partial reversal of the cell cycle alterations and the DNA damage level, as well as with partial restoration of cell survival/signalling pathways, when the expression of these molecules partially returned to their proper levels.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-10T06:35:23.944606-05:
      DOI: 10.1111/bcpt.12906
       
  • Opportunities for Students to Prescribe: An Evaluation of 185
           
    • Authors: Tim Schutte; Katinka Prince, Milan Richir, Erik Donker, Leonie van Gastel, Ferdynand Bastiaans, Henk de Vries, Jelle Tichelaar, Michiel van Agtmael
      Abstract: Involving students in CVRM could offer patients a structured CVRM programme and students a valuable learning opportunity. We describe and evaluate a student-run CVRM programme that was set up to offer primary prevention to patients with known risk factors in a general practitioner's practice. During a consultation, two undergraduate medical students assessed the patients’ actual risk and formulated a CVRM plan, which they discussed with the patient after approval by a GP. After the consultations, patients were asked to complete evaluation/feedback questionnaires. From December 2014 to December 2015, 185 consultations were carried out by 46 students. Feedback questionnaires of 153 consultations were returned, in which patient satisfaction was 8.43 (1-10, min-max). The cardiovascular risk of 95 patients was determined, and in>50% patients it was ‘high’. Participating students and GPs were enthusiastic about the (pharmacotherapy) learning opportunities and improved CVRM care while contributing to real patient care in this CVRM programme.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T00:30:23.220518-05:
      DOI: 10.1111/bcpt.12904
       
  • Overdoses with Aripiprazole: Signs, Symptoms and Outcomes in 239 Exposures
           Reported to the Danish Poison Information Center
    • Authors: Amalie P. Christensen; Soeren Boegevig, Mikkel B. Christensen, Kasper M. Petersen, Kim P. Dalhoff, Tonny S. Petersen
      Abstract: The aim of this study was to characterize the clinical signs and symptoms of exposures to aripiprazole overdoses. We retrospectively identified all aripiprazole exposures reported to the Danish Poisons Information Center (DPIC) from June 2007 to May 2015. Information concerning demographics, ingested dose and symptoms were extracted from the DPIC database and medical records. Information on death and admission to hospital was obtained from Danish national registers. We analysed 239 cases, 86 concerning single-drug exposures to aripiprazole, and 153 cases where aripiprazole had been taken with at least one other substance (mixed-drug). The median ingested aripiprazole dose was 105 mg (IQR; 50-1680 mg) in the single-drug exposure group and 120 mg (IQR; 60-225 mg) in the mixed-drug exposure group. The most commonly reported symptom was light sedation, reported in 63% of single-drug group and 50% in the mixed-drug exposure group. There were no malignant arrhythmias or ECG abnormalities following single-drug exposures. No deaths were recorded in relation to the intake We found a long-term mortality rate of 13 deaths per 1000 person years (95% CI: 7; 23 per 1000 person years), which is significantly higher than in an age and gender-matched population. In conclusion, we found that aripiprazole overdoses had few and mild symptoms predominantly related to the sedative properties. We detected a benign cardiovascular safety profile and no new safety concerns. Our findings may support an increased threshold of 300 mg for hospital admission following a single-drug exposure with aripiprazole and symptoms not worse than light sedation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-07T07:30:21.718976-05:
      DOI: 10.1111/bcpt.12902
       
  • Formyl Peptide Receptors in Mice and Men: Similarities and Differences in
           Recognition of Conventional Ligands and Modulating Lipopeptides
    • Authors: Malene Winther; Claes Dahlgren, Huamei Forsman
      Abstract: The pattern recognition formyl peptide receptors (FPRs) belong to the class of G protein-coupled receptors (GPCRs), the largest group of cell-surface receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, receptor reactivation and receptor cross-talk. When it comes to allosteric modulators, “tailor-made” lipopeptides (pepducins and lipopeptoids) represent a novel concept of GPCR/FPR regulation. This MiniReview is focused on the basis for recognition of conventional ligands and immunomodulating lipopeptids, novel allosteric modulators for the FPRs, receptors that are highly expressed by both human and mouse neutrophils. The FPRs play key roles in host defence against microbial infections, tissue homeostasis and the initiation as well as resolution of inflammation but there are both similarities and differences in ligand recognition between mice and men. Thus, identification and functional characterization of activating and inhibiting ligands should provide insights into future design of FPR-based animal models of human diseases and development of therapeutics for treating inflammatory diseases.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-07T07:25:48.533215-05:
      DOI: 10.1111/bcpt.12903
       
