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  Subjects -> ENVIRONMENTAL STUDIES (Total: 766 journals)
    - ENVIRONMENTAL STUDIES (695 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (39 journals)
    - WASTE MANAGEMENT (10 journals)

ENVIRONMENTAL STUDIES (695 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: 43)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 21)
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 Journal of Microbiology     Open Access   (Followers: 17)
American Naturalist     Full-text available via subscription   (Followers: 71)
Annals of GIS     Hybrid Journal   (Followers: 22)
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: 61)
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: 28)
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: 18)
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: 7)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 11)
Archives of Environmental Protection     Open Access   (Followers: 5)
Archives of Toxicology     Hybrid Journal   (Followers: 16)
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: 65)
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: 3)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 11)
Basic and Applied Ecology     Hybrid Journal   (Followers: 16)
Behavioral Ecology     Hybrid Journal   (Followers: 51)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 31)
Biodegradation     Hybrid Journal   (Followers: 1)
Biodiversity     Hybrid Journal   (Followers: 27)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 5)
Bioremediation Journal     Hybrid Journal   (Followers: 5)
BioRisk     Open Access   (Followers: 3)
BMC Ecology     Open Access   (Followers: 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: 11)
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: 12)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 43)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 13)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 20)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 12)
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: 5)
Change and Adaptation in Socio-Ecological Systems     Open Access   (Followers: 1)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 20)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 14)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 61)
Civil and Environmental Engineering     Open Access   (Followers: 7)
Civil And Environmental Engineering Reports     Open Access   (Followers: 5)
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: 30)
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: 21)
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: 22)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 13)
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 Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 6)
Current World Environment     Open Access   (Followers: 2)
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: 3)
Earth System Science Data (ESSD)     Open Access   (Followers: 7)
Earth System Science Data Discussions (ESSDD)     Open Access   (Followers: 5)
Earthquake Science     Hybrid Journal   (Followers: 11)
EchoGéo     Open Access   (Followers: 1)
Ecocycles     Open Access   (Followers: 1)
Ecohydrology     Hybrid Journal   (Followers: 11)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 3)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 158)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecological Complexity     Hybrid Journal   (Followers: 8)
Ecological Indicators     Hybrid Journal   (Followers: 19)
Ecological Informatics     Hybrid Journal   (Followers: 5)
Ecological Management & Restoration     Hybrid Journal   (Followers: 15)
Ecological Modelling     Hybrid Journal   (Followers: 93)
Ecological Monographs     Full-text available via subscription   (Followers: 35)
Ecological Processes     Open Access   (Followers: 5)
Ecological Questions     Open Access   (Followers: 7)
Ecological Research     Hybrid Journal   (Followers: 10)
Ecological Restoration     Full-text available via subscription   (Followers: 24)
Ecologist, The     Full-text available via subscription   (Followers: 27)
Ecology     Full-text available via subscription   (Followers: 314)
Ecology and Evolution     Open Access   (Followers: 67)
Ecology Letters     Hybrid Journal   (Followers: 225)
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: 6)
Ecosphere     Open Access   (Followers: 7)
Ecosystem Services     Hybrid Journal   (Followers: 7)
Ecosystems     Hybrid Journal   (Followers: 30)
Ecotoxicology     Hybrid Journal   (Followers: 11)
Ecotoxicology and Environmental Safety     Hybrid Journal   (Followers: 7)
Ecotrophic : Journal of Environmental Science     Open Access  
Ecozon@ : European Journal of Literature, Culture and Environment     Open Access   (Followers: 4)
Ekologija     Open Access  
Electronic Green Journal     Open Access   (Followers: 6)
Energy & Environmental Science     Full-text available via subscription   (Followers: 27)
Energy & Environment     Hybrid Journal   (Followers: 19)
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: 20)
Environment and Ecology Research     Open Access   (Followers: 7)
Environment and Natural Resources Research     Open Access   (Followers: 11)
Environment and Planning A     Full-text available via subscription   (Followers: 49)
Environment and Planning B : Planning and Design     Full-text available via subscription   (Followers: 34)
Environment and Planning C : Government and Policy     Full-text available via subscription   (Followers: 36)
Environment and Planning D : Society and Space     Full-text available via subscription   (Followers: 51)
Environment and Pollution     Open Access   (Followers: 11)
Environment and Society     Full-text available via subscription   (Followers: 8)
Environment International     Hybrid Journal   (Followers: 17)
Environment Systems & Decisions     Hybrid Journal   (Followers: 4)
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: 4)
Environmental Claims Journal     Hybrid Journal   (Followers: 2)
Environmental Communication: A Journal of Nature and Culture     Hybrid Journal   (Followers: 19)
Environmental Development     Hybrid Journal   (Followers: 3)
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: 5)
Environmental Forensics     Hybrid Journal   (Followers: 2)
Environmental Geosciences     Full-text available via subscription   (Followers: 5)
Environmental Geotechnics     Hybrid Journal   (Followers: 5)
Environmental Hazards     Hybrid Journal   (Followers: 2)
Environmental Health     Open Access   (Followers: 11)
Environmental Health Insights     Open Access   (Followers: 4)
Environmental Health Perspectives (EHP)     Open Access   (Followers: 16)

        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  [1579 journals]
  • 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
       
  • Cyclodextrins-based Formulations: A Non-Invasive Platform for Targeted
           Drug Delivery
    • Authors: Chutimon Muankaew; Thorsteinn Loftsson
      Abstract: Cyclodextrins (CDs) are recognised as promising pharmaceutical excipients due to their unique ability to form water-soluble inclusion complexes with various poorly soluble compounds. The numerous investigations on CDs and their use in nanomedicine have received considerable attention in the last three decades, leading to the rapid development of new CD-containing formulations that significantly facilitate targeted drug delivery and controlled drug release, with consequent improvements in drug bioavailability. This MiniReview highlights the efficacy and recent uses of CDs for non-invasive drug delivery. By using ophthalmic and nasal drug delivery as examples, an overview of chemical properties, mechanisms of CDs on drug solubilization, stabilization and permeation, along with their toxicological profiles relevant to nasal and ocular administration, are provided and discussed. The recent development and application of CD-based nanocarrier systems for targeted drug delivery are summarized.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-10T22:30:21.78901-05:0
      DOI: 10.1111/bcpt.12917
       