  • Important Aspects of Pharmacist-led Medication Reviews in an Acute Medical
           Ward
    • Authors: Cille Bülow; Kirstine Ullitz Færch, Helle Armandi, Birgitte Nybo Jensen, Jesper Sonne, Hanne Rolighed Christensen, Mikkel Christensen
      Abstract: In some hospitals, clinical pharmacists review the medication to find drug-related problems (DRPs) in acutely admitted patients. We aimed to identify the nature of identified DRPs and investigate factors of potential importance for the clinical implementation of pharmacist suggestions. In 100 randomly selected medication review notes, we retrospectively evaluated the clinical implementation and classified 1) timing and communication of the review; 2) DRPs and related suggestions for the physician; and 3) DRPs’ potential clinical relevance to patients as ‘beneficial’, ‘somewhat beneficial’, ‘no relevance’ or ‘other relevance’.Of 327 DRPs (0-13 DRPs/patient), 48% were implemented. The clinical implementation was higher if the medication review note was made prior to (instead of after) the physician's admission, and even higher if the suggestions were communicated verbally (instead of only in writing) to the physicians (44 versus 79%, P
      PubDate: 2017-09-04T21:26:26.592652-05:
      DOI: 10.1111/bcpt.12901
       
  • Population Pharmacokinetic/Pharmacodynamic Modelling of Auditory-Evoked
           Event-Related Potentials with Lorazepam
    • Authors: Aurélie Lombard; Claire Brittain, Graham Wishart, Stephen Lowe, Andrew McCarthy, William Landschulz, Georg Dorffner, Peter Anderer, Eunice Yuen
      Abstract: Event-Related Potentials (ERPs) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. ERPs are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave.In this study, auditory-evoked ERPs were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2mg doses of lorazepam. Population pharmacokinetics (PK)/ pharmacodynamics (PD) models were developed using non-linear mixed effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms.The PK/PD models showed that doses of 0.3 mg of lorazepam achieved approximately half of the maximum effect on the latency of the P3 waveform For P3 amplitude, half the maximum effect was achieved with a dose of 1.2 mg of lorazepam. The PK/PD models also predicted an efficacious dose range of lorazepam which was close to the recommended therapeutic range. The use of longitudinal P3 latency data allowed better predictions of the lorazepam efficacious dose range than P3 amplitude or aggregate exposure-response data, suggesting that latency could be a more sensitive parameter for drugs with similar mechanisms of action as lorazepam, and that time course rather than single time point ERP data should be collected.Overall, the results suggest that P3 ERP waveforms could be used as potential non-specific biomarkers for functional target engagement for drugs with brain activity, and PK/PD models can aid trial design and choice of doses for development of new drugs with ERP activity.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-04T13:40:49.647303-05:
      DOI: 10.1111/bcpt.12900
       
  • Neurological and Neurophysiological Findings in Workers with Chronic
           2,3,7,8-TCDD Intoxication 50 Years after Exposure
    • Authors: Daniela Pelclova; Pavel Urban, Zdenka Fenclova, Stepanka Vlckova, Petr Ridzon, Karel Kupka, Zuzana Meckova, Ondrej Bezdicek, Tomas Navratil, Jan Rosmus, Sergey Zakharov
      Abstract: The last eight survivors of 80 workers accidentally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during production of herbicides based on trichlorophenoxyacetic acid in 1965–1967 in a chemical factory were followed. All were men, mean age 72.4 ± 1.3 years. Their current median TCDD blood level was 112 (46–390) pg/g lipids.Neurological examination revealed central nervous system impairment in all subjects, and signs of polyneuropathy in 87.5%, which was confirmed by a nerve conduction study (NCS) in 75%. A Lanthony test demonstrated acquired dyschromatopsia in 87.5% of the patients, with deterioration of mean colour confusion index (CCI) from 1.52 ± 0.39 in 2010 to 1.73 ± 0.41 in 2016. Single-photon emission computer tomography (SPECT) of the brain showed focal reduction of perfusion in various brain locations in all patients and worsening in six patients. VEP was abnormal in 62.6% of subjects. Most patients complained of psychological problems. The neuropsychological test battery showed most positive impairments in the Trail Making Test evaluating processing speed (average level in the range of mild neurocognitive impairment), which correlated with mean CCI (p< 0.05).Conclusion50 years after exposure, blood levels of TCDD are still 10-fold higher than the general population. NCS, VEP, Lanthony test and SPECT findings deteriorated from examination of these patients in 2004 and in 2010. The total of abnormal tests per patient in 2016 is very high. Minor differences among patients and their reduced count may explain why the number of impairments in 2016 does not correlate with TCDD blood level.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-01T09:10:49.445283-05:
      DOI: 10.1111/bcpt.12899
       