  • Professor Thue W. Schwartz is the BCPT Nordic Prize Winner 2017 in Basic &
           Clinical Pharmacology & Toxicology
    • Authors: Kim Brøsen
      PubDate: 2017-10-09T02:15:20.121572-05:
      DOI: 10.1111/bcpt.12908
       
  • 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
       
  • The Combination of Valsartan and Sacubitril in the Treatment of
           Hypertension and Heart Failure – an Update
    • Authors: Peter Munch Nielsen; Daniela Grimm, Markus Wehland, Ulf Simonsen, Marcus Krüger
      Abstract: A novel antihypertensive drug, LCZ696 (Entresto®), has recently been introduced, which combines the action of an antagonist of the renin-angiotensin-aldosterone-system (RAAS), effectively decreasing the blood pressure, with an inhibition of neprilysin, which is responsible for metabolizing natriuretic peptides exerting anti-hypertensive and anti-fibrotic effects.In this MiniReview, we describe the pharmacokinetics and -dynamics, efficacy and side effects of the combined angiotensin receptor antagonist and neprilysin inhibitor LCZ696. We summarize the effect of LCZ696 treatment of patients suffering from hypertension and heart failure (HF) and further highlight the role of this new drug as a treatment option in the future. In the earlier stages of the treatment of patients with heart failure, LCZ696 was superior in lowering the blood pressure compared to olmesartan, while the effect on blood pressure at long-term treatment was comparable for the two drugs. The numbers of adverse effects were comparable. LCZ696 was superior to enalapril in reducing mortality, hospitalizations and HF symptoms. Adverse effects were reduced with a slower up-titrating regimen of 6 weeks. The current results are promising and suggest that LCZ696 will be a new candidate for first-line treatment of HF. However, it needs to be explored whether LCZ696 is safe in pregnant women, what are the effects of long-term LCZ696 treatment on survival, and whether the anti-fibrotic effects can be of major benefit in e.g. HF with preserved ejection fraction.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-25T06:25:22.812512-05:
      DOI: 10.1111/bcpt.12912
       
  • 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
       
  • Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: from
           Mechanisms to Novel Test Methods
    • Authors: Ali Alavian-Ghavanini; Joëlle Rüegg
      Abstract: Endocrine disrupting chemicals (EDCs) are man-made chemicals that interfere with hormonal signalling pathways. They are used in, e.g., production of common household materials, in resin-based medical supplies, pesticides. Thus, they are environmentally ubiquitous and humans and wildlife are exposed to them on a daily basis. Early life exposure to EDCs has been associated with later life adversities such as obesity, diabetes and cancer. Mechanisms underlying such associations are unknown but are likely to be mediated by epigenetic changes induced by EDCs. Epigenetics is the study of changes in gene function that are heritable but do not entail a change in DNA sequence. EDCs have been shown to affect epigenetic marks such as DNA methylation and histone modifications. The scope of this article is to review today's knowledge about mechanisms involved in EDC-induced epigenetic changes and to discuss how this knowledge could be used for designing novel methods addressing epigenetic effects of EDCs.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-26T03:51:08.217295-05:
      DOI: 10.1111/bcpt.12878
       
  • 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
       
  • Proximal Neuropathy and Associated Skeletal Muscle Changes Resembling
           Denervation Atrophy in Hind Limbs of Chronic Hypoglycaemic Rats
    • Authors: Vivi F. H. Jensen; Anne-Marie Molck, Henrik Soeborg, Jette Nowak, Melissa Chapman, Jens Lykkesfeldt, Ingrid B. Bogh
      Abstract: Peripheral neuropathy is one of the most common complications of diabetic hyperglycaemia. Insulin-induced hypoglycaemia (IIH) might potentially exacerbate or contribute to neuropathy as hypoglycaemia also causes peripheral neuropathy. In rats, IIH induces neuropathy associated with skeletal muscle changes. Aims of the present study were to investigate the progression and sequence of histopathologic changes caused by chronic IIH in rat peripheral nerves and skeletal muscle, and whether such changes were reversible. Chronic IIH was induced by infusion of human insulin, followed by an infusion-free recovery period in some of the animals. Sciatic, plantar nerves and thigh muscle were examined histopathologically after four or eight weeks of infusion and following the recovery period. IIH resulted in high incidence of axonal degeneration in sciatic nerves and low incidence in plantar nerves indicating proximo-distal progression of the neuropathy. The neuropathy progressed in severity (sciatic nerve) and incidence (sciatic and plantar nerve) with the duration of IIH. The myopathy consisted of groups of angular atrophic myofibres as they resembled histopathologic changes classically seen after denervation of skeletal muscle, and severity of the myofibre atrophy correlated with severity of axonal degeneration in sciatic nerve. Both neuropathy and myopathy were still present after four weeks of recovery, although the neuropathy was less severe. In conclusion, the results suggest that peripheral neuropathy induced by IIH progresses proximo-distally, that severity and incidence increase with duration of the hypoglycaemia, and that these changes are partially reversible within four weeks. Furthermore, IIH-induced myopathy is most likely secondary to the neuropathy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-16T23:30:34.380725-05:
      DOI: 10.1111/bcpt.12870
       
  • Mechanistic Model For Blood Pressure and Heart Rate Changes Produced by
           Telmisartan in Humans
    • Authors: Dong Woo Chae; Mijeong Son, Yukyung Kim, Hankil Son, Kyungsoo Park
      Abstract: Telmisartan, an angiotensin receptor blocker (ARB), is indicated for the treatment of essential hypertension. This study aimed to develop a mechanistic model of telmisartan drug effect in human using non-invasive markers.Data were acquired from a previous study where telmisartan 80 mg was given once daily for 6 days. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were measured before dosing for day 1 to 5 and serially after the last dose. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated from SBP and DBP. Relationships between MAP, PP, HR and total peripheral resistance(TPR) were developed. Circadian variation was incorporated into PP and HR, and TPR was assumed to adjust itself in response to changes in PP and HR based on baroreflex mechanism. Drug effects were then described as lowering the set point of MAP through TPR with a physiological feedback effect stimulating HR and PP.Drug concentrations were described by a two compartment disposition model with first-order absorption and lag time, and first-order elimination. Circadian variation was described by cosine functions, having periods of 12 and 24 hr. A log-linear model was used to describe drug effect, with estimated drug effect parameter of 0.051/hr. Estimated fractional turnover rate of PP, HR and TPR was 11.2 hr. The model successfully described the time courses of these cardiovascular variables.This work demonstrated the feasibility of using non-invasive cardiovascular measurements to derive a mechanistic model for telmisartan in humans. The model may be suitable for other ARBs.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T04:21:33.405236-05:
      DOI: 10.1111/bcpt.12856
       