  • Patient and Cell Type-Specific Heterogeneity of Metformin Response
    • Authors: Michael K. Asiedu; Matthew Barron, Marie Christine Aubry, Dennis A. Wigle
      Abstract: Most FDA approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient-specific and cell-context-specific heterogeneity of metformin response, using fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages. We performed cell survival analysis, transcriptome and whole exome sequencing analysis on both patient-derived cell lines and cancer cell lines to assess differential metformin response and identify response genes. We found differences in response to metformin treatment across a variety of cell lines and cellular contexts, suggesting heterogeneity that may be patient and cell type-specific. Gene expression profiling and analysis of metformin-sensitive and -resistant cells identified differentially expressed genes that may be able to stratify patients into metformin responders and non-responders. Sequencing analysis found genomic alterations that correlated with metformin response. These results suggest that identification of genomic biomarkers for patients who may respond to metformin treatment can provide an opportunity for individualizing metformin chemoprevention in the clinical setting.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-01T09:10:47.904427-05:
      DOI: 10.1111/bcpt.12898
       
  • Bisphenol A Exposure Impairs Epididymal Development during the
           Peripubertal Period of Rats: Inflammatory Profile and Tissue Changes
    • Authors: Fernanda Mithie Ogo; Glaucia Eloisa Munhoz de Lion Siervo, Larissa Staurengo-Ferrari, Leonardo de Oliveira Mendes, Nicla Renata Luchetta, Henrique Rodrigues Vieira, Victor Fattori, Waldiceu Aparecido Verri, Wellerson Rodrigo Scarano, Glaura Scantamburlo Alves Fernandes
      Abstract: Bisphenol A (BPA) is a synthetic non-steroidal oestrogen used in the production of plastics. BPA can cause alterations in the endocrine system of humans and animals at varied stages of development. During puberty, altered morphological, sexual behaviour and completion of the epididymal development occurs. Therefore, this study aimed to evaluate the effects of BPA on epididymal development during the peripubertal period of rats. Male Wistar rats were treated with BPA via gavage at doses of 20 μg/kg or 200 μg/kg/day (postnatal day (PND) 36–66). The control group received the vehicles under the same conditions. Feed and water were provided ad libitum. On PND 67, the epididymis was removed, weighed, divided into caput/corpus and cauda sections. It was then used for: sperm count determination; histopathological and stereological evaluation; inflammatory cell enzymatic profiling (myeloperoxidase activity-MPO; N-acetylglucosaminidase-NAG); immunohistochemistry for IL-6; and evaluation of superoxide anion levels and malondialdehyde-MDA. Exposure to BPA at 200 μg/kg caused a significant increase of MPO activity and immunoreactivity to IL-6 (Interleukin 6) as well as remodelling of tissue components in the caput/corpus and cauda regions of the epididymis. Under these experimental conditions, it is concluded that BPA alters postnatal epididymal development.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T10:30:42.689507-05:
      DOI: 10.1111/bcpt.12894
       