  • Birth Outcomes of Children Fathered by Men Treated with Systemic
           Corticosteroids during the Conception Period – A Cohort Study based on
           Nationwide Data
    • Authors: M D Larsen; S Friedman, B Magnussen, B M Nørgård
      Abstract: Information on the safety of paternal use of medications prior to the time of conception is limited, and there is little available evidence regarding possible adverse effects of paternal use of systemic corticosteroids (SCS). In this cohort study, based on nationwide data, we examined the association between paternal use of SCS prior to conception and adverse birth outcomes. The study includes data from all singletons born in Denmark from 1January 1997 through 2013 (N=1,013,994). Children fathered by men who redeemed a prescription of SCS within 3 months before conception (N=2,380) constituted the exposed groups. The outcomes were congenital abnormalities (CAs), pre-term birth and small for gestational age (SGA). We adjusted for co-variates in multilevel logistic regression analyses.The adjusted odds ratios for pre-term birth and SGA were 0.81 (95% CI: 0.55-1.21) and 1.06 (95% CI: 0.68-1.64), respectively. The adjusted odds ratios for CAs were 1.08 (95% CI: 0.87-1.40) in children fathered by men who redeemed one prescription within 3 months before conception, and 1.33 (95% CI: 0.99-1.79) in children fathered by men who redeemed two or more prescriptions.This study is the largest to date examining the effect of paternal use of SCS prior to conception on birth outcomes. We found no significantly increased risk of pre-term birth or SGA. In children of fathers who redeemed at least two prescriptions of SCS within 3 months before conception, we found an increased risk of CAs, though not statistically significant. The types of CAs did not show a distinct pattern.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T03:42:28.907561-05:
      DOI: 10.1111/bcpt.12857
       
  • Clinical Aspects of Opium Adulterated with Lead in Iran: A Review
    • Authors: Samira Alinejad; Jan Aaseth, Mohammad Abdollahi, Hossein Hassanian-Moghaddam, Omid Mehrpour
      Abstract: Adulteration of drugs with poisonous substances during production or consumption has caused numerous health problems. Among contaminants that have the potential of producing poisonous effects are the heavy metals lead, arsenic and thallium that make up an important group of toxic substances. The emergence of these new health problems related to opioid abuse has precipitated this MiniReview on the status of the most hazardous and common opioid adulterants. In fact, adulterated opium is a major public health problem and can threaten the health of users. In this study, we searched for information on opium, opiates, lead poisoning, toxicity, intoxication, Iran and heavy metals in the TUMS Digital Library, PubMed, Scopus, EMBASE and Google Scholar bibliographical databases. This MiniReview primarily included articles on lead poisoning, signs and symptoms, and management in opioid-dependent individuals. Exclusion criteria were articles dealing with animal studies, specific paediatric studies, adulterants other than heavy metals and substances other than opioids. Adulterated opium is one of the new sources of exposure to lead and has precipitated an increase in lead-poisoned cases owing to the widespread use of opium. The toxicology of lead and general guidelines on diagnosis and treatment of lead poisoning is briefly reviewed. The symptoms of lead toxicity mimic several diseases often leading to unnecessary diagnostic methods, misdiagnoses and even surgery. Finally, owing to the fact that lead toxicity shows non-specific signs and symptoms, screening for this disease, by taking blood samples and assessing blood lead levels in high-risk people, should be given an utmost priority. It is recommended that screening tests are adopted and applied for any drug abusing patient with non-specific subacute signs and symptoms like abdominal pain, constipation and anaemia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-12T09:20:20.000818-05:
      DOI: 10.1111/bcpt.12855
       
  • Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung
           Cancer Patients with Bone Metastasis
    • Authors: Katalin Fábián; Rita Puskás, Tímea Kakuk, László Prés, Dorottya Fejes, Zsolt Szegedi, Lívia Rojkó, Zoltán Szállási, Balázs Döme, Orsolya Pipek, Judit Moldvay
      Abstract: Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Co-morbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 μmol/l, p
      PubDate: 2017-07-21T02:25:27.753067-05:
      DOI: 10.1111/bcpt.12854
       
  • Chitosan-Fe (III) Complex as a Phosphate Chelator in Uraemic Rats: A Novel
           Treatment Option
    • Authors: Wander Barros do Carmo; Bárbara Bruna Abreu Castro, Clóvis Antônio Rodrigues, Melani Ribeiro Custódio, Helady Sanders-Pinheiro
      Abstract: Phosphate retention and hyperphosphataemia are associated with increased mortality in chronic kidney disease (CKD) patients. We tested the use of cross-linked iron chitosan III (CH-FeCl) as a potential phosphate chelator in rats with CKD. We evaluated 96 animals, divided equally into 4 groups (control, CKD, CH-FeCl, and CKD/CH-FeCl), over 7 weeks. We induced CKD by feeding animals an adenine-enriched diet (0.75% in the first 4 weeks and 0.1% in the following 3 weeks). We administered 30 mg/kg daily of the test polymer, by gavage, from the third week until the end of the study. All animals received a diet supplemented with 1% phosphorus. Uraemia was confirmed by the increase in serum creatinine in week 4 (36.24 ± 18.56 versus 144.98 ± 22.1 μmol/L; p=0.0001) and week 7 (41.55 ± 22.1 versus 83.98 ± 18.56 μmol/L; p=0.001) in CKD animals. Rats from the CKD group treated with CH-FeCl had a 54.5% reduction in serum phosphate (6.10 ± 2.23 versus 2.78 ± 0.55 mmol/L) compared to a reduction of 25.6% in the untreated CKD group (4.75 ± 1.45 versus 3.52 ± 0.74 mmol/L, p=0.021), between week 4 and week 7. At week 7, renal function in both CKD groups was similar (serum creatinine: 83.98 ± 18.56 versus 83.10 ± 23.87 μmol/L, p=0.888); however, the CH-FeCl-treated rats had a reduction in phosphate overload measured by fractional phosphate excretion (FEPi) (0.71 ± 0.2 versus 0.4 ± 0.16, p=0.006) compared to the untreated CKD group. Our study demonstrated that CH-FeCl had an efficient chelating action on phosphate.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-20T06:20:54.960911-05:
      DOI: 10.1111/bcpt.12849
       