  • Systemic TLR2 Antibody Application in Renal Ischaemia and Reperfusion
           Injury Decreases AKT Phosphorylation and Increases Apoptosis in the Mouse
           Kidney
    • Authors: Anja Urbschat; Patrick Baer, Kai Zacharowski, Vera Sprunck, Bertram Scheller, Florian Raimann, Thorsten Jürgen Maier, Axel Hegele, Rainer Hofmann, Jan Mersmann
      Abstract: Acute kidney injury remains an important cause of renal dysfunction. In this context, toll-like receptors have been demonstrated to play a critical role in the induction of innate and inflammatory responses. Among these, toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells of the kidney and is also known to mediate ischaemia reperfusion (IR) injury. Adult male C57BL/6JRj mice were randomized into 7 groups (n=8): A non-operative control group (CTRL) and 6 interventional groups in which mice were subjected to a 30-min. bilateral renal ischaemia. Immediately before reperfusion, mice were treated either with saline or TLR2 antibody (clone T2.5) and harvested after ischaemia and reperfusion for 3 hr, 24 hr and 48 hr. Analysed kidney homogenates of TLR2 antibody-treated mice displayed significantly decreased levels of TLR2 protein after 3 hr of IR compared to saline-treated mice. Accordingly, the degree of AKT phosphorylation was significantly decreased after 3 hr of IR compared to saline-treated animals. TUNEL staining revealed significantly higher apoptosis rates in TLR2 antibody-treated animals compared to saline-treated mice after 3 hr and 24 hr of IR. Further, a positive correlation between TLR2 protein expression and phosphorylation of AKT as well as a negative correlation with the number of TUNEL positive cells could be observed. Inhibition of TLR2 and its signalling pathway by a single application of TLR2 antibody results in reduced phosphorylation of AKT and consecutively increased apoptosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T09:55:21.610706-05:
      DOI: 10.1111/bcpt.12896
       
  • LC-MS-sMRM Method Development and Validation of Different Classes of Pain
           Panel Drugs and Analysis of Clinical Urine Samples
    • Authors: M. Athar Masood; Timothy D. Veenstra
      Abstract: Urine Drug Testing (UDT) is an important analytical/bio-analytical technique that has inevitably become an integral and vital part of a testing program for diagnostic purposes. This manuscript presents a tailor-made LC-MS/MS quantitative assay method development and validation for a custom group of 33 pain panel drugs and their metabolites belonging to different classes (opiates, opioids, benzodiazepines, illicit, amphetamines, etc.) that are prescribed in pain management and depressant therapies. The LC-MS/MS method incorporates two experiments to enhance the sensitivity of the assay and has a run time of about 7 min. with no prior purification of the samples required and a flow rate of 0.7 mL/min. The method also includes the second stage metabolites for some drugs that belong to different classes but have first stage similar metabolic pathways that will enable to correctly identify the right drug or to flag the drug that might be due to specimen tampering. Some real case examples and difficulties in peak picking were provided with some of the analytes in subject samples. Finally, the method was deliberated with some randomly selected de-identified clinical subject samples, and the data evaluated from “direct dilute and shoot analysis” and after “glucuronide hydrolysis” were compared. This method is now used to run routinely more than 100 clinical subjects samples on a daily basis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-26T04:45:25.445044-05:
      DOI: 10.1111/bcpt.12877
       
  • 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: 2017-08-21T09:55:19.108812-05:
      DOI: 10.1111/bcpt.12876
       
  • The Pharmacogenetics of Metformin in Women with PCOS: a Randomized Trial
    • Authors: Andreas J. T.  Pedersen; Tore Bjerregaard Stage, Dorte Glintborg, Marianne Andersen, Mette Marie Hougaard Christensen
      Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 mg desogestrel + 30 μg ethinylestradiol). In the entire study population, treatment was associated with reduced weight (median weight change -2.4 kg, 25th – 75th percentile -5.2-0.3 kg, p
      PubDate: 2017-08-21T01:30:18.228147-05:
      DOI: 10.1111/bcpt.12874
       
  • Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and
           Hydroxymethylation
    • Authors: Louise K. Sjöholm; Yusuf Ransome, Tomas J. Ekström, Oskar Karlsson
      Abstract: The number of epigenetic studies on brain functions and diseases are dramatically increasing but little is known about the impact of post-mortem intervals and post-sampling effects on DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we examined post-mortem induced changes in global brain 5mC and 5hmC levels at post-mortem intervals up to 540 min., and studied effects of tissue heat stabilization, by using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post-mortem interval reaching a significantly lower level in cerebellum tissue at the post-mortem interval 540 min. (2.9 ±0.7%; mean±SEM) compared to control (3.7 ±0.6%). The global 5hmC levels increased with post-mortem interval reaching a significantly higher level at 540 min. (0.29 ±0.06%) compared to control (0.19 ±0.03%). This suggests that the post-mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post-mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post-mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post-mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-20T04:20:20.668787-05:
      DOI: 10.1111/bcpt.12875
       