  • Gait and balance impairment after acute methanol poisoning
    • Authors: Kamila Peterová; Hana Brožová, Jiří Klempíř, Irena Lišková, Ondřej Bezdíček, Petr Ridzoň, Manuela Vaněčková, Sergej Zakharov, Daniela Pelclová, Michal Miovský, Evžen Růžička
      Abstract: Neurological sequelae including gait impairment were reported in survivors after methanol intoxication; however, no systematic study has been published so far. We aimed to analyse gait and balance impairment in a group of Czech methanol poisoning survivors.We examined 43 patients (age 46±13 years) 2-8 months after methanol poisoning and 43 healthy controls. Investigations contained a shortened version of Falls Efficacy Scale (FES), clinical tests of gait and balance including Timed Up and Go test (TUG) and gait analysis using GaitRite® system, neurological and neuropsychological examination, brain imaging, EMG and tests of alcohol consumption.Nineteen patients admitted balance and gait impairment according to FES. Mild to moderate parkinsonian signs showed 7 patients. Patients were slower (8.8 versus 5.7s, p
      PubDate: 2017-07-19T11:05:26.221356-05:
      DOI: 10.1111/bcpt.12853
       
  • Huprine X attenuates the neurotoxicity induced by kainic acid, especially
           brain inflammation
    • Authors: J. Relat; B. Pérez, P. Camps, D. Muñoz-Torrero, A. Badia, M.V. Clos
      Abstract: Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models in vivo and in vitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In the present study, we assessed the ability of HX (0.8 mg/kg, 21 days) to prevent the damage induced by kainic acid (KA; 28 mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain. KA administration significantly modified the levels of pAkt1, Bcl2, pGSK3β, p25/p35, increased the glial cell markers and reduced the neurogenesis process. We also observed that pre-treatment with HX significantly reduced the p25/p35 ratio and increased synaptophysin levels, which suggests a protective effect against apoptosis and an improvement of neuroplasticity. The increase in GFAP (88%) and Iba-1 (72%) induced by KA was totally prevented by HX pre-treatment, underlying a relevant anti-inflammatory action of the anticholinesterasic drug. Our findings highlight the potential of HX, in particular, and of AChEIs, in general, to treat a number of diseases that course with both cognitive deficits and chronic inflammatory processes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T11:00:32.814942-05:
      DOI: 10.1111/bcpt.12852
       
  • Role of the Long Non-Coding RNA GAS5 in Glucocorticoid Response in
           Children with Inflammatory Bowel Disease
    • Authors: Marianna Lucafò; Alessia Di Silvestre, Maurizio Romano, Alice Avian, Roberta Antonelli, Stefano Martelossi, Samuele Naviglio, Alberto Tommasini, Gabriele Stocco, Alessandro Ventura, M D Giuliana Decorti, Sara De Iudicibus
      Abstract: Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, in order to confirm the sensitivity and specificity of these lncRNA. These cells showed a different sensitivity to GCs, and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC-resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knockdown reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up-regultation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T10:15:56.792932-05:
      DOI: 10.1111/bcpt.12851
       
  • Effects of GIP, GLP-1 and GLP-1RAs on Bone Cell Metabolism
    • Authors: Morten S S Hansen; Michaela Terencova, Jacob Frølich, Moustapha Kassem, Morten Frost
      Abstract: The relationship between gut and skeleton is increasingly recognised as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism.We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify if similar effects are present and clinically relevant in humans.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T10:10:33.783209-05:
      DOI: 10.1111/bcpt.12850
       
  • Characterization of the Rabbit as an In Vitro and In Vivo Model to Assess
           the Effects of Fibrinogenolytic Activity of Snake Venom on Coagulation
    • Authors: Vance G. Nielsen; Elda E. Sánchez, Daniel T. Redford
      Abstract: Several in vitro investigations have demonstrated that anticoagulant effects of fibrinogenolytic snake venom metalloproteinases have been abrogated in human plasma by modifying fibrinogen with iron (Fe) and carbon monoxide (CO) to prevent catalysis or by directly inhibiting these enzymes with CO. In order to translate these findings, we chose to assess the rabbit as a model of envenomation with Crotalus atrox venom. It was determined with thrombelastography that 15-fold the concentration of venom noted to compromise coagulation in plasma in vitro was required to cause coagulopathy in vivo, likely secondary to venom binding to blood cells and being cleared from the circulation rapidly. Unlike human plasma, rabbit plasma pretreated with Fe/CO was not protected from fibrinogenolysis by venom. Consequently, the administration of purified human fibrinogen (with or without Fe/CO) would be required before venom administration to rabbits. Of greater interest, venom exposed to CO had complete loss of fibrinogenolytic effect in rabbit plasma and partial loss of activity in whole blood, indicative of unbinding of CO from venom and binding to hemoglobin. Thus, venom exposed to CO could remain partially or completely inhibited in whole blood long enough for clearance from the circulation, allowing rabbits to be a useful model to test the efficacy of regional CO administration to the bite site. Future investigations are planned to test these novel approaches to attenuate venom-mediated coagulopathy in the rabbit.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T09:25:42.666225-05:
      DOI: 10.1111/bcpt.12848
       
  • Tranexamic Acid in Total Knee Arthroplasty: Mixed Treatment Comparisons
           and Recursive Cumulative Meta-Analysis of Randomized, Controlled Trials
           and Cohort Studies
    • Authors: Kannan Sridharan; Gowri Sivaramakrishnan
      Abstract: Tranexamic acid (TXA) has been shown to be effective in patients with total knee arthroplasty (TKA) in clinical studies with no consensus with regard to the most appropriate route of administration. We conducted a network meta-analysis to compare the evidences available on efficacy and safety of TXA in TKA. Electronic databases were searched for randomized, clinical trials and cohort studies that evaluated TXA in TKA. Publication bias, risk of bias and inconsistencies were assessed. Direct and indirect comparisons were carried out for blood transfusion rate and incidence of thrombotic complications. Sensitivity analyses and grading of evidence was performed for key comparisons. A cumulative meta-analysis was conducted for comparisons that had a minimum of 10 included studies. A total of 19 studies with 8916 participants were pooled for this network meta-analysis. No inconsistencies and publication bias were observed. Low risk of bias was observed for the majority of the included studies. When compared to placebo, the pooled estimates for mixed treatment analyses favoured (in the order of higher ranking) the combined pre-operative oral and topical TXA, intra-operative intravenous TXA with topical TXA, pre-operative intravenous TXA, intra-operative and post-operative intravenous TXA, intra-operative intravenous bolus and topical TXA. Additionally, combined intravenous and topical TXA performed better than topical TXA alone. No significant changes were observed in the sensitivity analyses. No significant differences were observed in the risk of thrombotic complications between the interventions. TXA is efficacious and safe in patients with TKA. The combined topical and intra-operative intravenous TXA may perform better.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:17:01.423572-05:
      DOI: 10.1111/bcpt.12847
       
  • Statins and ACE Inhibitors are Associated with Reduced Mortality and
           Morbidity in Chronic Liver Disease
    • Authors: Knut Stokkeland; Christine Takami Lageborn, Anders Ekbom, Jonas Höijer, Matteo Bottai, Per Stål, Karin Söderberg-Löfdal
      Abstract: Liver fibrosis is a common response to many chronic liver diseases.The aim of our study was to explore whether pharmacotherapy for concurrent diseases affects overall mortality, liver-related mortality and liver-related morbidity in patients with chronic liver disease.We performed a register-based cohort study of all patients with a first-time diagnosis of chronic liver disease between 2005 and 2012 in Sweden (n=70 546). Data from the Patient Register, the Prescribed Drug Register and the Death Certificate Register were linked. We studied whether the use of statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and antibiotics affected the risk of total mortality, liver-specific mortality and morbidity.We found a reduction in mortality risk for statin users (n= 11 245) with hazard ratios from 0.57 (95%, CI 0.32-0.99) for patients with autoimmune hepatitis, to 0.84 (95%, CI 0.75-0.95) for alcoholic liver disease. There was a significant reduced liver-related mortality for patients with alcoholic liver disease who used angiotensin-converting enzyme inhibitors, 0.85 (95%, CI 0.65-0.96). There were increased overall mortality risks for antibiotic users (n=44 572), with hazard ratios up to 1.67 (95% CI, 1.55-1.80) for viral hepatitis.Statin use was associated with decreased risks of liver-specific mortality and morbidity, and reduced total mortality foremost among patients with alcoholic liver disease. Angiotensin-converting enzyme inhibitors was associated with reduced liver-related mortality among patients with alcoholic liver disease.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:11:16.801738-05:
      DOI: 10.1111/bcpt.12844
       
  • A Flow Cytometry-based Method for the Screening of Nanomaterial-induced
           Reactive Oxygen Species Production in Leukocyte Sub-Populations in Whole
           Blood
    • Authors: Ali Kermanizadeh; Kim Jantzen, David M Brown, Peter Møller, Steffen Loft
      Abstract: To date, the use and translation of nanomedicine from the laboratory to the clinic has been relatively slow. Amongst other issues, one of the reasons for this tardiness is the lack of the availability of quick and reliable toxicity tools for the screening of nanomaterials (NMs). In the present investigation, we apply a flow cytometry-based method for the detection of nanomaterial-induced oxidative stress by measurement of reactive oxygen species production in specific leukocyte sub-populations in human whole blood. The screening of a panel of relevant nanomedical-associated materials (liposomes, silica, iron oxide and functionalised single-walled carbon nanotubes) demonstrated that only the carbon nanotubes induced oxidative stress in human circulating leukocytes. In summary, we apply and corroborate a flow cytometry based method for the simple and effective measurement of NM-induced oxidative stress in human blood sub-populations following realistic and relevant exposure scenarios which is extremely useful in future toxicological applications.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:11:15.229852-05:
      DOI: 10.1111/bcpt.12845
       
  • Crotalus atrox Venom Exposed to Carbon Monoxide Has Decreased
           Fibrinogenolytic Activity In Vivo in Rabbits
    • Authors: Vance G. Nielsen
      Abstract: Envenomation by hemotoxic enzymes remains a significant source of human morbidity and mortality worldwide, with administration of long-acting or multiple doses of antivenom first-line therapy. However, coagulopathy can still occur and recur. Of interest, it has been recently demonstrated that direct, isolated exposure of snake venom enzymes with fibrinogenolytic activity to carbon monoxide (CO) abrogates venom-mediated loss of coagulation in human plasma. These observations of CO inhibition of venom fibrinogenolytic activity were subsequently repeated in rabbit whole blood. The present study sought to translate these findings in an in vivo rabbit model of envenomation with fibrinogenolytic Crotalus atrox venom. Sedated rabbits were intravenously administered C. atrox venom (400 μg/kg) pre-exposed to 0 or 1000 μM carbon monoxide releasing molecule-2 (CORM-2) in vitro. Arterial whole-blood samples demonstrated that compared to pre-envenomation values, the CORM-2 naïve venom significantly prolonged the onset of coagulation, decreased the velocity of clot growth and decreased clot strength as determined by thrombelastography an hour after venom injection. In contrast, CORM-2 pre-exposure prevented or attenuated C. atrox venom effects on coagulation kinetics. Future studies to determine if rabbits injected with such venom subcutaneously/intramuscularly can have consequent coagulopathy abrogated by injection of carbon monoxide releasing molecules into the “bite site” are justified.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-10T03:11:08.501134-05:
      DOI: 10.1111/bcpt.12846
       
  • Relaxing Responses to Hydrogen Peroxide and Nitric Oxide in Human
           Pericardial Resistance Arteries Stimulated with Endothelin-1
    • Authors: Thomas M. Leurgans; Maria Bloksgaard, Akhmadjon Irmukhamedov, Lars P. Riber, Jo G. R. De Mey
      Abstract: In human pericardial resistance arteries, effects of the endothelium-dependent vasodilator bradykinin are mediated by NO during contraction induced by K+ or the TxA2 analogue U46619 and by H2O2 during contraction by endothelin-1 (ET-1), respectively. We tested the hypotheses that ET-1 reduces relaxing effects of NO and increases those of H2O2 in resistance artery smooth muscle of patients with cardiovascular disease.Arterial segments, dissected from the parietal pericardium of 39 cardiothoracic surgery patients, were studied by myography during amplitude-matched contractions induced by K+, the TXA2 analogue U46619 or ET-1. Effects of the NO-donor Na-nitroprusside (SNP) and of exogenous H2O2 were recorded in absence and presence of inhibitors of cyclooxygenases, NO-synthases and small and intermediate conductance calcium-activated K+ channels.During contractions induced by either of the three stimuli, the potency of SNP did not differ and was not modified by the inhibitors. In vessels contracted with ET-1, the potency of H2O2 was on average and in terms of inter-individual variability considerably larger than in K+-contracted vessels. Both differences were not statistically significant in presence of inhibitors of mechanisms of endothelium-dependent vasodilatation.In resistance arteries from patients with cardiovascular disease, ET-1 does not selectively modify smooth muscle relaxing responses to NO or H2O2. Furthermore, the candidate endothelium-derived relaxing factor H2O2 also acts as an endothelium-dependent vasodilator.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-07T10:15:23.489656-05:
      DOI: 10.1111/bcpt.12843
       