  • Assessment of Appropriateness of an Initial Dosing Regimen of Vancomycin
           and Development of a New Dosing Nomogram
    • Authors: Seonghae Yoon; Kyoung Ryun Park, SeungHwan Lee, Sang-Hoon Song, Wan Beom Park, In-Jin Jang, Kyung-Sang Yu
      Abstract: Vancomycin is a glycopeptide antibiotic used to treat Gram-positive infections including methicillin-resistant Staphylococcus aureus (MRSA). The objectives of this study were to evaluate the appropriateness of the initial dosing regimen of vancomycin, identify factors to be considered in regimen selection and develop a new dosing nomogram. Therapeutic drug monitoring (TDM) data of vancomycin obtained from Seoul National University Hospital from 2011 to 2013 were included in this analysis. The vancomycin trough concentrations at steady state were estimated using Abbott's PKS software program and then categorized into three levels: subtherapeutic, therapeutic and toxic. The newly developed nomograms were evaluated by analysing the percentage of patients with target vancomycin trough concentration using the data of 2,570 patients of the first TDM cases. Therapeutic level was achieved only in approximately one-fifth of the cases while 56.0% and 23.8% of the TDMs were considered subtherapeutic and toxic, respectively. As body weight and creatinine clearance (CrCL) increased, the proportion of patients with a sub-therapeutic level increased. Using the newly developed nomogram increased the proportion of patients who achieved therapeutic levels from 23.1% to 45.0% or 13.8% to 36.2% (target, 10–15 and 15–20 mg/L, respectively). These results suggest that the vancomycin concentrations fail to reach the therapeutic level or exceed the safe upper margin of the therapeutic level depending on age, body weight and CrCL. Considering these factors, the new nomograms provide a strategy to achieve target concentrations of vancomycin more rapidly than existing regimens.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-20T04:15:37.453212-05:
      DOI: 10.1111/bcpt.12873
       
  • Protective Effect of Atazanavir Sulfate against Pulmonary Fibrosis In Vivo
           and In Vitro
    • Authors: Shina Song; Yunxia Ji, Guanghua Zhang, Xue Zhang, Bin Li, Defang Li, Wanglin Jiang
      Abstract: Atazanavir sulfate, an antiretroviral protease inhibitor, has been used to treat HIV/AIDS, but its ability to serve as an anti-pulmonary fibrosis (PF) agent remains unknown. In this study, the effects of atazanavir sulfate on various aspects of PF were examined and CoCl2 was used to induce the hypoxia-mimicking condition in vitro, including epithelial-mesenchymal transition (EMT) in A549 cells, endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells (HPMECs), proliferation in human lung fibroblasts (HLF-1) and potential protective effects in human type I alveolar epithelial cells (AT I). Additionally, the effects of atazanavir sulfate were examined using a bleomycin (BLM)-induced pulmonary fibrosis model. Following atazanavir sulfate treatment, in A549 cells and HPMECs, the expression of vimentin, HMGB1, toll-like receptor 4 (TLR-4) and p-NF-κB decreased, while the expression of E-cadherin and VE-cadherin increased. In AT I cells, the expression of aquaporin 5 and RAGE were increased following atazanavir treatment. Proliferation of HLF-1 was reduced following atazanavir treatment, meanwhile the expression of hypoxia-inducible factor-1α (HIF-1α), prolylhydroxylase domain protein 2 (PHD-2), HMGB1, TLR-9, p-NF-κB, collagen I and collagen III were decreased. In the BLM-induced pulmonary fibrosis rat model, atazanavir sulfate ameliorated PF by reducing pathological score, collagen deposition and the expression of α-SMA, HIF-1α, PHD-2, HMGB1, TLR-4, TLR-9 and p-NF-κB. In summary, our study supports the proposal that atazanavir sulfate may have a therapeutic potential in reducing the progression of pulmonary fibrosis by suppressing HMGB1/TLR signalling.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-16T23:35:25.650746-05:
      DOI: 10.1111/bcpt.12871
       
 
 
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