  • GSTP1 c.313A>G, XPD c.934G>A, XPF c.2505T>C and CASP9 c.-1339A>G
           Polymorphisms and Severity of Vomiting in Head and Neck Cancer Patients
           treated with Cisplatin Chemoradiation
    • Authors: Juliana Carron; Leisa Lopes-Aguiar, Ericka Francislaine Dias Costa, Guilherme Augusto Silva Nogueira, Tathiane Regine Penna Lima, Eder Carvalho Pincinato, Marilia Berlofa Visacri, Júlia Coelho França Quintanilha, Patrícia Moriel, Gustavo Jacob Lourenço, Carmen Silvia Passos Lima
      Abstract: Cisplatin (CDDP) chemotherapy associated with radiation (RT) has been used in advanced head and neck squamous cell carcinoma (HNSCC) patients, and vomiting is a common side effect during treatment. This prospective study aimed to identify the roles of GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.−93G>A, MSH2 c.211+9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-1168G>T, CASP9 c.-1339A>G, CASP8 c.-937_-932delAGTAAG, FAS c.-1378G>A and c.-671A>G, and FASL c.-157-687C>T single nucleotide polymorphisms, involved in CDDP metabolism, in vomiting severity in 88 HNSCC patients treated with CDDP and RT. Ondansetron and dexamethasone were administered as antiemetic therapy. Patients with GSTP1 c.313AG or GG genotype alone and combined with XPD c.934GA or AA, XPF c.2505TC or CC, and CASP9 c.-1339AG or GG genotypes had 4.28, 5.00, 5.45, and 5.38 more chances of presenting moderate/severe vomiting than patients with others genotypes. Our data suggest, for the first time, that inherited abnormality in apoptosis pathway alone or combined with inherited abnormalities in DNA repair pathway, are capable of modulating emesis in HNSCC patients under CDDP chemoradiation and may be used for selecting patients who should receive preemptive antiemetic therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-07T08:40:20.992785-05:
      DOI: 10.1111/bcpt.12842
       
  • Global Trends in Aspirin Resistance-Related Research from 1990 to 2015: A
           Bibliometric Analysis
    • Authors: Samah W. Al-Jabi
      Abstract: Aspirin resistance can be defined as the inability of the usual dose of aspirin medication to produce its antithrombotic effect. Patients with diabetes or cardiovascular disease are at higher risk of stroke, myocardial infarction or cardiovascular death due to aspirin resistance. The aim of this bibliometric study was to identify and analyse the status and trends of aspirin resistance research production at global level through publications indexed in Scopus database; this will shed new light on future research trends and help researchers predict dynamic direction of research. Literature search using Scopus database was conducted to assess publications related to aspirin resistance. The selected publications included the terms related to aspirin resistance in the title, abstract or keywords. The searching was accomplished on 20 March 2016 and can be considered to include all publications up to 31 December 2015. Global cumulative publication output on aspirin resistance consists of 986 papers during 1990–2015. Among the 986 documents, 19 (1.9%) were published before 2000, 567 (57.5%) were published from 2000 to 2009 and 400 (40.6%) were published from 2010-2015, with peak of publications on this topic in 2008. The leading country in the field of aspirin resistance was the USA, which had the greatest counts of independent articles (165) and international collaboration articles (44). Turkey was in the second rank with 78 articles, followed by Italy (68), the UK (62) and Poland (60). The total number of citations for all documents was 26,342, and the average citations per document were 26.7. The h-index for all aspirin resistance publications was 82. This study presents the results of the first bibliometric study (including quantitative and qualitative analysis) of scientific publications in the field of aspirin renitence at global level. Aspirin resistance-related researches have notably increased in the last years, especially from 2000 to 2015. The USA is the most prolific country, not only in research quantity but also in quality. Furthermore, Turkey and European countries provided more research related to aspirin resistance than other regions such as the developing countries.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-01T09:25:24.188738-05:
      DOI: 10.1111/bcpt.12840
       
  • Oral Administration of Polaprezinc Attenuates Fluorouracil-induced
           Intestinal Mucositis in a Mouse Model
    • Authors: Zhaoyang Liu; Wenbo Xie, Mingru Li, Nan Teng, Xiao Liang, Ziqiang Zhang, Zhaogang Yang, Xiaobing Wang
      Abstract: 5-fluorouracil (5-FU) has broadly been applied to treat colorectal cancer as one of the most effective chemotherapeutic agents. However, it frequently causes intestinal mucosal injury and related side effects, such as abdominal pain and diarrhoea, which limit the use of 5-FU in a clinic setting. Polaprezinc has gradually become known as a mucosal protective agent for the management of gastric ulcer. This study aimed to investigate the prophylactic efficacy of Polaprezinc administered orally against intestinal mucositis induced by 5-FU in mice on the condition that the anti-tumour effect could not be compromised. We induced intestinal mucositis in SPF grade ICR mice with 5-FU, and evaluated intestinal damage in the absence or presence of Polaprezinc. We examined the score of diarrhoea and the loss of weight following the 5-FU treatment, and assessed the integrity of villus and the proliferation of small intestine crypt cells by Hematoxylin&Eosin staining and PCNA immunohistochemical detection. The anti-tumour effect of 5-FU on colorectal cancer was assessed with or without Polaprezinc in a xenograft model. The result showed that Polaprezinc significantly reduced the elevated diarrhoea score and the body weight loss caused by 5-FU, abolished histological abnormality and crypt cell hypoproliferation in a dose-dependent manner, without affecting 5-FU efficacy on colon xenograft tumour in mice. We conclude that Polaprezinc could inhibit 5-FU-induced diarrhoea and alleviate the weight loss during 5-FU chemotherapy, as a possible candidate for treatment and prevention of intestinal mucositis, through protecting intestinal mucosa and improving the quality of life following chemotherapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-01T09:25:21.76578-05:0
      DOI: 10.1111/bcpt.12841
       
  • Haloperidol Decreases Hyperalgesia and Allodynia Induced by Chronic
           Constriction Injury
    • Authors: Josué Vidal Espinosa-Juárez; Osmar Antonio Jaramillo-Morales, Francisco Javier López-Muñoz
      Abstract: Neuropathic pain has proven to be a difficult condition to treat, so investigational therapy has been sought that may prove useful, such as the use of sigma-1 antagonists. Haloperidol (HAL) is a compound that shows a high affinity with these receptors, acting as an antagonist. Therefore, the objective of this study was to demonstrate its effect in an experimental model of neuropathic pain and corroborate its antagonistic action of the sigma-1 receptors under these conditions. BD-1063 was used as a sigma-1 antagonist control and gabapentin was used as a positive control. The anti-hyperalgesic and anti-allodynic effects of the drugs were determined after single-dose trials. In every case, the effects increased in a dose-dependent manner. HAL had the same efficacy as both BD-1063 and gabapentin. In the analysis of pharmacological potency, in which the ED50 were compared, HAL was the most potent drug of all. The effect of HAL on chronic constriction injury (CCI) rats was reversed by the sigma-1 agonist (PRE-084). HAL reversed the hyperalgesic and allodynic effects of PRE-084 in naïve rats. The dopamine antagonist, (-)-sulpiride, showed no effect in CCl rats. These results suggest that HAL presents an antinociceptive effect via sigma-1 receptor antagonism at the spinal level in the CCl model.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-27T10:45:20.529354-05:
      DOI: 10.1111/bcpt.12839
       
  • Sensitivity and Reliability of Halothane-Anaesthetized Microminipigs to
           Assess Risk of Drug-induced Long QT Syndrome
    • Authors: Xin Cao; Takeshi Wada, Yuji Nakamura, Suchitra Matsukura, Hiroko Izumi-Nakaseko, Kentaro Ando, Atsuhiko T. Naito, Atsushi Sugiyama
      Abstract: Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n=4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 μg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane-anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT-interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-27T10:45:19.13994-05:0
      DOI: 10.1111/bcpt.12838
       
  • Physicians’ Non-Uniform Approach to Prescribing Drugs to Older Patients
           – A Qualitative Study
    • Authors: Line Due Christensen; Janne Petersen, Ove Andersen, Susanne Kaae
      Abstract: Multi-morbidity and polypharmacy are common in older patients and increase their susceptibility to adverse drug events and hospitalizations. Rational drug prescription is critical, however, little is known about physicians’ perspectives on how to prescribe drugs for older patients. The aim of this study was to explore physicians’ approach to prescribe drugs to older patients, including identifying the drugs that physicians perceive to be risk drugs for older patients and comparing them with established lists of potentially inappropriate medications. Short semi-structured interviews were conducted with 50 medical specialists in 23 different specialities throughout Denmark who had contact with older patients. Content analysis was performed to identify the relevant themes. Regardless of their medical or surgical background and how often they prescribed drugs for older patients in daily work, all physicians expressed a cautious approach when prescribing risk drugs. Despite their shared caution, physicians had different strategies for prescribing drugs to older patients. The following strategies were identified: 1) “Start low, go slow”, 2) “Trial and error”, 3) “Dose reduction”, and 4) “Never prescribe”. The most frequently mentioned risk drugs considered to cause hospitalization were vitamin K antagonists, opioids and diuretics; these drugs are relatively highly consistent with established lists of PIMs.Physicians were relatively knowledgeable about risk drugs. Although the physicians agreed that a cautious approach was needed when prescribing drugs for older people, there was no consensus about how to best accomplish this in practice.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T12:10:22.010742-05:
      DOI: 10.1111/bcpt.12837
       
  • A High HASBLED Score Identifies Poor Warfarin Control in Patients treated
           for Non-Valvular Atrial Fibrillation in Australia and Singapore
    • Authors: Nijole Bernaitis; Ching Chi Keong, Chen Liping, Hon Jin Shing, Teo Siew Chong, Tony Badrick, Andrew K. Davey, Shailendra Anoopkumar-Dukie
      Abstract: Warfarin reduces stroke risk in atrial fibrillation (AF) patients. The quality of warfarin control, measured by time in therapeutic range (TTR), impacts outcomes and adverse events. One tool evaluating risk of adverse events and potential warfarin control would simplify risk-benefit assessment of warfarin. Recently, HASBLED was demonstrated effective for this purpose but this was in well-controlled patients with deep vein thrombosis. HASBLED as a predictor of warfarin control has not been validated in other populations including differing indications, warfarin control levels and ethnicities. The aim of this study was to determine if HASBLED can predict warfarin control in patients with AF in Australia and Singapore.Retrospective data were collected for patients receiving warfarin between January and June 2014 in Australia and Singapore. Patient data were used to calculate HASBLED at the start and end of the study period. TTR was calculated for each patient, and mean TTR used for analysis to stratified HASBLED scores.Of the 4370 patients, there were 3199 in Australia and 1171 in Singapore with mean TTRs of 82% and 58%, respectively. At the start of the study, a HASBLED score ≥3 predicted significantly lower TTR in Singapore, whilst at the end of the study, this score identified patients with poor control in both Australia and Singapore.A HASBLED score ≥3 in patients treated with warfarin can differentiate significantly lower TTRs in Australian and Singapore patients with AF. HASBLED may assess bleed risk and warfarin control, identifying patients at high risk of poor warfarin outcomes requiring additional INR monitoring or alternative anticoagulation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:35:24.92709-05:0
      DOI: 10.1111/bcpt.12836
       
  • The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy
           Danish Volunteers
    • Authors: Claus Stage; Gesche Jürgens, Louise Schow Guski, Ragnar Thomsen, Ditte Bjerre, Laura Ferrero-Miliani, Yassine Kamal Lyauk, Henrik Berg Rasmussen, Kim Dalhoff,
      Abstract: The present study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: Group 1 (controls, n=16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n=5) with four copies of CES1; group 3 (n=6) harbouring the G143E polymorphism; group 4 (n=2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n=4) harbouring the CES1A1c variant; and group 6 (n=10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 μg/l x h in the control group versus 310, 282, 294, 344 and 306 μg/l x h in group 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared to the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:32:48.074534-05:
      DOI: 10.1111/bcpt.12835
       
  • Vascular Calcification, Vitamin K and Warfarin Therapy – Possible or
           Plausible Connection'
    • Authors: Aino Siltari; Heikki Vapaatalo
      Abstract: Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long-term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma-carboxylation, is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K–dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:32:44.369507-05:
      DOI: 10.1111/bcpt.12834
       
  • Decrease in Oxidative Stress Parameters after Post-Ischaemic Recombinant
           Human Erythropoietin Administration in the Hippocampus of Rats Exposed to
           Focal Cerebral Ischaemia
    • Authors: Jasenka Mršić-Pelčić; Kristina Pilipović, Goran Pelčić, Dinko Vitezić, Gordana Župan
      Abstract: Recombinant human erythropoietin (rhEpo) is a multifunctional drug with antioxidant potential. However, the underlying molecular mechanisms of its action are still unclear. The purpose of this study was to investigate the effects of rhEpo on the brain infarct volume as well as on the levels of the neuronal damage, oxidative stress parameters and active caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expressions in the hippocampi of rats exposed to the right middle cerebral artery occlusion (MCAO) for 1 hr. Ischaemic animals received either vehicle or rhEpo (5000 IU/kg, i.p.) immediately or 3 hr after the induction of ischaemia. Sham-operated, vehicle-treated animals served as the control group. Rats were killed 24 hr after the onset of the ischaemic or sham experimental procedure. MCAO caused ipsilateral brain infarction within the striatum and cortex. In the CA1 region of the hippocampi, we did not find significant neuronal loss but a statistically significant rise in the active caspase-3 and Nrf2 protein expressions was registered. We detected also significant increases in the hippocampal levels of oxidative stress parameters (thiobarbituric acid-reactive substances, superoxide dismutase, glutathione peroxidase). Post-ischaemic administration of rhEpo significantly reduced the brain infarct volume, decreased levels of all tested oxidative stress parameters and increased the Nrf2 expression level. These findings suggest that decrease in oxidative stress parameters in the hippocampus could be an early indicator of post-ischaemic neuroprotective effect of rhEpo in rats exposed to focal cerebral ischaemia, and that this effect could be attributable to additional post-ischaemic activation of Nrf2 endogenous antioxidant system.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T19:32:21.324049-05:
      DOI: 10.1111/bcpt.12833
       
  • Suspected Methadone Toxicity; from Hospital to Autopsy Bed
    • Authors: Jaber Gharehdaghi; Asieh Takalloo-Bakhtiari, Hossein Hassanian-Moghaddam, Nasim Zamani, Mohammad-Javad Hedayatshode
      Abstract: High mortality rates have been reported for methadone in both adults and children. We aimed to determine the pattern of toxicity, possible underlying diseases and treatment challenges in patients referred to our center with early diagnosis of methadone toxicity and who later died. Medical files of all methadone-poisoned patients who had been admitted to a referral center of toxicology between March 2011 and March 2016, died during the hospital stay and sent for autopsy to Legal Medicine Organization were retrospectively evaluated. In a total of 94 patients, autopsy findings and laboratory evaluations showed that cause of death was pure methadone toxicity in 57 (60.6%). Other causes of death were ischaemic heart disease in ten, co-ingestions (toxicities including methadone) in eight, brain haemorrhage, multi organ failure, and pneumosepsis (each in four), meningitis/encephalitis in three, and head trauma and other toxicities (other than methadone but including an opioid, each in two) patients. Time of cardiopulmonary arrest was significantly different between those with pure methadone toxicity and those who died due to other causes (p=0.01). Patients who had died due to co-ingestions and other toxicities were younger (p=0.029) and took more bolus doses of naloxone (p=0.042). In methadone users, especially in older ages and those with trivial response to naloxone administration, loss of consciousness should not be strictly attributed to methadone toxicity. In such patients, thorough evaluation for other possible causes of loss of consciousness is mandatory.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-19T07:01:03.409213-05:
      DOI: 10.1111/bcpt.12831
       
  • The Acute Effect of Loperamide on Ileostomy Output: A Randomized,
           Double-blinded, Placebo-controlled, Cross-over Study
    • Authors: Katrine Kristensen; Niels Qvist
      Abstract: High stoma output is a common problem in patients with ileostomy and can lead to dehydration and electrolyte disturbances. The first drug of choice to reduce stoma output is often loperamide.The aim was to assess the acute effect of loperamide on (a) ileostomy output in g/day, (b) gastrointestinal transit time and (c) patient-reported effects.A total of 12 patients completed this double-blinded, randomized, placebo-controlled, cross-over study, consisting of a 3-day treatment period with loperamide 12 mg/day or placebo followed by the reverse after a washout period of 5-7 days. Patients collected stoma output and noted food and fluid intake over 48 hr and swallowed a capsule with radiopaque markers for the determination of gastrointestinal transit time over 24 hr. At the end of the study, patients were asked to report their treatment sequence.Ileostomy output was significantly reduced during loperamide treatment (P
      PubDate: 2017-06-19T07:00:42.571229-05:
      DOI: 10.1111/bcpt.12830
       
  • Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias
    • Authors: Gerrit Frommeyer; Jan Weller, Christian Ellermann, Nils Bögeholz, Patrick Leitz, Dirk G. Dechering, Simon Kochhäuser, Kristina Wasmer, Lars Eckardt
      Abstract: The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of the present study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias.Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34ms,p
      PubDate: 2017-06-19T06:55:35.371747-05:
      DOI: 10.1111/bcpt.12829
       
  • Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental
           Chronic Kidney Disease
    • Authors: Badreldin H. Ali; Suhail Al-Salam, Yousuf Al Suleimani, Jamila Al Kalbani, Shadia Al Bahlani, Mohammed Ashique, Priyadarsini Manoj, Buthaina Al Zhili, Nadia Al Abri, Heba T. Naser, Javed Yasin, Abderrahim Nemmar, Mohamed Al Za'abi, Christina Hartmann, Nicole Schupp
      Abstract: Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong anti-oxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD.Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue.Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-β-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced the adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1β, IL-6 and TNFα, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level.In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-31T07:25:30.445982-05:
      DOI: 10.1111/bcpt.12817
       
  • Issue Information
    • Pages: 451 - 452
      PubDate: 2017-11-10T08:56:45.766744-05:
      DOI: 10.1111/bcpt.12742
       
 
 
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